© 1999 American Heart Association, Inc.
Original Contributions |
Role of ApoCs in Lipoprotein Metabolism
Functional Differences Between ApoC1, ApoC2, and ApoC3
From TNO–Prevention and Health, Gaubius Laboratory (M.C.J.); MGC–Department of Human Genetics (M.H.H.); and the Departments of Cardiology and Internal Medicine, Leiden University Medical Center (L.M.H.), Leiden, The Netherlands.
Correspondence to Dr M.C. Jong, TNO–Prevention and Health, Gaubius Laboratory, Zernikedreef 9, 2333 CK Leiden or PO Box 2215, 2301 CE Leiden, The Netherlands. E-mail mc.jong{at}pg.tno.nl
Key Words: apolipoproteins • lipoprotein lipase • lipoproteins, VLDL • triglycerides • mice, transgenic
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Introduction |
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 Top Introduction APOC GenesMolecular Defects in Human...ApoC ProteinsInteraction of ApoCs With...Transgenic Mouse Models...Transgenic Mice Overexpressing...Transgenic Mouse Models...Transgenic Mice Overexpressing...ConclusionsReferences |
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The human apoCs (ie, apoC1, apoC2, and apoC3) are often portrayed as members of 1 consistent protein family because of their similar distributions among lipoprotein classes, their low molecular weights, and coincident purification. The human apoCs are protein constituents of chylomicrons, VLDL, and HDL. In comparison with the intensely studied apoE, apoB, and apoA1, which play important roles in the development of hyperlipidemia and atherosclerosis, only modest attention has been paid so far to the roles of the apoCs in lipoprotein metabolism. Many of the studies regarding the functional properties of apoCs have been hampered by methodological problems dealing with purification, quantification, and their poorly understood association with hyperlipidemia and other lipoprotein disorders. In the past few years, however, new insights into the metabolic properties of apoCs have been provided, in particular by the technologies of transgenesis and gene targeting in mice.
The present review addresses the influence of apoCs on the major metabolic pathways in lipoprotein metabolism. Therefore, a number of important in vitro and in vivo studies will be discussed that point to a distinct role for each of the individual apoCs in lipoprotein metabolism and human disease.
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APOC Genes |
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TopIntroductionAPOC GenesMolecular Defects in Human...ApoC ProteinsInteraction of ApoCs With...Transgenic Mouse Models...Transgenic Mice Overexpressing...Transgenic Mouse Models...Transgenic Mice Overexpressing...ConclusionsReferences |
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The genes coding for human apoC1 and human apoC2 are members of a 48-kb gene cluster on chromosome 19 that also includes the APOE and pseudo-APOC1' genes.1 2 3 4 5 It has been reported that the human APOC1 gene is located either 4.32 3 or 5.34 kb downstream from the APOE gene in the same transcriptional orientation. The APOC1 gene is
4.7
kb and is primarily expressed in the liver, but lower amounts are also
found to be expressed in the lung, skin, testes, and spleen (Table 1
).4 One
copy of the APOC1 gene, the so-called
pseudo-APOC1' gene, is located 7.5 kb downstream from
APOC1.1 4 No mRNA products of the
pseudo-APOC1' gene have been detected in any
tissue.4 APOC2 spans a region of 3.4 kb
and is primarily expressed in the liver and
intestine6 7 8 (Table 1). An additional gene
within the APOE/C1/C2 gene cluster,
designated the APOC2-linked gene, was first discovered in
mice.9 Recently, a similar gene was found in
humans.10 On the basis of its properties and location (555
bp upstream from APOC2), this 3.3-kb gene was designated
APOC4. RNase protection analysis indicated
relatively low APOC4 mRNA levels in the human
liver.10
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The regulation of human APOC1 gene expression, together with
that of the APOE gene, is under control of an array of
elements found throughout the whole
APOE/C1/C2/C4 gene cluster
(for a review, see References 11 and 1211 12 ). The hepatic control region
(HCR), an element located 17 kb downstream from the APOE
gene and 9 kb downstream from the APOC1 gene, was found
to regulate the expression of both APOC1 and APOE
genes in the liver.13 14 A second hepatic controlling
element within the APOE/C1/C2 cluster
was identified 27 kb downstream from the APOE
gene.15 Recently, it was shown that both HCRs can
individually coordinate the hepatic expression of all 4 genes in the
APOE/C1/C2/C4 gene cluster
and that the presence of at least 1 of the regions is sufficient for
significant liver expression of each of the
genes.16
The human APOC3 gene is located in a gene cluster together
with the APOA1 and APOA4
genes17 on the long arm of chromosome 11 and is
3.1 kb (Table 1
).18 19 20 21 22 The human
APOC3 gene is expressed in the liver and intestine and is
controlled by positive and negative regulatory elements that are spread
throughout the gene cluster.23 24 25 26 27 Experiments with
transgenic animals have allowed the localization of an element
controlling the intestinal expression of APOC3,
APOA1, and APOA4 in the proximal 5' human
APOC3 region.28 29
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Molecular Defects in Human APOC Genes and Their Association With Lipoprotein Disorders |
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TopIntroductionAPOC GenesMolecular Defects in Human...ApoC ProteinsInteraction of ApoCs With...Transgenic Mouse Models...Transgenic Mice Overexpressing...Transgenic Mouse Models...Transgenic Mice Overexpressing...ConclusionsReferences |
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Little is known about naturally occurring mutations in the human APOC1 gene. So far, only 1 study has reported a case of apoC1 deficiency in patients with familial chylomicronemia30 (Table 2
). Because these patients
suffered from apoC2 deficiency as well, the chylomicronemia is most
likely caused by the apoC2 defect. Remarkably, however, the
apoC1/apoC2-deficient patient exhibited markedly decreased levels of
cholesterol ester, especially apparent in HDL, which was
much more severe than previously reported in cases of apoC2
deficiency.30 These observations suggest that apoC1
deficiency in HDL may modulate lecithin-cholesterol
acyltransferase (LCAT) activity, which is known to catalyze the
esterification of free cholesterol in
plasma.31
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The importance of apoC2 as an activator of lipoprotein
lipase (LPL) has unequivocally been demonstrated in patients with
genetic defects in the structure or production of apoC2, all of
whom display high circulating levels of triglycerides (TGs)
and are phenotypically indistinguishable from patients with LPL
deficiency.32 33 34 35 36 As summarized in Table 2,
sequence analysis of the APOC2 gene in families with
familial hyperchylomicronemia has revealed a variety of molecular
defects in this particular gene. In 7 families (Nijmegen, Paris,
Barcelona, Japan, Venezuela, Padova, and Bari), a single base change
resulted in the introduction of a premature stop that led to the
synthesis of truncated forms of apoC2 that were either not secreted or
rapidly cleared from the circulation37 38 39 40 41 (Table 2). A donor splice-site mutation in the first base of the second
intron of the APOC2 gene was found in a Hamburg family and
in a neonatal Japanese patient
(APOC2Hamburg and
APOC2Tokyo, respectively). This mutation
caused abnormal splicing of APOC2 mRNA and was associated
with low levels of apoC2 in plasma.42 43 In addition,
a variety of single–amino acid substitutions in the APOC2
gene has been described (Table 2) that either resulted in the
inability to initiate apoC2 synthesis44 or in the
production of nonfunctional apoC2.45 46 47 For 2
APOC2 variants
(APOC2SanFrancisco and the APOC2
Lys19
Thr mutation), a direct relationship
between this mutant form of apoC2 and lipoprotein abnormalities could
not be established.48 49 50 51
Several lines of evidence have implicated apoC3 as possibly
contributing to the development of
hypertriglyceridemia. A positive
correlation has been observed between plasma apoC3 levels and elevated
levels of plasma TGs52 53 54 and VLDL-TGs.55
However, structural mutations in the human APOC3 gene fail
to clearly show an association between the mutation and an altered
lipid/lipoprotein metabolism. Five genetic variants of
apoC3 were identified by the presence of additional bands after
isoelectric focusing of VLDL (Table 2). Two of these variants
differed from normal apoC3 by their degree of sialylation; ie, 1 was
oversialylated56 while the other was not sialylated
at all because of a Thr74Ala mutation at the
glycosylation site.57 58 59 Carriers of these mutants were
normolipidemic, indicating that the degree of apoC3 sialylation has
little or no impact on lipoprotein metabolism. The 3
remaining apoC3 variants represented amino acid
substitutions in both the N-terminal and
C-terminal domains of apoC3 (Table 2). The
Lys58Glu mutation was associated with low
plasma apoC3 concentrations and atypically large
HDL.60 The number of carriers for this mutation,
however, was too small to demonstrate a direct relationship between the
mutation and altered lipoprotein levels. The
Asp45Asn variant was found in a Turkish
patient who underwent coronary bypass surgery but failed to
show a clear association between the mutation and an abnormal
lipoprotein metabolism.61 The APOC3
Gln38Lys mutation was observed in a boy of
Mexican origin, and family studies in 16 individuals who were
heterozygous for this APOC3 mutation revealed mildly
elevated levels of plasma TGs in these subjects.62
Several studies have also reported a complete apoC3 deficiency in
families with an increased prevalence of premature coronary
heart disease.63 64 In addition, 1 family with apoC3
deficiency demonstrated an increased fractional catabolic rate of
VLDL.65 However, in all cases, apoC3 deficiency was
associated with an apoA1 deficiency, making it difficult to estimate
the exact contribution of the lack of apoC3 to changes in lipoprotein
levels.
In addition to the genetic mutations described above, several restriction fragment length polymorphisms (RFLPs) in or around the human APOC genes have been identified that are associated with lipoprotein disorders or altered plasma lipid concentrations in humans. One population-based, genetic association study has reported an HpaI RFLP in the APOC1 promoter,66 located at a site 317 bp 5' from the apoC1 transcription initiation site.67 Recently, it has been shown by cell expression analysis that the promoter carrying the HpaI site in combination with the HCR mediates enhanced gene expression.68 These results suggest that under certain conditions, the HpaI promoter variant causes overexpression of APOC1, which may contribute to the development of hyperlipidemia.
It has been demonstrated that a minor allele (S2) of an SstI RFLP in the APOC3 gene is associated with hypertriglyceridemia in several distinct populations,69 70 71 72 73 74 75 76 77 78 79 but not in all.80 81 Furthermore, Shoulders et al82 reported that healthy carriers of the S2 allele had higher plasma apoC3 levels than did noncarriers. These results indicate that the S2 allele may influence plasma TG levels through modulation of APOC3 gene expression. However, the SstI RFLP is located in the noncoding region of exon 4 of the APOC3 gene, suggesting that the S2 allele may modulate plasma TG levels by linkage disequilibrium with other functional sequences in or near the APOC3 gene. Dammerman et al79 and Xu et al83 have identified several polymorphic sites in and around the APOC3 gene that show strong allelic association with each other and with the SstI site. A detailed overview of these polymorphic sites has recently been published.84
Other RFLPs within the APOA1/C3/A4
gene cluster such as XmnI and PstI have also been
reported to be associated with
hypertriglyceridemia85 or
coronary artery disease.86 In 1 study of selected
British families, the XmnI RFLP within the
APOA1/C3/A4 gene cluster was shown to
be linked with familial combined hyperlipidemia
(FCH),87 but this finding has not been confirmed by
others.88 89 FCH is a common inherited disorder of lipid
metabolism that is characterized by an
overproduction of apoB-100–containing lipoproteins and
elevated levels of VLDL and LDL.90 91 92 Recently, it was
reported that the XmnI polymorphism together with
MspI and SstI aggravated
hypercholesterolemia and
hypertriglyceridemia in FCH probands; ie, a
higher frequency of these minor alleles was associated with
elevated plasma cholesterol, TGs, LDL
cholesterol, apoB, and apoC3 levels.93 A
more detailed analysis of a combination of haplotypes within
the APOA1/C3/A4 gene cluster showed 2
different susceptibility loci for FCH within this cluster, consisting
of an S2-bearing haplotype behaving as a dominant trait and
an X2M2 haplotype behaving as a permissive
trait.94 Furthermore, a
C1100T polymorphism in exon 3 of the
APOC3 gene was found to be associated with an increased
number of VLDL and IDL particles in the circulation of FCH
probands.95 Altogether, these results suggest that
the APOA1/C3/A4 gene cluster may
contribute to FCH in a rather complex genetic manner, thereby acting as
a modifier gene rather than representing the primary cause
of FCH.
Further evidence that APOC3 overexpression may underlie hypertriglyceridemia in humans comes from studies with fibrates, a hypotriglyceridemic class of drugs. Fibrates effectively decrease the apoC3 synthesis rate in humans54 as well as APOC3 mRNA levels in isolated human hepatocytes and rat livers via a peroxisome proliferator–activated receptor–dependent pathway.96 97 98
In summary, the characterization of mutations in the APOC2 gene of patients with hyperchylomicronemia has clearly established an important role for apoC2 as an activator of LPL. In contrast, the mechanisms underlying the hyperlipidemia and hypertriglyceridemia that are suggested as being associated with genetic mutations and polymorphisms of the APOC1 and APOC3 genes remain largely unknown.
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ApoC Proteins |
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Nucleotide sequence analysis has indicated that apoC1 is synthesized with a 26-residue signal peptide that is cleaved cotranslationally in the rough endoplasmic reticulum.99 The remaining single-chain polypeptide of 57 amino acid residues has a molecular mass of 6.6 kDa (Table 1
).100 101 ApoC1 has a high content of lysine (16
mol%) and contains no histidine, tyrosine, cysteine, or
carbohydrate.102 It has been demonstrated that residues 7
to 24 and 35 to 53 of apoC1 are important for the binding to
lipoproteins.102 The plasma concentration of apoC1 in
humans is 6 mg/dL.103
ApoC2 is synthesized with a 22-residue signal peptide that is cleaved
cotranslationally in the rough endoplasmic reticulum.104
The remaining single polypeptide chain of 79 amino acid residues has a
calculated molecular mass of 8.8 kDa.6 104 105 106 The
structure of apoC2 is predicted to contain 3 helical regions between
residue 13 to 22, 29 to 40, and 43 to 52, which are thought to be
involved in phospholipid binding.107 Studies using
synthetic peptides of apoC2 have shown that LPL interacts with the
COOH-terminal amino acids 56 to 79 of apoC2.108 In line
with these data, deletion of the COOH-terminal tetrapeptide residues 76
through 79 impairs the ability of the protein to activate
LPL.109 ApoC2 is present in human plasma at a
concentration of 4 mg/dL.8
ApoC3 is synthesized in the liver and in minor quantities by the
intestine as a 99–amino acid peptide. After removal of the 20–amino
acid signal peptide in the endoplasmic reticulum, a mature apoC3
protein of 79 amino acids comprises a molecular mass of 8.8 kDa (Table 1).110 Thrombin cleavage of apoC3 results in an
N-terminal domain, residues 1 to 40, and a
C-terminal domain, residues 41 to 79, corresponding to the
products of exons 3 and 4, respectively.111
Structural analysis demonstrated that the binding of apoC3 to
surface phospholipids of lipoproteins is mediated by an amphipathic
helix at residues 50 to 69 residing in the C-terminal domain
of apoC3.112 Isoelectric focusing separates apoC3
into 3 isoforms that differ in their degree of O-linked
sialylation at the threonine residue in position 74: apoC3–0 (no
sialic acid), apoC3-1 (1 mol sialic acid), and apoC3-2 (2 mol sialic
acid).113 114 115 ApoC3 is the most abundant C
apolipoprotein in human plasma, at a concentration of 12
mg/dL.116
Little has been reported on how and in which form apoCs are secreted into plasma. Studies by Roghani and Zannis59 have shown that cell clones expressing the APOC3 gene exclusively secrete the desialylated form of apoC3 (apoC3-2), suggesting that apoC3-2 must be desialylated after secretion in plasma to produce the monosialo (apoC3-1) and asialo (apoC3-0) forms. Furthermore, it was shown that the intracellular glycosylation of apoC3 is not an absolute prerequisite for its secretion and ability to associate with plasma lipoproteins.59 Although it has been reported that nascent apoCs are largely secreted in the lipid-poor form by different cell lines in vitro,59 116 it is likely due to their high affinity toward lipid surfaces that apoCs rapidly associate with VLDL and HDL in plasma.117 118 119 A detailed study by Gibson et al120 showed that apoC3 was found in the broad distribution of particles the size of VLDL, on particles slightly larger than LDL, and on particles slightly larger than HDL. It has been reported that in the fasting state, apoCs are mainly associated with HDL, whereas in the fed state, they preferentially redistribute to the surface of chylomicron and VLDL particles.121 Similarly, release of LPL and hepatic lipase in subjects intravenously injected with heparin induced a shift in the distribution of apoC2 and apoC3 from VLDL to particles slightly larger than HDL.122 At least for apoC3, there is also a nonexchangeable pool present on both VLDL and HDL that accounts for 30% to 60% of the total apoC3 mass in each lipoprotein fraction.123 124
The relatively low human APOC4 gene expression in the liver
and the total lack of the apoC4 protein in human plasma (Table 1) suggest that apoC4 plays no major role in lipoprotein
metabolism. The apoC4 protein sequence was predicted to
comprise 127 amino acid residues, which contain a putative 25-residue
signal peptide and 2 potential amphipathic 
-helical
domains.10 In other species such as the rabbit, it
has been demonstrated that apoC4 is secreted at a more substantial
level.125 The rabbit apoC4 protein is synthesized as a
124–amino acid protein that includes a typical signal peptide of 27
residues and has a molecular weight of 14 kDa. The mature rabbit
apoC4 protein of 97 amino acids is primarily associated with VLDL and
HDL.125
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Interaction of ApoCs With Receptors and Enzymes Involved in Lipoprotein Metabolism |
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TopIntroductionAPOC GenesMolecular Defects in Human...ApoC ProteinsInteraction of ApoCs With...Transgenic Mouse Models...Transgenic Mice Overexpressing...Transgenic Mouse Models...Transgenic Mice Overexpressing...ConclusionsReferences |
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Studies in the early 1980s have demonstrated that enrichment of chylomicrons and VLDL with a mixture of apoCs significantly inhibits their uptake by the isolated, perfused rat liver.126 127 128 129 130 131 132 133 In line with these studies, it was shown that the apoE-mediated uptake of TG-rich emulsions by HepG2 cells and rat hepatocytes in culture was effectively inhibited by apoC3 and apoC1.131 133 Ligand blotting assays showed that apoC1 and apoC2 inhibit the apoE-mediated binding of ß-VLDL to the low density lipoprotein receptor (LDLR)–related protein (LRP), apoC1's being a more effective inhibitor than apoC2.134 135 As shown in Table 3
, apoC3 had no
effect on the binding affinity of ß-VLDL to LRP.135 It
is suggested that the inhibitory action of apoC1 on
lipoprotein binding to LRP was due to displacement of apoE from the
lipoprotein particle. In line with these results, it was shown that
synthetic peptides corresponding to the lipid-binding domain of apoC1
were also able to displace significant amounts of apoE from ß-VLDL
and inhibit the binding of ß-VLDL to LRP.136 Sehayek and
Eisenberg137 reported that apoC1 and apoC2 impaired the
apoE-mediated binding of VLDL to the LDLR in cultured fibroblasts
(Table 3). In line with the LRP ligand blotting assays, the
strongest inhibition of lipoprotein binding to the LDLR was observed
with apoC1. In this study, it was concluded that the inhibition of
lipoprotein binding to the LDLR occurred through masking or altering
the conformation of apoE by apoC1 rather than through displacement of
apoE, as suggested by Weisgraber et al.135
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Previous studies have shown that apoC3 completely abolishes the
apoB-mediated binding of lipoproteins to the LDLR (see Table 3).
It is suggested that this inhibitory action of apoC3 on
lipoprotein binding was due to a masking of the receptor domain of apoB
by apoC3.138 139 An inhibitory effect was also
observed for apoC2, whereas apoC1 did not inhibit apoB-mediated binding
of lipoproteins to the LDLR.139 Recent studies have shown
that apoCs can also interfere with the binding of lipoproteins to other
lipoprotein receptors, including the VLDL receptor140 and
lipolysis-stimulated receptor.141 The binding of
lipoproteins to the VLDL receptor was completely inhibited by
apoC1,140 whereas apoC3 specifically inhibited the binding
of chylomicrons and VLDL to the lipolysis-stimulated
receptor.141
Numerous in vitro studies have investigated the influence of apoCs on
the LPL-mediated lipolysis of TG-rich lipoproteins. As shown in Table 3, apoC2 is an essential activator of LPL. However,
at high protein concentrations, apoC2 was demonstrated to inhibit LPL
activity rather than stimulate it.142 The mechanism by
which apoC2 activates LPL is not fully
understood.143 144 It has been suggested that apoC2
activates LPL after binding of LPL to phospholipids on the
surface of TG-rich lipoproteins. On the other hand, apoC2 may also bind
directly to LPL. Recent studies by Olivecrona and
Beisiegel145 showed that the lipid binding domain of apoC2
is essential for activation of LPL.
Studies in the early 1970s have indicated that both apoC1 and apoC3
inhibit LPL activity142 146 147 148 149 (Table 3). In a
study with hypertriglyceridemic patients,
it was shown that apoC3 was 1 of the most specific
inhibitors of LPL.150 Further in vitro kinetic
analysis with bovine LPL and purified apoC3 demonstrated that
apoC3 displays noncompetitive inhibitory properties against
both apoC2 and triolein, indicating that apoC3 exerts its
inhibitory effect directly on LPL.150 In line
with these results, McConathy et al151 used synthetic
polypeptide fragments of apoC3 and observed that the
N-terminal domain of apoC3 is primarily responsible for
inhibition of LPL activity. Studies by Ginsberg et
al65 showed that sera from subjects deficient for
both apoC3 and apoA1 were able to normally activate human milk
LPL at increasing volumes of sera, whereas normal sera effectively
inhibits LPL activity at increasing concentrations. Furthermore,
addition of purified apoC3 to the apoC3/A1-deficient sera progressively
reduced maximal levels of LPL activity, suggesting that apoC3 inhibits
the LPL-mediated lipolysis of TG-rich lipoproteins.
In addition to LPL, it has been demonstrated that apoCs can act on
several other enzymes involved in lipoprotein processing (see Table 3). In vitro, high concentrations of apoC3 have been shown to
inhibit hepatic lipase (HL).152 In line with this study,
apoC3 inhibited the lipolysis of TG emulsions by
heparin-immobilized HL in the presence of
apoE.153 An inhibitory effect on the
HL-mediated lipolysis of TG emulsions was also observed for apoC2,
although to a lesser extent than with apoC3.153 In the
latter study, however, the inhibitory action of apoC3 and
apoC2 may have been due to interference of the apoCs with the
apoE-mediated binding of the substrate to the lipase-loaded
heparin-Sepharose column rather than a direct inhibitory
action of the apoCs on HL itself.
ApoCs also appeared to affect LCAT activity (Table 3). Whereas
apoA1 is known to be the most powerful LCAT activator,
apoC1 was shown to activate LCAT to 78% of that of
apoA1.154 155 156 Both apoC2 and apoC3 were reported to
inhibit LCAT activity, probably by displacing the activating
apolipoproteins from the lipoprotein surface.157
Furthermore, LCAT is also able to esterify lysophosphatidylcholine to
phosphatidylcholine.158 This lysolecithin
acyltransferase activity was found to be activated by apoC1 as
well. In this respect, apoC1 was 70% as effective as
apoA1.159
It has been reported that in a family of baboons with high plasma HDL cholesterol levels, the transfer of cholesteryl ester from HDL to lower-density lipoproteins is inhibited by a 4-kDa protein.160 This 4-kDa protein appeared to correspond to the N-terminal domain of apoC1. Further in vitro studies demonstrated that a synthetic peptide comprising the 38–amino acid N-terminal domain of apoC1 was indeed able to inhibit cholesteryl ester transfer protein (CETP) activity.160 In addition, the 4-kDa protein was associated with apoA1 on HDL and, to a lesser extent, with apoE on VLDL, thereby resulting in modification of these apolipoproteins. From these data, it was hypothesized that an association of the apoC1 fragment with apoA1 on the surface of HDL and with apoE on VLDL may hamper the accessibility of CETP to these substrate lipoproteins.
Little has been published about the effects of apoC2 and apoC3 on
CETP activity. Preliminary studies as discussed by Sparks and
Pritchard161 demonstrate that by using recombinant HDL
particles, apoC3 stimulates CETP activity (Table 3).
In summary, in vitro studies have demonstrated that apoCs have an
inhibitory or stimulatory effect on a variety of receptors
and enzymes involved in lipoprotein metabolism (Table 3). These data suggest a complex role for apoCs in human
disease. However, it is important to know which of these in vitro
effects extends to the in vivo situation, because several in vitro
effects of apoCs on receptors and enzymes may appear nonspecific or
secondary, ie, due to the displacement of other activating or
inhibiting components of the lipoprotein particle.
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Transgenic Mouse Models Overexpressing or Lacking ApoC1 |
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Studies relating to the in vivo metabolism of apoCs have been hampered in humans owing to the highly complex nature of lipoprotein metabolism that can be influenced by multiple genetic and environmental factors. To study the in vivo functions of the individual apoCs in lipoprotein metabolism against a defined genetic background and under strictly controlled environmental conditions, several laboratories have created mouse models lacking or overexpressing the respective APOC genes through the technologies of transgenesis and gene targeting. As shown in Table 4
, APOC1-transgenic
mice were generated by using different DNA constructs that all
contained the 154-bp HCR that directs expression of the human
APOC1 gene to the liver. Human APOC1–transgenic
mice exhibited elevated levels of cholesterol and TGs owing
to an accumulation of VLDL-size particles in the
circulation.162 163 164 165
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To investigate the mechanisms underlying the hyperlipidemia in human APOC1–transgenic mice, in vivo turnover studies were performed using labeled VLDL. The clearance of both VLDL TG and VLDL apoB was severely hampered in hyperlipidemic human APOC1–transgenic mice,163 164 165 suggesting that apoC1 interferes with either the lipolysis or hepatic uptake of VLDL. The findings that (1) VLDL from APOC1-transgenic mice bound as efficiently to heparin-Sepharose as did VLDL from wild-type mice,164 (2) the in vitro lipolysis by LPL of VLDL TG fractions isolated from APOC1-transgenic mice was not impaired, and (3) the in vivo extrahepatic lipolysis of VLDL TG in APOC1-transgenic mice was not different from that in wild-type mice165 indicate that apoC1 does not interfere with lipolysis of VLDL TGs in vivo. Furthermore, it was demonstrated that the production rate of VLDL TGs in APOC1-transgenic mice is not different from that in control mice.164 165 In conclusion, the elevated lipid levels in the plasma of APOC1-transgenic mice are primarily due to an impaired uptake of VLDL by the liver rather than to an enhanced production or disturbed lipolysis of VLDL.163 164 165
Overexpression of apoC1 in LDLR-knockout mice leads to extremely elevated levels of plasma cholesterol and TGs compared with cholesterol and TG levels in LDLR-knockout mice.165 These results suggest that apoC1 inhibits the alternative lipoprotein clearance pathway. The fact that overexpression of the receptor-associated protein (RAP) greatly enhances serum cholesterol and TG levels in LDLR-/- mice whereas it does not alter serum lipid levels in APOC1/LDLR-/- mice indicates that RAP and APOC1 overexpression act on the same pathway in inhibiting the clearance of VLDL remnants by the liver. Because RAP overexpression is known to block LRP, it can be concluded that apoC1 inhibits the uptake of lipoproteins via LRP in vivo, thereby sustaining the in vitro findings that apoC1 is the most efficient apoC for inhibiting the binding of VLDL to the LRP.135 136
The in vitro observation that apoC1 is a potent activator of LCAT suggests that the increases in VLDL/IDL and LDL cholesterol observed in human APOC1–transgenic mice164 165 may also partly result from an increase in the cholesterol esterification rate. Increased LCAT activity, as found in transgenic mice overexpressing human LCAT, has been reported to elevate HDL cholesterol esters levels.166 167 168 However, the findings that the free to total cholesterol ratios were unchanged in APOC1-transgenic mice164 and that HDL cholesterol esters were not significantly elevated in APOC1-transgenic mice compared with wild-type mice165 argue against an LCAT-mediated elevation in cholesterol levels in APOC1-transgenic mice.
In addition to hyperlipidemia, it has recently been reported that APOC1-transgenic animals exhibit several abnormalities, consisting of elevated plasma free fatty acid levels, epidermal hyperplasia and hyperkeratosis, atrophic sebaceous glands, lack of sebum, and (subcutaneous) adipose tissue.169 These results suggest an additional role for apoC1 in epidermal lipid synthesis as well as adipose tissue formation.
Because transgenic mice overexpressing APOC1 develop
hyperlipidemia, a hypolipidemic phenotype was
expected in ApoC1-knockout mice. It was, however, surprising
to observe that ApoC1-knockout mice had normal serum lipid
levels on a chow diet (Table 4).170 Only when
fed a high-fat and high-cholesterol diet did
apoC1-deficient mice develop
hypercholesterolemia. In vitro binding
experiments revealed that apoC1-deficient VLDL was a poor competitor
for LDL binding to the LDLR, suggesting that total apoC1 deficiency
leads to an impaired receptor-mediated clearance of remnant
lipoproteins.170 Later, these results were confirmed in a
more detailed characterization of these ApoC1-knockout mice,
demonstrating that an impaired in vivo hepatic uptake of VLDL is the
primary metabolic defect in apoC1-deficient
mice.171
In summary, whereas overexpression of human APOC1 in transgenic mice predominantly inhibits the uptake of VLDL particles by the liver, the absence of endogenous mouse ApoC1 in mice appears to have the same effect, though to a lesser extent. It has been suggested that apoC1 may impair VLDL clearance either directly, by a specific interaction between apoC1 and the hepatic receptor, or indirectly, as caused by an apoC1-induced displacement of apoE from the lipoprotein particle.164 165 On the other hand, it is suggested that the impaired interaction of apoC1-deficient VLDL with hepatic receptors is due to an enrichment of the VLDL particle with apoA1 and apoA4.170 171
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Transgenic Mice Overexpressing Human ApoC2 |
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TopIntroductionAPOC GenesMolecular Defects in Human...ApoC ProteinsInteraction of ApoCs With...Transgenic Mouse Models...Transgenic Mice Overexpressing...Transgenic Mouse Models...Transgenic Mice Overexpressing...ConclusionsReferences |
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Transgenic mice overexpressing human APOC2 were generated by using a vector containing the human APOC2 gene joined to a cytochrome P450 CYPIA1 promoter172 (Table 4
). This promoter is normally silent in intrauterine life
but can lead to transgene expression after administration of
ß-naphthoflavone. Strikingly, transgenic mice overexpressing human
apoC2 were hypertriglyceridemic, due to an
accumulation of TG-rich VLDL particles in the circulation. This
hypertriglyceridemia was shown to be caused
by impaired clearance of VLDL TGs.172 This finding
suggests that high levels of apoC2 interfere with either the
peripheral lipolysis of VLDL or the uptake of the VLDL
particle by the liver. The observation that APOC2-transgenic
mice accumulate large, TG-rich VLDLs and have only minimally elevated
levels of plasma cholesterol is most consistent
with a defective LPL-mediated hydrolysis of VLDL TGs in these mice
rather than an impaired hepatic VLDL uptake. The observation that VLDL
isolated from APOC2-transgenic mice showed decreased binding
affinity to heparin-Sepharose suggests that these lipoprotein fractions
may be less accessible to cell surface–bound LPL172
and therefore sustains the hypothesis that excess apoC2 on the VLDL
particle inhibits LPL activity in vivo. These results are in striking
contrast to the human studies discussed earlier, in which it was shown
that apoC2 is the physiological
activator of LPL. Altogether, these data suggest that apoC2
may play a complex role in plasma TG metabolism; ie, apoC2
activates LPL, most likely at low protein concentrations,
whereas at high protein levels, apoC2 directly inhibits VLDL
lipolysis. |
Transgenic Mouse Models Overexpressing or Lacking ApoC3 |
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TopIntroductionAPOC GenesMolecular Defects in Human...ApoC ProteinsInteraction of ApoCs With...Transgenic Mouse Models...Transgenic Mice Overexpressing...Transgenic Mouse Models...Transgenic Mice Overexpressing...ConclusionsReferences |
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Two laboratories have reported the generation of human APOC3–transgenic mice by using DNA fragments of different sizes, both of which resulted in high levels of human APOC3 mRNA in the liver and intestine173 174 (Table 4
). Human APOC3–transgenic mice exhibited very
elevated levels of VLDL TGs. Recently, it was reported that mouse
ApoC3–transgenic mice are also
hypertriglyceridemic.175
Human and mouse APOC3–transgenic mice had impaired
clearance of VLDL TGs, concomitant with a decreased VLDL apoE to apoC
ratio.174 175 176 Because crossbreeding of human
APOC3–transgenic mice with human
APOE–overexpressing transgenic mice normalizes plasma TG
levels,174 175 it was concluded that the delayed
clearance of VLDL TGs in APOC3-transgenic mice was due to
the low amount of apoE relative to apoC3 on the VLDL particle. More
recent studies, however, have shown that the
hypertriglyceridemia in
APOC3-transgenic mice is most probably caused by an excess
of apoC3 rather than by the apoC3-induced displacement of apoE.
ApoE-knockout mice normally accumulate large amounts of VLDL
that is enriched in cholesterol ester but relatively poor
in TG.177 Crossbreeding of ApoE-knockout
mice with transgenic mice overexpressing human apoC3 resulted in a
massive accumulation of TG-rich VLDL-size
particles,178 indicating that it is the amount of
apoC3 that causes hypertriglyceridemia. From in vitro binding studies, it was suggested that excess apoC3 inhibits the binding of VLDL to the LDLR.174 175 However, the prolonged residence time of the predominantly enlarged, TG-rich VLDL particles in APOC3-transgenic mice implies that apoC3 impairs the hydrolysis of VLDL TGs. In line with this observation, VLDL isolated from APOC3-transgenic mice displayed decreased binding affinity to heparin-Sepharose.164 175 In addition, the observations that apoC3-deficient mice are protected from postprandial hypertriglyceridemia and exhibit reduced serum lipid levels compared with control mice also points to an inhibitory action of apoC3 on VLDL lipolysis.179
|
Transgenic Mice Overexpressing Human ApoC4 |
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TopIntroductionAPOC GenesMolecular Defects in Human...ApoC ProteinsInteraction of ApoCs With...Transgenic Mouse Models...Transgenic Mice Overexpressing...Transgenic Mouse Models...Transgenic Mice Overexpressing...ConclusionsReferences |
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The recently identified human APOC4 gene was overexpressed in transgenic mice180 (Table 4
).
Under normal conditions, the APOC4 gene is poorly expressed
in human liver, most likely as a consequence of a TATA-less
promoter.10 Therefore, to enhance liver expression of
the human APOC4 gene in mice, a vector was constructed
containing human APOC4 cDNA and the HCR element under
control of the human APOE gene promoter. Human
APOC4–transgenic mice were
hypertriglyceridemic compared with their
nontransgenic littermates, owing to an accumulation of TG-rich VLDL
particles. Because there was little change in serum
cholesterol levels in these transgenic mice, apoC4 may
interfere with the clearance of VLDL TGs via an inhibitory
effect on lipolysis in a way similar to that discussed for apoC2 and
apoC3.180 The fact that apoC4 is totally absent in
human plasma indicates no major modulating role for apoC4 in VLDL TG
metabolism in humans. |
Conclusions |
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TopIntroductionAPOC GenesMolecular Defects in Human...ApoC ProteinsInteraction of ApoCs With...Transgenic Mouse Models...Transgenic Mice Overexpressing...Transgenic Mouse Models...Transgenic Mice Overexpressing...ConclusionsReferences |
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Clinical evidence, as well as in vitro data and in vivo work on transgenic mouse models, have demonstrated that each of the individual human apoCs effectively modulates lipoprotein metabolism. As schematically depicted in panel A of the Figure
, apoC1 inhibits the uptake of
TG-rich lipoproteins via hepatic receptors, particularly the LRP. As a
consequence, the presence of apoC1 on the lipoprotein particle may
prolong their residence time in the circulation and subsequently
facilitate their conversion to LDL.
|
) and
inhibitory action (
) of the individual apoCs on
lipoprotein lipolysis, clearance, and hepatic uptake is depicted.
ApoC2 is an important activator of LPL and is required for
efficient lipolysis of TG-rich lipoproteins in the circulation. The
total absence of apoC2 or defects in its structure severely hamper
LPL-mediated lipolysis of TG-rich lipoproteins, resulting in strongly
elevated levels of plasma TGs. In contrast, excess apoC2 on the
lipoprotein particle has been demonstrated to inhibit LPL-mediated
hydrolysis of TGs (panel B of the Figure).
At least from in vivo studies with APOC3-transgenic mice, it
appears that apoC3 inhibits the lipolysis of TG-rich lipoproteins by
hampering the interaction of these lipoproteins with the heparan
sulfate proteoglycan–LPL complex (panel C of the Figure).
Subsequently, the poorly lipolyzed apoC3-containing lipoprotein
particles may accumulate in plasma because of their lower binding
affinity to hepatic receptors as a consequence of their lipid
composition, large size, or the presence of apoC3 on the particle.
These results suggest that the amount of apoC3 on the lipoprotein
particle is a strong modulator of plasma TG metabolism and
may contribute to hypertriglyceridemia in
the human population.
Several in vitro studies have shown that apoCs can also modulate
enzymes that are involved in the transport of cholesterol
from extrahepatic tissues to the liver (the Figure). Although
these specific functions remain to be established in vivo, it has been
demonstrated that apoC1 can effectively activate LCAT. In
contrast, both apoC2 and apoC3 have been reported to inhibit LCAT
activity, most likely as a consequence of displacing the activating
components of the HDL particle. CETP, which mediates the transfer of
cholesterol ester from HDL to apoB-containing lipoprotein
particles, was shown to be inhibited by apoC1, whereas apoC3 was
reported to activate this process.
In conclusion, human apoCs have been demonstrated to have distinct effects on the major metabolic pathways in lipoprotein metabolism, implying that changes in human APOC gene expression may play an important role in the etiology of human hyperlipidemias.
|
Acknowledgments |
|---|
This work was supported by the Netherlands Heart Foundation and the Netherlands Foundation of Scientific Research (projects 97-067 and 903-39-117) (to L.M.H.). We are grateful to Hans van der Boom for excellent technical help.
Received June 3, 1998; accepted July 10, 1998.
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References |
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TopIntroductionAPOC GenesMolecular Defects in Human...ApoC ProteinsInteraction of ApoCs With...Transgenic Mouse Models...Transgenic Mice Overexpressing...Transgenic Mouse Models...Transgenic Mice Overexpressing...ConclusionsReferences |
|---|
1. Davison PJ, Norton P, Wallis SC, Gill L, Cook M., Williamson R, Humphries SR. There are two gene sequences for human apolipoprotein C1 (APO C1) on chromosome 19, one of which is 4 kb from the gene for apoE. Biochem Biophys Res Commun. 1986;136:876–884.[Medline] [Order article via Infotrieve]
2. Myklebost O, Rogne S. The gene for human apolipoprotein C1 is located 4.3 kilobases away from the apolipoprotein E gene on chromosome 19. Hum Genet. 1986;73:286–289.[Medline] [Order article via Infotrieve]
3. Smit M, van der Kooij-Meijs E, Frants RR, Havekes LM, Klasen EC. Apolipoprotein gene cluster on chromosome 19: definite localization of the APOC2 gene and the polymorphic HpaI site associated with type III hyperlipoproteinemia. Hum Genet. 1988;78:90–93.[Medline] [Order article via Infotrieve]
4.
Lauer S, Walker D, Elshourbagy NA, Reardon CA,
Levy-Wilson B, Taylor JM. Two copies of the human apolipoprotein C-I
gene are linked closely to the apolipoprotein E gene. J Biol
Chem. 1988;263:7277–7286.
5. Li W-H, Tanimura M, Luo C-C, Datta S, Chan L. The apolipoprotein multigene family: biosynthesis, structure, structure-function relationships, and evolution. J Lipid Res. 1988;29:245–271.[Medline] [Order article via Infotrieve]
6.
Myklebost O, Williamson B, Markham AF, Myklebost SR,
Rogers J, Woods DE, Humphries SE. The isolation and characterization of
cDNA clones for human apolipoprotein CII. J Biol Chem. 1984;259:4401–4404.
7.
Wei C-F, Tsao Y-K, Robberson DL, Gotto AM Jr, Brown
K, Chan L. The structure of the human apolipoprotein C-II gene.
J Biol Chem. 1985;260:15211–15221.
8.
Das HK, Jackson CL, Miller DA, Leff T, Breslow JL.
The human apolipoprotein C-II gene sequence contains a novel chromosome
19-specific minisatellite in its third intron. J Biol
Chem. 1987;262:4787–4793.
9. van Eck MM, Hoffer MJV, Havekes LM, Frants RR, Hofker MH. The apolipoprotein C2-linked (AcI) gene: a new gene within the mouse apolipoprotein e-c1–c2 gene cluster. Genomics. 1994;21:110–115.[Medline] [Order article via Infotrieve]
10. Allan CM, Walker D, Segrest JP, Taylor JM. Identification and characterization of a new human gene (APOC4) in the apolipoprotein E, C-I, and C-II gene locus. Genomics. 1995;28:291–300.[Medline] [Order article via Infotrieve]
11. Taylor JM, Simonet WS, Bucay N, Lauer SJ, de Silva HV. Expression of the human apolipoprotein E/apolipoprotein C-I locus in transgenic mice. Curr Opin Lipidol. 1991;2:73–80.
12. Zannis VI, Kardassis D, Cardot P, Hadzopoulou-Cladaras M, Zanni EE, Cladaras C. Molecular biology of the human apolipoprotein genes: gene regulation and structure/function relationship. Curr Opin Lipidol. 1992;3:96–113.
13. Shachter NS, Zhu Y, Walsh A, Breslow JL, Smith JD. Localization of a liver-specific enhancer in the apolipoprotein E/C-I/C-II gene locus. J Lipid Res. 1993;34:1699–1707.[Abstract]
14.
Simonet WS, Bucay N, Lauer SJ, Taylor JM. A
far-downstream hepatocyte-specific control region directs
expression of the linked human apolipoprotein E and C-I genes in
transgenic mice. J Biol Chem. 1993;268:8221–8229.
15.
Allan CM, Walker D, Taylor JM. Evolutionary
duplication of a hepatic control region in the human apolipoprotein E
locus: identification of a second region that confers high level and
liver-specific expression of the human apolipoprotein E gene in
transgenic mice. J Biol Chem. 1995;270:26278–26281.
16.
Allan CM, Taylor S, Taylor JM. Two hepatic enhancers,
HCR.1 and HCR.2, coordinate the liver expression of the entire human
apolipoprotein E/C-I/C-IV/CII gene cluster. J Biol
Chem. 1997;272:29113–29119.
17.
Karathanasis SK. Apolipoprotein multigene family:
tandem organization of human apolipoprotein AI, CIII, and AIV genes.
Proc Natl Acad Sci U S A. 1985;82:6374–6378.
18. Protter AA, Levy-Wilson B, Miller J, Bencen G, White T, Seilhamer JJ. Isolation and sequence analysis of the human apolipoprotein CIII gene and the intergenic region between the apo AI and apo CIII genes. DNA. 1984;3:449–456.[Medline] [Order article via Infotrieve]
19.
Elshourbagy NA, Walker DN, Boguski MS, Gordon JI,
Taylor JM. The nucleotide and derived amino acid sequence
of human apolipoprotein A-IV mRNA and the close linkage of its gene to
the genes of apolipoproteins A-I and C-III. J Biol
Chem. 1986;261:1998–2002.
20.
Sharpe CR, Sidoli A, Shelley CS, Lucero MA, Shoulders
CC, Baralle FE. Human apolipoproteins AI, AII, CII and CIII, cDNA
sequences and mRNA abundance. Nucleic Acids Res. 1984;12:3917–3932.
21. Karathanasis SK, Zannis VI, Breslow JL. Isolation and characterization of cDNA clones corresponding to two different human apoC-III alleles. J Lipid Res. 1985;26:451–456.[Abstract]
22.
Cheung P, Kao FT, Law ML, Jones C, Puck TT, Chan L.
Localization of the structural gene for human apolipoprotein A-I on the
long arm of human chromosome 11. Proc Natl Acad Sci U S A. 1984;81:508–511.
23. Zannis VI, Cole SF, Jackson C, Kurnit DM, Karathanasis SK. Distribution of apolipoprotein A-I, C-II, C-III, and E mRNA in fetal human tissues: time-dependent induction of apolipoprotein mRNA by cultures of human monocyte-macrophages. Biochemistry. 1985;24:4450–4455.[Medline] [Order article via Infotrieve]
24.
Reue K, Leff T, Breslow JL. Human apolipoprotein CIII
gene expression is regulated by positive and negative cis-acting
elements and tissue specific protein factors. J Biol
Chem. 1988;263:6857–6864.
25.
Ogami K, Hadzopoulou-Cladaras M, Cladaras C, Zannis
VJ. Promoter elements and factors required for hepatic and intestinal
transcription of the human apoCIII gene. J Biol Chem. 1990;265:9808–9815.
26. Omori K, Vergnes L, Zakin MM, Ochoa A. The apolipoprotein AI-CIII-AIV gene cluster: sequence of the apoCIII-apoAIV intergenic region. Gene. 1995;159:231–234.[Medline] [Order article via Infotrieve]
27. Vergnes L, Taniguchi T, Omori K, Zakin MM, Ochoa A. The apolipoprotein A-I/C-III/A-IV gene cluster: apoC-III and apoA-IV expression is regulated by two common enhancers. Biochim Biophys Acta. 1997;1348:299–310.[Medline] [Order article via Infotrieve]
28. Lauer SJ, Simonet WS, Bucay N, de Silva HV, Taylor JM. Tissue-specific expression of the human apolipoprotein A-IV gene in transgenic mice. Circulation. 1991;84(suppl II):II-17. Abstract.
29. Walsh AM, Azrolan N, Wang K, Marcigliano A, O'Connell A, Breslow JL. Intestinal expression of the human apoA-I gene in transgenic mice is controlled by a DNA region 3' to the gene in the promoter of the adjacent convergently transcribed apoC-III gene. J Lipid Res. 1993;34:617–623.[Abstract]
30. Dumon MF, Clerc M. Preliminary report on a case of apolipoprotein CI and CII deficiency. Clin Chim Acta. 1986;157:239–248.[Medline] [Order article via Infotrieve]
31. Glomset JA, Janssen ET, Kennedy R, Dobbins J. Role of plasma lecithin:cholesterol acyltransferase in the metabolism of high density lipoproteins. J Lipid Res. 1966;7:638–648.
32. Breckenridge WC, Little JA, Steiner G, Chow A, Poapst M. Hypertriglyceridemia associated with deficiency of apolipoprotein CII. N Engl J Med. 1978;298:1265–1273.[Abstract]
33. Cox DW, Breckenridge WC, Little JA. Inheritance of apolipoprotein C-II deficiency with hypertriglyceridemia and pancreatitis. N Engl J Med. 1978;299:1421–1424.[Abstract]
34. Wang CS. Structure and functional properties of apolipoprotein C-II. Prog Lipid Res. 1991;30:253–258.[Medline] [Order article via Infotrieve]
35. Santamarina-Fojo S. Genetic dyslipoproteinemias: role of lipoprotein lipase and apolipoprotein C-II. Curr Opin Lipidol. 1992;3:186–195.
36. Fojo SS, Brewer HB Jr. Hypertriglyceridaemia due to genetic defects in lipoprotein lipase and apolipoprotein C-II. J Intern Med. 1992;231:669–677.[Medline] [Order article via Infotrieve]
37.
Fojo SS, Stalenhoef AF, Marr K, Gregg RE, Ross RS,
Brewer HB Jr. A deletion mutation in the ApoC-II gene
(ApoC-IINijmegen) of a patient with a deficiency
of apolipoprotein C-II. J Biol Chem. 1988;263:17913–17916.
38. Parrot CL, Alsayed N, Rebourcet R, Santamarina-Fojo S. ApoC-IIParis2: a premature termination mutation in the signal peptide of apoC-II resulting in familial chylomicronemia syndrome. J Lipid Res. 1992;33:361–367.[Abstract]
39. Xiong W, Li W-H, Posner I, Yamamura T, Yamamoto A, Gotto AM Jr, Chan L. No severe bottleneck during human evolution: evidence from two apolipoprotein C-II deficiency alleles. Am J Hum Genet. 1991;48:383–389.[Medline] [Order article via Infotrieve]
40. Fojo SS, Lohse P, Parrot C, Baggio G, Gabelli C, Thomas F, Hoffman J, Brewer HB Jr. A nonsense mutation in the apolipoprotein C-IIPadova gene in a patient with apolipoprotein C-II deficiency. J Clin Invest. 1989;84:1215–1219.
41. Crecchio C, Capurso A, Pepe G. Identification of the mutation responsible for a case of plasmatic apolipoprotein CII deficiency (apo CII-Bari). Biochem Biophys Res Commun. 1990;168:1118–1127.[Medline] [Order article via Infotrieve]
42. Fojo SS, Beisiegel U, Beil U, Higuchi K, Bojanouski M, Gregg RE, Greten H, Brewer HB Jr. Donor splice site mutation in the apolipoprotein (Apo) C-II gene (Apo C-IIHamburg) of a patient with Apo C-II deficiency. J Clin Invest. 1988;82:1489–1494.
43. Okubo M, Hasegawa Y, Aoyama Y, Murase T. A G+1 to C mutation in a donor splice site of intron 2 in the apolipoprotein (apo) C-II gene in a patient with apo C-II deficiency: a possible interaction between apo C-II deficiency and apo E4 in a severely hypertriglyceridemic patient. Atherosclerosis. 1997;130:153–160.[Medline] [Order article via Infotrieve]
44.
Fojo SS, Gennes JL, Chapman J, Parrot C, Lohse P,
Kwan SS, Truffert J, Brewer HB Jr. An initiation codon mutation in the
apoC-II gene (apoC-IIParis) of a patient with a
deficiency of apolipoprotein C-II. J Biol Chem. 1989;264:20839–20842.
45.
Connelly PW, Maguire GF, Hofmann T, Little JA.
Structure of apolipoprotein C-IIToronto,
a nonfunctional human apolipoprotein. Proc Natl Acad Sci
U S A. 1987;84:270–273.
46. Connelly PW, Maguire GF, Little JA. Apolipoprotein C-IISt. Michael: familial apolipoprotein CII deficiency associated with premature vascular disease. J Clin Invest. 1987;80:1597–1606.
47.
Inadera H, Hibino A, Kobayashi J, Kanzaki T, Shirai
K, Yukawa S, Saito Y, Yoshida S. A missense mutation (Trp
26Arg) in exon 3 of the apolipoprotein CII gene in a patient
with apolipoprotein CII deficiency (apo CII-Wakayama). Biochem
Biophys Res Commun. 1993;193:1174–1183.[Medline]
[Order article via Infotrieve]
48.
Pullinger CR, Zysow BR, Hennessy LK, Frost PH, Malloy
MJ, Kane JP. Molecular cloning and characteristics of a new
apolipoprotein C-II mutant identified in three unrelated individuals
with hypercholesterolemia and
hypertriglyceridemia. Hum Mol
Genet. 1993;2:69–74.
49. Huff MW, Evans AJ, Wolfe BM, Connelly PW, Maguire GF, Strong WL. Identification and metabolic characteristics of an apolipoprotein C-II variant isolated from a hypertriglyceridemic subject. J Lipid Res. 1990;31:385–396.[Abstract]
50.
Hegele RA, Connelly PW, Maguire GF, Huff MW, Leiter
L, Wolfe BM, Evans AJ, Little JA. An apolipoprotein CII mutation,
CIILys19Thr identified in patients with
hyperlipidemia. Dis Markers. 1991;9:73–80.[Medline]
[Order article via Infotrieve]
51.
Zysow BR, Pullinger CR, Hennessy LK, Farese RV,
Ghassemzadeh J, Kane JP. The apolipoprotein C-II variant
apoC-IILys19Thr is not associated with dyslipidemia
in affected kindred. Clin Genet. 1994;45:292–297.[Medline]
[Order article via Infotrieve]
52. Carlson LA, Ballantyne D. Changing relative proportions of apolipoproteins CII and CIII of very low density lipoproteins in hypertriglyceridaemia. Atherosclerosis. 1976;23:563–568.[Medline] [Order article via Infotrieve]
53. Schonfeld G, George PK, Miller J, Reilly P, Witztum J. Apolipoprotein C-II and C-III levels in hyperlipoproteinemia. Metabolism. 1979;28:1001–1010.[Medline] [Order article via Infotrieve]
54. Malmendier CL, Lontie JF, Delcroix C, Dubois DY, Magot T, De Roy L. Apolipoproteins C-II and C-III metabolism in hypertriglyceridemic patients: effect of a drastic triglyceride reduction by combined diet restriction and fenofibrate administration. Atherosclerosis. 1989;77:139–149.[Medline] [Order article via Infotrieve]
55. Le N-A, Gibson JC, Ginsberg HN. Independent regulation of plasma apolipoprotein C-II and C-III concentrations in very low density and high density lipoproteins: implications for the regulation of the catabolism of these lipoproteins. J Lipid Res. 1988;29:669–677.[Abstract]
56. Jabs H-U, Assmann G. Characterization of an apolipoprotein C-III mutant by high performance liquid chromatography and time-of-flight secondary ion mass spectrometry. J Chromatogr. 1987;414:323–333.[Medline] [Order article via Infotrieve]
57. Maeda H, Uzawa H, Kamei R. Unusual familial apolipoprotein C-III associated with apolipoprotein C-III-0 preponderance. Biochim Biophys Acta. 1981;665:578–585.[Medline] [Order article via Infotrieve]
58.
Maeda H, Hashimoto R, Ogura T, Hiraga S, Uzawa H.
Molecular cloning of a human apoC-III variant: Thr 74 Ala 74
mutation prevents O-glycosylation. J Lipid Res. 1987;28:1405–1409.[Abstract]
59.
Roghani A, Zannis VI. Mutagenesis of the
glycosylation site of human apoC-III: O-linked glycosylation
is not required for apoC-III secretion and lipid binding. J
Biol Chem. 1988;263:17925–17932.
60.
von Eckardstein A, Holz H, Sandkamp M, Weng W, Funke
H, Assmann G. Apolipoprotein C-III(Lys58
Glu): identification of an apolipoprotein C-III variant in a family
with hyperalphalipoproteinemia. J Clin Invest. 1991;87:1724–1731.
61.
Luttmann S, von Eckardstein A, Wei W, Funke H,
Köhler E, Mahley RW, Assmann G. Electrophoretic screening for
genetic variation in apolipoprotein C-III: identification of a novel
apoC-III variant, apoC-III (Asp45Asn) in a Turkish patient.
J Lipid Res. 1994;35:1431–1440.[Abstract]
62.
Pullinger CR, Malloy MJ, Shahidi AK, Ghassemzadeh M,
Duchateau P, Villagomez J, Allaart J, Kane JP. A novel apolipoprotein
C-III variant, apoC-III (Gln38Lys), associated with moderate
hypertriglyceridemia in a large kindred of
Mexican origin. J Lipid Res. 1997;38:1833–1840.[Abstract]
63. Norum NA, Lakier JB, Goldstein S, Angel A, Goldberg RB, Block WD, Noffze DK, Dolphin PJ, Edelglass J, Bogorad DD, Alaupovic P. Familial deficiency in apolipoprotein A-I and C-III and precocious coronary heart disease. N Engl J Med. 1982;306:1513–1519.[Abstract]
64. Schaefer EJ, Ordovas J, Law S, Ghiselli G, Kashyap L, Srivastava L, Heaton WH, Albers J, Connor W, Lindgren F. Familial apolipoprotein A-I and C-III deficiency: variant II. J Lipid Res.. 1985;26:1089–1101.[Abstract]
65. Ginsberg HN, Le NA, Goldberg IJ, Gibson JC, Rubinstein A, Wang-Iverson P, Norum R, Brown WV. Apolipoprotein B metabolism in subjects with deficiency of apolipoproteins CIII and AI: evidence that apolipoprotein CIII inhibits catabolism of triglyceride-rich lipoproteins by lipoprotein lipase in vivo. J Clin Invest. 1986;78:1287–1295.
66. Klasen EC, Talmud PJ, Havekes L, de Wit E, van der Kooij-Meijs E, Smit M, Hansson G, Humphries SE. A common restriction fragment length polymorphism of the human apolipoprotein E gene and its relationship to type III hyperlipoproteinemia. Hum Genet. 1987;75:244–247.[Medline] [Order article via Infotrieve]
67. Smit M, van der Kooij-Meijs E, Woudt LP, Havekes LM, Frants RR. Exact localization of the familial dysbetalipoproteinemia associated HpaI restriction site in the promoter region of the APOC1 gene. Biochem Biophys Res Commun. 1988;152:1282–1288.[Medline] [Order article via Infotrieve]
68. Xu Y, Leff T, Shachter N. A common polymorphism in the apoC1 promoter significantly increases apoC1 gene expression. Circulation. 1996;94(suppl I):I-274. Abstract.
69. Rees A, Stocks J, Sharpe CR, Vella MA, Shoulders CC, Katz J, Jowet NI, Baralle FE, Galton DJ. Deoxyribonucleic acid polymorphism in the apolipoprotein A-1-CIII gene cluster: association with hypertriglyceridemia. J Clin Invest. 1985;76:1090–1095.
70. Aalto-Setälä K, Kontula K, Sane T, Nieminen M, Nikki E. DNA polymorphisms of apolipoprotein A-I/C-II and insulin genes in familial hypertriglyceridemia and coronary heart disease. Atherosclerosis. 1987;66:145–152.[Medline] [Order article via Infotrieve]
71.
Tass S. Strong association of a single
nucleotide substitution in the 3'-untranslated region of
the apolipoprotein C-III gene with common
hypertriglyceridemia in Arabs. Clin
Chem. 1989;35:256–259.
72. Ahn YL, Valdez R, Reddy AP, Cole SA, Weiss KM, Ferrell RE. DNA polymorphisms of the apolipoprotein AI/CIII/AIV gene cluster influence plasma cholesterol and triglyceride levels in the Mayans of the Yucatan Peninsula, Mexico. Hum Hered. 1991;41:281–289.[Medline] [Order article via Infotrieve]
73. Zheng Q, Dammerman M, Takada Y, Matsunaga A, Breslow JL, Sasaki J. An apolipoprotein CIII marker associated with hypertriglyceridemia in Caucasians also confers increased risk in a west Japanese population. Hum Genet. 1994;95:371–375.
74. Ordovas JM, Civeira F, Genest J Jr, Graig S, Robbins AH, Meade T, Pocovi M, Frossard PM, Masharani U, Wilson PWF, Salem DN, Ward RH, Schaefer EJ. Restriction fragment length polymorphisms of the apolipoprotein A-I, C-III, A-IV gene locus: relationships with lipids, apolipoproteins and premature coronary artery disease. Atherosclerosis. 1991;87:75–86.[Medline] [Order article via Infotrieve]
75. Shoulders CC, Ball MJ, Baralle FE. Genetic marker in apolipoprotein A1/CIII gene complex associated with hypercholesterolemia. Lancet. 1986;ii:1286–1288.
76. Shoulders CC, Ball MJ, Baralle FE. Variation of the apoA1/CIII/AIV gene complex: its association with hyperlipidaemia. Atherosclerosis. 1989;80:111–118.[Medline] [Order article via Infotrieve]
77. Henderson HE, Landon SV, Michie J, Berger MB. Association of a DNA polymorphism in the apolipoprotein CIII gene with diverse hyperlipidaemic phenotypes. Hum Genet. 1987;75:62–65.[Medline] [Order article via Infotrieve]
78.
Hong SH, Park WH, Lee CC, Song JH, Kim JQ.
Association between genetic variations of apoAI-CIII-AIV cluster gene
and hypertriglyceridemic subjects.
Clin Chem. 1997;43:13–17.
79.
Dammerman M, Sandkuijl LA, Halaas JL, Chung W,
Breslow JL. An apolipoprotein CIII haplotype protective against
hypertriglyceridemia is specified by
promoter and 3' untranslated region polymorphisms. Proc Natl
Acad Sci U S A. 1993;90:4562–4566.
80. Helio T, Paliotie A, Sane T, Tikkanen MJ, Kontula K. No evidence for linkage between familial hypertriglyceridemia and apolipoprotein B, apolipoprotein C-III or lipoprotein lipase genes. Hum Genet. 1994;94:271–278.[Medline] [Order article via Infotrieve]
81. Paul-Hayase H, Rosseneu M, Robinson D, Biervliet JPV, Deslypere JP, Humphries SE. Polymorphisms in the apolipoprotein A-I/C-III/AIV gene cluster: detection of genetic variation determining plasma apoA-I, apoC-III and apoA-IV concentrations. Hum Genet. 1992;88:439–446.[Medline] [Order article via Infotrieve]
82. Shoulders CC, Harry PJ, Lagrost L, White SE, Shah NF, North JD, Gilligan M, Gambert P, Ball MJ. Variation at the apoA1/CIII/AIV gene complex is associated with elevated plasma levels of apoCIII. Atherosclerosis. 1991;87:239–247.[Medline] [Order article via Infotrieve]
83. Xu CF, Talmud P, Humphries S. Three new polymorphisms of the apoAI-CIII-AIV gene cluster. Mol Cell Probes. 1994;8:331–332.[Medline] [Order article via Infotrieve]
84. Talmud PJ, Humphries SE. Apolipoprotein C-III gene variation and dyslipidaemia. Curr Opin Lipidol. 1997;8:154–158.[Medline] [Order article via Infotrieve]
85. Kessling AM, Berg J, Mockleby E, Humphries SE. DNA polymorphisms around the apo AI gene in normal and hyperlipidaemic individuals selected for a twin study. Clin Genet. 1986;29:485–490.[Medline] [Order article via Infotrieve]
86. Ordovas JM, Schaefer EJ, Salem D, Ward RH, Glueck CJ, Vergani C, Wilson PW, Karathanasis SK. Apolipoprotein A-I gene polymorphism associated with premature coronary artery disease and familial hypoalphalipoproteinemia. N Engl J Med. 1986;314:671–677.[Abstract]
87. Wojciechowski AP, Farall M, Cullen P, Wilson TME, Bayliss JD, Griffin BA, Caslake MD, Packard CJ, Sheperd J, Thakker R, Scott J. Familial combined hyperlipidemia linked to the apolipoprotein A-I/C-III/A-IV gene cluster on chromosome 11q23–q24. Nature. 1991;349:161–164.[Medline] [Order article via Infotrieve]
88. Wijsman EM, Motulsky AG, Guo SW, Yang M, Austin MA, Brunzell JD, Deeb S. Evidence against linkage of familial combined hyperlipidemia to the apoAI-CIII-AIV gene complex. Circulation. 1992;86(suppl I):I-420. Abstract.
89. Marcil M, Boucher B, Gagné E, Davignon J, Hayden M, Genest J Jr. Lack of association of the apolipoprotein A-I-CIII-A-IV gene XmnI and SstI polymorphisms and of the lipoprotein lipase gene mutations in familial combined hyperlipoproteinemia in French Canadian subjects. J Lipid Res. 1996;37:309–319.[Abstract]
90. Cortner JA, Coates PM, Bennet MJ, Cryer DR, Le N-A. Familial combined hyperlipidemia: use of stable isotopes to demonstrate overproduction of very low density apolipoprotein B by the liver. J Inherited Metab Dis. 1991;14:915–922.[Medline] [Order article via Infotrieve]
91.
Venkatesan S, Cullen P, Pacy P, Halliday D, Scott J.
Stable isotopes show a direct relation between VLDL apoB
overproduction and serum triglyceride levels and
indicate a metabolically and biochemically coherent basis
for familial combined hyperlipidemia.
Arterioscler Thromb. 1993;13:1110–1118.
92. Chait A, Albers JJ, Brunzell JD. Very low density lipoprotein overproduction in genetic forms of hypertriglyceridemia. Eur J Clin Invest. 1980;110:12–22.
93. Dallinga-Thie GM, Bu X-D, van Linde-Sibenius Trip M, Rotter JI, Lusis AJ, de Bruin TWA. Apolipoprotein A-I/C-III/A-IV gene cluster in familial combined hyperlipidemia: effects on LDL-cholesterol and apolipoproteins B and C-III. J Lipid Res. 1996;37:136–147.[Abstract]
94. Dallinga-Thie GM, van Linde-Sibenius Trip M, Rotter JI, Cantor RM, Bu X-D, Lusis AJ, de Bruin TWA. Complex genetic contribution of the apo AI-CIII-AIV gene cluster to familial combined hyperlipidemia. J Clin Invest. 1997;99:953–961.[Medline] [Order article via Infotrieve]
95. Ribalta J, La Ville AE, Vallvé JC, Humphries S, Turner PR, Masana L. A variation in the apolipoprotein C-III gene is associated with an increased number of circulating VLDL and IDL particles in familial combined hyperlipidemia. J Lipid Res. 1997;38:1061–1069.[Abstract]
96. Staels B, Vu-Dac N, Kosykh VA, Saladin R, Fruchart J-C, Dallongeville J, Auwerx J. Fibrates downregulate apolipoprotein C-III expression independent of induction of peroxisomal acyl coenzyme A oxidase. J Clin Invest. 1995;95:705–712.
97.
Hertz R, Bishara-Shieban J, Bar-Tana J. Mode of
action of peroxisome proliferators as hypolipidemic drugs. J
Biol Chem. 1995;270:13470–13475.
98. Auwerx J, Schoonjans K, Fruchart J-C, Staels B. Transcriptional control of triglyceride metabolism: fibrates and fatty acids change the expression of the LPL and apo C-III genes by activating the nuclear receptor PPAR. Atherosclerosis. 1996;124(suppl):S29–S37.
99.
Knott TJ, Robertson ME, Priestly LM, Wallis S, Scott
J. Characterization of mRNAs encoding the precursor for human
apolipoprotein CI. Nucleic Acids Res. 1984;12:3909–3915.
100.
Jackson RL, Sparrow JT, Baker HN, Morrisett J, Taunton
OD, Gotto AM Jr. The primary structure of apolipoprotein-serine.
J Biol Chem. 1974;249:5308–5313.
101.
Shulmann RS, Herbert PN, Wehrly K, Frederickson DS.
The complete amino acid sequence of C-I (apoLP-Ser), an apolipoprotein
from human very low density lipoproteins. J Biol Chem. 1975;250:182–190.
102. Rozek A, Buchko GW, Cushley RJ. Conformation of two peptides corresponding to human apolipoprotein C-I residues 7-24 and 35-53 in the presence of sodium dodecyl sulfate by CD and NMR spectroscopy. Biochemistry. 1995;34:7401–7408.[Medline] [Order article via Infotrieve]
103.
Curry MD, McConathy WJ, Fesmire JD, Alaupovic P.
Quantitative determination of apolipoproteins C-I and C-II in human
plasma by separate electroimmunoassays. Clin Chem. 1981;27:543–548.
104. Sharpe CR, Sidoli A, Shelley CS, Lucero MA, Shoulders CC, Baralle FE. Human apolipoproteins AI, AII, CII and CIII, cDNA sequences and mRNA abundance. Nucleic Acids Res. 1984;12:3917–3932.
105.
Jackson CL, Bruns GAP, Breslow JL. Isolation and
sequence of a human apolipoprotein CII cDNA clone and its use to
isolate and map to human chromosome 19 the gene for apolipoprotein CII.
Proc Natl Acad Sci U S A. 1984;81:2945–2949.
106.
Fojo SS, Law SW, Brewer HB Jr. Human apolipoprotein
C-II: complete nucleic acid sequence of preapolipoprotein C-II.
Proc Natl Acad Sci U S A. 1984;81:6354–6357.
107. Captano AL, Kinnunen PKJ, Breckenridge WC, Gotto AM Jr, Jackson RL, Little JA, Smith LC, Sparrow JT. Lipolysis of apoC-II deficient very low density lipoproteins: enhancement of lipoprotein lipase action by synthetic fragments of apoC-II. Biochem Biophys Res Commun. 1979;89:951–957.[Medline] [Order article via Infotrieve]
108.
Kinnunen PKJ, Jackson RL, Smith LC, Gotto AM Jr,
Sparrow JT. Activation of lipoprotein lipase by native and synthetic
fragments of human plasma apolipoprotein C-II. Proc Natl Acad Sci
U S A. 1977;74:4848–4851.
109. Cheng Q, Blackett P, Jackson KW, Conathy WJ, Wang C-S. C-terminal domain of apolipoprotein CII as both activator and competitive inhibitor of lipoprotein lipase. Biochem J. 1990;269:403–407.[Medline] [Order article via Infotrieve]
110. Herbert PN, Assmann G, Gotto AM Jr, Frederickson DS. Disorders of the lipoprotein and lipid metabolism. In: Stanbury JB, Wyngaarden JB, Frederickson DS, Goldstein JL, Brown MS, eds. The Metabolic Basis of Inherited Diseases. 5th ed. New-York, NY: McGraw-Hill; 1983:589–651.
111. Sparrow JT, Pownall HJ, Hsu F-J, Blumenthal LD, Culwell AR, Gotto AM. Lipid binding by fragments of apolipoprotein CIII-1 obtained by thrombin cleavage. Biochemistry. 1977;16:5427–5431.[Medline] [Order article via Infotrieve]
112. Trieu VN, McConathy WJ. APOC-III-ß-Galactosidase hybrid distinguishes between VLDL and LDL phospholipids. Biochem Biophys Res Commun. 1995;211:754–760.[Medline] [Order article via Infotrieve]
113.
Brown WB, Levy RI, Frederickson DS. Further
characterization of apolipoproteins from the human plasma very low
density lipoproteins. J Biol Chem. 1970;245:6588–6594.
114. Vaith P, Assmann G, Uhlenbruck G. Characterization of the oligosaccharide chain of apolipoprotein C-III from human plasma very low density lipoproteins. Biochim Biophys Acta. 1978;541:234–240.[Medline] [Order article via Infotrieve]
115. Ito Y, Breslow JL, Chait BT. Apolipoprotein C-III0 lacks carbohydrate residues: use of mass spectrometry to study apolipoprotein structure. J Lipid Res. 1989;30:1781–1787.[Abstract]
116. Nestel PJ, Fidge NH. Apoprotein C metabolism in man. Adv Lipid Res. 1982;19:55–83.[Medline] [Order article via Infotrieve]
117. Bilheimer DW, Eisenberg S, Levy RI. The metabolism of very low density lipoprotein proteins, I: preliminary in vitro and in vivo observations. Biochim Biophys Acta. 1972;260:212–221.[Medline] [Order article via Infotrieve]
118. Eisenberg S, Bilheimer DW, Levy RI. The metabolism of very low density lipoprotein proteins, II: studies on the transfer of apoproteins between plasma lipoproteins. Biochim Biophys Acta. 1972;280:94–104.[Medline] [Order article via Infotrieve]
119. McKeone BJ, Massey JB, Knapp RD, Pownall HJ. Apolipoprotein C-I, C-II, and C-III: kinetics of association with model membranes and intermembrane transfer. Biochemistry. 1988;27:4500–4505.[Medline] [Order article via Infotrieve]
120.
Gibson JC, Rubinstein A, Brown WV, Ginsberg HN, Greten
H, Norum R, Kayden H. ApoE-containing lipoproteins in low or high
density lipoprotein deficiency.
Arteriosclerosis. 1985;5:371–380.
121. Mahley RW, Innerarity TL, Rall SC Jr, Weisgraber KH. Plasma lipoproteins: apolipoprotein structure and function. J Lipid Res. 1984;25:1277–1294.[Abstract]
122. Rubinstein A, Gibson JC, Paterniti JR, Kakis G Jr, Little A, Ginsberg HN, Brown WV. Effect of heparin-induced lipolysis on the distribution of apolipoprotein E among lipoprotein subclasses. J Clin Invest. 1985;75:710–721.
123. Bukberg PR, Le N-A, Ginsberg HN, Gibson JC, Rubinstein A, Brown WV. Evidence for non-equilibrating pools of apolipoprotein C-III in plasma lipoproteins. J Lipid Res. 1985;26:1047–1057.[Abstract]
124. Tornoci L, Scheraldi CA, Li X, Ide H, Goldberg IJ, Le N-A. Abnormal activation of lipoprotein lipase by non-equilibrating apoC-II: further evidence for the presence of non-equilibrating pools of apolipoproteins C-II and C-III in plasma lipoproteins. J Lipid Res. 1993;34:1793–1803.[Abstract]
125.
Zhang L-H, Kotite L, Havel RJ. Identification,
characterization, cloning and expression of apolipoprotein C-IV, a
novel sialoglycoprotein of rabbit plasma lipoproteins.
J Biol Chem. 1996;271:1776–1783.
126.
Windler E, Chao Y, Havel RJ. Determinants of hepatic
uptake of triglyceride-rich lipoproteins and their remnants
in the rat. J Biol Chem. 1980;255:5475–5480.
127.
Windler E, Chao Y, Havel RJ. Regulation of the hepatic
uptake of triglyceride-rich lipoproteins in the rat.
J Biol Chem. 1980;255:8303–8307.
128.
Windler EE, Kovanen PT, Chao YS, Brown MS, Havel RJ,
Goldstein JL. The estradiol-stimulated lipoprotein receptor of rat
liver: a binding site that membrane mediates the uptake of rat
lipoproteins containing apoproteins B and E. J Biol
Chem. 1980;255:10464–10471.
129. Windler E, Havel RJ. Inhibitory effects of C apolipoproteins from rats and humans on the uptake of triglyceride-rich lipoproteins and their remnants by the perfused rat liver. J Lipid Res. 1985;26:556–565.[Abstract]
130. Shelburne F, Hanks J, Meyers W, Quarfordt S. Effect of apolipoproteins on hepatic uptake of triglyceride emulsions in the rat. J Clin Invest. 1980;65:652–658.
131.
Quarfordt SH, Michalopoulos G, Schirmer B. The effect
of human C apolipoproteins on the in vitro hepatic
metabolism of triglyceride emulsions in the
rat. J Biol Chem. 1982;257:14642–14647.
132. Kortz WJ, Schirmer BD, Mansbach CM II, Shelburne F, Toglia MR, Quarfordt SH. Hepatic uptake of chylomicrons and triglyceride emulsions in rats fed diets of differing fat content. J Lipid Res. 1984;25:799–804.[Abstract]
133. Oswald B, Quarfordt S. Effect of apoE on triglyceride emulsion interaction with hepatocytes and hepatoma G2 cells. J Lipid Res. 1987;28:798–809.[Abstract]
134.
Kowal RC, Herz J, Weisgraber KH, Mahley RW, Brown MS,
Goldstein JL. Opposing effects of apolipoprotein E and C on lipoprotein
binding to the low density lipoprotein receptor-related protein.
J Biol Chem. 1990;265:10771–10779.
135.
Weisgraber KH, Mahley RW, Kowall RC, Herz J, Goldstein
JL, Brown MS. Apolipoprotein C-I modulates the interaction of
apolipoprotein E with ß-migrating very low density lipoproteins
(ß-VLDL) and inhibits binding of ß-VLDL to low density lipoprotein
receptor-related protein. J Biol Chem. 1990;265:22453–22459.
136. Swaney JB, Weisgraber KH. Effect of apolipoprotein C-I peptides on the apolipoprotein E content and receptor-binding properties of ß-migrating very low density lipoproteins. J Lipid Res. 1994;35:134–142.[Abstract]
137.
Sehayek E, Eisenberg S. Mechanisms of inhibition by
apolipoprotein C of apolipoprotein E-dependent cellular
metabolism of human triglyceride-rich
lipoproteins through the low density lipoprotein receptor pathway.
J Biol Chem. 1991;266:18259–18267.
138.
Agnani G, Bard JM, Candelier L, Delattre S, Fruchart
JC, Clavey V. Interaction of LpB, LpB:E, LpB:C-III, and LpB:C-III:E
lipoproteins with the low density lipoprotein receptor of HeLa cells.
Arterioscler Thromb. 1991;11:1021–1029.
139.
Clavey V, Lestavel-Delattre S, Copin C, Bard JM,
Fruchart JC. Modulation of lipoprotein B binding to the LDL receptor by
exogenous lipids and apolipoproteins CI, CII, CIII and E.
Arterioscler Thromb Vasc Biol. 1995;15:963–971.
140. Jong MC, Dahlmans VEH, van Gorp PJJ, Willems van Dijk K, Koopmans S-J, Chan L, Hofker MH, Havekes LM. The binding of VLDL to the VLDL receptor is inhibited by an excess of apoC1. Circulation. 1996;94(suppl I):I-698. Abstract.
141.
Mann CJ, Troussard AA, Yen FT, Hannouche N, Najib J,
Fruchart J-C, Lotteau V, André P, Bihain BE.
Inhibitory effects of specific apolipoprotein C-III
isoforms on the binding of triglyceride-rich lipoproteins
to the lipolysis-stimulated receptor. J Biol Chem. 1997;272:31348–31354.
142. Havel RJ, Fielding CJ, Olivecrona T, Shore VG, Fielding PE, Egelrud T. Cofactor activity of protein components of human very low density lipoproteins in the hydrolysis of triglycerides by lipoprotein lipase from different sources. Biochemistry. 1973;12:1828–1833.[Medline] [Order article via Infotrieve]
143. LaRosa JC, Levy RI, Herbert P, Lux SE, Frederickson DS. A specific apoprotein activator for lipoprotein lipase. Biochem Biophys Res Commun. 1970;41:57–62.[Medline] [Order article via Infotrieve]
144.
Goldberg IJ, Scheraldi CA, Yacaoub LK, Saxena U,
Bisgaier CL. Lipoprotein apoC-II activation of lipoprotein lipase.
J Biol Chem. 1990;265:4266–4272.
145.
Olivecrona G, Beisiegel U. Lipid binding of
apolipoprotein CII is required for stimulation of lipoprotein lipase
activity against apolipoprotein CII-deficient chylomicrons.
Arterioscler Thromb Vasc Biol. 1997;17:1545–1549.
146. Ekman R, Nilsson-Ehle P. Effects of apolipoproteins on lipoprotein lipase activity of human adipose tissue. Clin Chim Acta. 1975;63:29–35.[Medline] [Order article via Infotrieve]
147. Brown V, Baginsky ML. Inhibition of lipoprotein lipase by an apolipoprotein of human very low density lipoprotein. Biochem Biophys Res Commun. 1972;46:375–382.[Medline] [Order article via Infotrieve]
148.
Krauss RM, Herbert PN, Levy RI, Frederickson DS.
Further observations on the activation and inhibition of lipoprotein
lipase by apolipoproteins. Circ Res. 1973;33:403–411.
149. Jackson RL, Tajima S, Yamamura T, Yokoyama S, Yamamoto A. Comparison of apolipoprotein C-II-deficient triacylglycerol-rich lipoproteins and trioleoylglycerol/phosphatidylcholine-stabilized particles as substrates for lipoprotein lipase. Biochim Biophys Acta. 1986;875:211–219.[Medline] [Order article via Infotrieve]
150. Wang C, McConathy WJ, Kloer HJ, Alaupovic P. Modulation of lipoprotein lipase activity by apolipoproteins: effect of apolipoprotein C-III. J Clin Invest.. 1985;75:384–390.
151. McConathy WJ, Gesquiere JC, Bass H, Tartar A, Fruchart JC. Inhibition of lipoprotein lipase activity by synthetic peptides of apolipoprotein C-III. J Lipid Res. 1992;33:995–1003.[Abstract]
152. Kinnunen PKJ, Ehnholm C. Effect of serum and C apoproteins from very low density lipoproteins on human postheparin plasma hepatic lipase. Fed Eur Biochem Soc Lett. 1976;65:354–357.
153. Landis BA, Rotolo FS, Meyers WC, Clark AB, Quarfordt SH. Influence of apolipoprotein E on soluble and heparin immobilized hepatic lipase. Am J Physiol. 1987;252(Gastrointest: Liver Physiol 15):G805–G810.
154. Soutar AK, Garner CW, Baker HN, Sparrow JT, Jackson RL, Gotto AM Jr, Smith LC. Effect of the human plasma apolipoproteins and phosphatidylcholine acyl donor on the activity of lecithin:cholesterol acyltransferase. Biochemistry. 1975;14:3057–3064.[Medline] [Order article via Infotrieve]
155. Soutar AK, Sigler GF, Smith LC, Gotto AM Jr, Sparrow JT. Lecithin:cholesterol acyltransferase activation and lipid binding by synthetic fragments of apolipoprotein C-I. Scand J Clin Lab Invest. 1978;38(suppl 150):53–58.
156. Steyrer E, Kostner GM. Activation of lecithin-cholesterol acyltransferase by apolipoprotein E: comparison of proteoliposomes containing apolipoprotein D, A-I or C-I. Biochim Biophys Acta. 1988;958:484–491.[Medline] [Order article via Infotrieve]
157.
Nishida HI, Nakanishi T, Yen EA, Arai H, Yen FT,
Nishada T. Nature of the enhancement of
lecithin-cholesterol acyltransferase reaction by various
apolipoproteins. J Biol Chem. 1986;261:12028–12035.
158.
Subbaiah PV, Albers JJ, Chen CH, Bagdade JD. Low
density lipoprotein-activated lysolecithin
acylation by human plasma lecithin-cholesterol
acyltransferase. J Biol Chem. 1980;255:9275–9280.
159. Liu M, Subbaiah PV. Activation of plasma lysolecithin acyltransferase reaction by apolipoproteins A-I, C-I and E. Biochim Biophys Acta. 1993;1168:144–152.[Medline] [Order article via Infotrieve]
160. Kushwaha RS, Hasan SQ, McGill HC Jr, Getz GS, Dunham RG, Kanda P. Characterization of cholesteryl ester transfer protein inhibitor from plasma of baboons (Papio sp). J Lipid Res. 1993;34:1288–1297.
161. Sparks DL, Pritchard PH. Transfer of cholesteryl ester into high density lipoprotein by cholesteryl ester transfer protein: effect of HDL lipid and apolipoprotein content. J Lipid Res. 1989;30:1491–1498.[Abstract]
162.
Simonet WS, Bucay N, Pitas RE, Lauer SJ, Taylor JM.
Multiple tissue-specific elements control the apolipoprotein E/C-I gene
locus in transgenic mice. J Biol Chem. 1991;266:8651–8654.
163.
Jong MC, Dahlmans VEH, van Gorp PJJ, Breuer ML, Mol
MJTM, van der Zee A, Frants RR, Hofker MH, Havekes LM. Both lipolysis
and hepatic uptake of VLDL are impaired in transgenic mice coexpressing
human apolipoprotein E*3Leiden and human apolipoprotein C1.
Arterioscler Thromb Vasc Biol. 1996;16:934–940.
164. Shachter NS, Ebara T, Ramakrishnan R, Steiner G, Breslow JL, Ginsberg HN, Smit JD. Combined hyperlipidemia in transgenic mice overexpressing human apolipoprotein C1. J Clin Invest. 1996;98:846–855.[Medline] [Order article via Infotrieve]
165. Jong MC, Dahlmans VEH, van Gorp PJJ, Willems van Dijk K, Breuer ML, Hofker MH, Havekes LM. In the absence of the low density lipoprotein receptor, human apolipoprotein C1 overexpression in transgenic mice inhibits the hepatic uptake of very low density lipoproteins via a receptor-associated protein-sensitive pathway. J Clin Invest. 1996;98:2259–2267.[Medline] [Order article via Infotrieve]
166.
Vaisman BL, Klein H-G, Rouis M, Bérard AM, Kindt
MR, Talley GD, Meyn SM, Hoyt RF, Marcovina SM, Albers JJ, Hoeg JM,
Brewer HB Jr, Santamarina-Fojo S. Overexpression of human
lecithin:cholesterol acyltransferase leads to
hyperalphalipoproteinemia in transgenic mice. J Biol
Chem. 1995;270:12269–12275.
167. Mehlum A, Staels B, Duverger N, Tailleux A, Castro G, Fievet C, Luc G, Fruchart J-C, Olivecrona G, Skretting G, Auwerx J, Pritz H. Tissue-specific expression of the human gene for lecithin:cholesterol acyl transferase alters blood lipids, lipoproteins and lipases towards a less atherogenic profile. Eur J Biochem. 1995;230:567–575.[Medline] [Order article via Infotrieve]
168. Francone OL, Gong EL, Ng DS, Fielding CJ, Rubin EM. Expression of human lecithin-cholesterol acyltransferase in transgenic mice. J Clin Invest. 1995;96:1440–1448.
169. Jong MC, Gijbels MJJ, Dahlmans VEH, van Gorp PJJ, Koopmans S-J, Ponec M, Hofker MH, Havekes LM. Hyperlipidemia and cutaneous abnormalities in transgenic mice overexpressing human apolipoprotein C1. J Clin Invest. 1998;101:145–152.[Medline] [Order article via Infotrieve]
170. van Ree JH, Hofker MH, van den Broek WJAA, van Deursen JMA, van der Boom H, Frants RR, Wieringa B, Havekes LM. Increased response to cholesterol feeding in apolipoprotein C1-deficient mice. Biochem J. 1995;305:905–911.
171. Jong MC, van Ree JH, Dahlmans VEH, Frants RR, Hofker MH, Havekes LM. Reduced very-low-density lipoprotein fractional catabolic rate in apolipoprotein C1-deficient mice. Biochem J. 1997;321:445–450.
172. Shachter NS, Hayek T, Leff T, Smith JD, Rosenberg DW, Walsh A, Ramakrishnan R, Goldberg IJ, Ginsberg HN, Breslow JL. Overexpression of apolipoprotein C-II causes hypertriglyceridemia in transgenic mice. J Clin Invest. 1994;93:1683–1690.
173.
Ito Y, Azrolan N, O'Connell A, Walsh A, Breslow JL.
Hypertriglyceridemia as a result of human
apo CIII gene expression in transgenic mice. Science. 1990;249:790–793.
174.
de Silva HV, Lauer SJ, Wang J, Simonet WS, Weisgraber
KH, Mahley RW, Taylor JM. Overexpression of human apolipoprotein C-III
in transgenic mice results in an accumulation of apolipoprotein B48
remnants that is corrected by excess apolipoprotein E. J
Biol Chem. 1994;269:2324–2335.
175. Aalto-Setälä K, Weinstock PH, Bisgaier CL, Wu L, Smith JD, Breslow JL. Further characterization of the metabolic properties of triglyceride-rich lipoproteins from human and mouse apoC-III transgenic mice. J Lipid Res. 1996;37:1802–1811.[Abstract]
176. Aalto-Setälä K, Fisher EA, Chen X, Chajek-Shaul T, Hayek T, Zechner R, Walsh A, Ramakrishnan R, Ginsberg HN, Breslow JL. Mechanism of hypertriglyceridemia in human apolipoprotein (apo) CIII transgenic mice: diminished very low density lipoprotein fractional catabolic rate associated with increased apoCIII and reduced apoE on the particles. J Clin Invest. 1992;90:1889–1900.
177. Jong MC, Dahlmans VEH, Hofker MH, Havekes LM. Nascent very low density lipoprotein triglyceride hydrolysis by lipoprotein lipase is inhibited by apolipoprotein E in a dose-dependent manner. Biochem J. 1997;328:745–750.
178. Ebara T, Ramakrishnan R, Steiner G, Shachter NS. Chylomicronemia due to apolipoprotein CIII overexpression in apolipoprotein E-null mice: apolipoprotein CIII-induced hypertriglyceridemia is not mediated by effects on apolipoprotein E. J Clin Invest. 1997;99:2672–2681.[Medline] [Order article via Infotrieve]
179.
Maeda N, Li H, Lee D, Oliver P, Quarfordt SH, Osada J.
Targeted disruption of the apolipoprotein C-III gene in mice results in
hypotriglyceridemia and protection from postprandial
hypertriglyceridemia. J Biol
Chem. 1994;269:23610–23616.
180. Allan CM, Taylor JM. Expression of a novel human apolipoprotein (apoC-IV) causes hypertriglyceridemia in transgenic mice. J Lipid Res. 1996;37:1510–1518.[Abstract]
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 C. S. Gangabadage, J. Zdunek, M. Tessari, S. Nilsson, G. Olivecrona, and S. S. Wijmenga Structure and Dynamics of Human Apolipoprotein CIII J. Biol. Chem., June 20, 2008; 283(25): 17416 - 17427. [Abstract] [Full Text] [PDF]
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K. Abildayeva, J. F. P. Berbee, A. Blokland, P. J. Jansen, F. J. Hoek, O. Meijer, D. Lutjohann, T. Gautier, T. Pillot, J. De Vente, et al. Human apolipoprotein C-I expression in mice impairs learning and memory functions J. Lipid Res., April 1, 2008; 49(4): 856 - 869. [Abstract] [Full Text] [PDF]
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 |
|
 M. Westerterp, J. F.P. Berbee, N. M.M. Pires, G. J.D. van Mierlo, R. Kleemann, J. A. Romijn, L. M. Havekes, and P. C.N. Rensen Apolipoprotein C-I Is Crucially Involved in Lipopolysaccharide-Induced Atherosclerosis Development in Apolipoprotein E Knockout Mice Circulation, November 6, 2007; 116(19): 2173 - 2181. [Abstract] [Full Text] [PDF]
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M. Dreux, B. Boson, S. Ricard-Blum, J. Molle, D. Lavillette, B. Bartosch, E.-I. Pecheur, and F.-L. Cosset The Exchangeable Apolipoprotein ApoC-I Promotes Membrane Fusion of Hepatitis C Virus J. Biol. Chem., November 2, 2007; 282(44): 32357 - 32369. [Abstract] [Full Text] [PDF]
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L. Lichtenstein, J. F.P. Berbee, S. J. van Dijk, K. W. van Dijk, A. Bensadoun, I. P. Kema, P. J. Voshol, M. Muller, P. C.N. Rensen, and S. Kersten Angptl4 Upregulates Cholesterol Synthesis in Liver via Inhibition of LPL- and HL-Dependent Hepatic Cholesterol Uptake Arterioscler. Thromb. Vasc. Biol., November 1, 2007; 27(11): 2420 - 2427. [Abstract] [Full Text] [PDF]
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 D. S Kelley, D. Siegel, M. Vemuri, and B. E Mackey Docosahexaenoic acid supplementation improves fasting and postprandial lipid profiles in hypertriglyceridemic men Am. J. Clinical Nutrition, August 1, 2007; 86(2): 324 - 333. [Abstract] [Full Text] [PDF]
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S. Zadelaar, R. Kleemann, L. Verschuren, J. de Vries-Van der Weij, J. van der Hoorn, H. M. Princen, and T. Kooistra Mouse Models for Atherosclerosis and Pharmaceutical Modifiers Arterioscler. Thromb. Vasc. Biol., August 1, 2007; 27(8): 1706 - 1721. [Abstract] [Full Text] [PDF]
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A. Kontush, P. Therond, A. Zerrad, M. Couturier, A. Negre-Salvayre, J. A. de Souza, S. Chantepie, and M. J. Chapman Preferential Sphingosine-1-Phosphate Enrichment and Sphingomyelin Depletion Are Key Features of Small Dense HDL3 Particles: Relevance to Antiapoptotic and Antioxidative Activities Arterioscler. Thromb. Vasc. Biol., August 1, 2007; 27(8): 1843 - 1849. [Abstract] [Full Text] [PDF]
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M. Westerterp, J. F. P. Berbee, D. J. M. Delsing, M. C. Jong, M. J. J. Gijbels, V. E. H. Dahlmans, E. H. Offerman, J. A. Romijn, L. M. Havekes, and P. C. N. Rensen Apolipoprotein C-I binds free fatty acids and reduces their intracellular esterification J. Lipid Res., June 1, 2007; 48(6): 1353 - 1361. [Abstract] [Full Text] [PDF]
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V. Petit, L. Arnould, P. Martin, M.-C. Monnot, T. Pineau, P. Besnard, and I. Niot Chronic high-fat diet affects intestinal fat absorption and postprandial triglyceride levels in the mouse J. Lipid Res., February 1, 2007; 48(2): 278 - 287. [Abstract] [Full Text] [PDF]
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 A. Kharitonenkov, V. J. Wroblewski, A. Koester, Y.-F. Chen, C. K. Clutinger, X. T. Tigno, B. C. Hansen, A. B. Shanafelt, and G. J. Etgen The Metabolic State of Diabetic Monkeys Is Regulated by Fibroblast Growth Factor-21 Endocrinology, February 1, 2007; 148(2): 774 - 781. [Abstract] [Full Text] [PDF]
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 H. Kondo, Y. Minegishi, Y. Komine, T. Mori, I. Matsumoto, K. Abe, I. Tokimitsu, T. Hase, and T. Murase Differential regulation of intestinal lipid metabolism-related genes in obesity-resistant A/J vs. obesity-prone C57BL/6J mice Am J Physiol Endocrinol Metab, November 1, 2006; 291(5): E1092 - E1099. [Abstract] [Full Text] [PDF]
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 |
|
 C.-M. Li, M. E. Clark, M. F. Chimento, and C. A. Curcio Apolipoprotein localization in isolated drusen and retinal apolipoprotein gene expression. Invest. Ophthalmol. Vis. Sci., July 1, 2006; 47(7): 3119 - 3128. [Abstract] [Full Text] [PDF]
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J.-F. Mauger, P. Couture, N. Bergeron, and B. Lamarche Apolipoprotein C-III isoforms: kinetics and relative implication in lipid metabolism J. Lipid Res., June 1, 2006; 47(6): 1212 - 1218. [Abstract] [Full Text] [PDF]
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A. Kawakami, M. Aikawa, P. Libby, P. Alcaide, F. W. Luscinskas, and F. M. Sacks Apolipoprotein CIII in Apolipoprotein B Lipoproteins Enhances the Adhesion of Human Monocytic Cells to Endothelial Cells Circulation, February 7, 2006; 113(5): 691 - 700. [Abstract] [Full Text] [PDF]
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K. G. Jackson, V. Maitin, D. S. Leake, P. Yaqoob, and C. M. Williams Saturated fat-induced changes in Sf 60-400 particle composition reduces uptake of LDL by HepG2 cells J. Lipid Res., February 1, 2006; 47(2): 393 - 403. [Abstract] [Full Text] [PDF]
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 A. Hamsten, A. Silveira, S. Boquist, R. Tang, M. G. Bond, U. de Faire, and J. Bjorkegren The apolipoprotein CI content of triglyceride-rich lipoproteins independently predicts early atherosclerosis in healthy middle-aged men J. Am. Coll. Cardiol., April 5, 2005; 45(7): 1013 - 1017. [Abstract] [Full Text] [PDF]
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 M. Patalay, I. E. Lofgren, H. C. Freake, S. I. Koo, and M. L. Fernandez The Lowering of Plasma Lipids following a Weight Reduction Program Is Related to Increased Expression of the LDL Receptor and Lipoprotein Lipase J. Nutr., April 1, 2005; 135(4): 735 - 739. [Abstract] [Full Text] [PDF]
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K. Conde-Knape, K. Okada, R. Ramakrishnan, and N. S. Shachter Overexpression of apoC-III produces lesser hypertriglyceridemia in apoB-48-only gene-targeted mice than in apoB-100-only mice J. Lipid Res., December 1, 2004; 45(12): 2235 - 2244. [Abstract] [Full Text] [PDF]
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H. Wassef, L. Bernier, J. Davignon, and J. S. Cohn Synthesis and Secretion of ApoC-I and ApoE during Maturation of Human SW872 Liposarcoma Cells J. Nutr., November 1, 2004; 134(11): 2935 - 2941. [Abstract] [Full Text] [PDF]
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 J. S. Cohn, B. W. Patterson, K. D. Uffelman, J. Davignon, and G. Steiner Rate of Production of Plasma and Very-Low-Density Lipoprotein (VLDL) Apolipoprotein C-III Is Strongly Related to the Concentration and Level of Production of VLDL Triglyceride in Male Subjects with Different Body Weights and Levels of Insulin Sensitivity J. Clin. Endocrinol. Metab., August 1, 2004; 89(8): 3949 - 3955. [Abstract] [Full Text] [PDF]
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J. S. Cohn, C. Rodriguez, H. Jacques, M. Tremblay, and J. Davignon Storage of human plasma samples leads to alterations in the lipoprotein distribution of apoC-III and apoE J. Lipid Res., August 1, 2004; 45(8): 1572 - 1579. [Abstract] [Full Text] [PDF]
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I. Lofgren, K. Herron, T. Zern, K. West, M. Patalay, N. S. Shachter, S. I. Koo, and M. L. Fernandez Waist Circumference Is a Better Predictor than Body Mass Index of Coronary Heart Disease Risk in Overweight Premenopausal Women J. Nutr., May 1, 2004; 134(5): 1071 - 1076. [Abstract] [Full Text] [PDF]
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 C.C. Shoulders, E.L. Jones, and R.P. Naoumova Genetics of familial combined hyperlipidemia and risk of coronary heart disease Hum. Mol. Genet., April 1, 2004; 13(90001): R149 - 160. [Abstract] [Full Text] [PDF]
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|
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B. F. Asztalos, K. V. Horvath, K. Kajinami, C. Nartsupha, C. E. Cox, M. Batista, E. J. Schaefer, A. Inazu, and H. Mabuchi Apolipoprotein composition of HDL in cholesteryl ester transfer protein deficiency J. Lipid Res., March 1, 2004; 45(3): 448 - 455. [Abstract] [Full Text] [PDF]
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D. S. Ng, C. Xie, G. F. Maguire, X. Zhu, F. Ugwu, E. Lam, and P. W. Connelly Hypertriglyceridemia in Lecithin-cholesterol Acyltransferase-deficient Mice Is Associated with Hepatic Overproduction of Triglycerides, Increased Lipogenesis, and Improved Glucose Tolerance J. Biol. Chem., February 27, 2004; 279(9): 7636 - 7642. [Abstract] [Full Text] [PDF]
|
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A. Kolmakova, P. Kwiterovich, D. Virgil, P. Alaupovic, C. Knight-Gibson, S. F. Martin, and S. Chatterjee Apolipoprotein C-I Induces Apoptosis in Human Aortic Smooth Muscle Cells via Recruiting Neutral Sphingomyelinase Arterioscler. Thromb. Vasc. Biol., February 1, 2004; 24(2): 264 - 269. [Abstract] [Full Text]
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O. Olivieri, A. Bassi, C. Stranieri, E. Trabetti, N. Martinelli, F. Pizzolo, D. Girelli, S. Friso, P. F. Pignatti, and R. Corrocher Apolipoprotein C-III, metabolic syndrome, and risk of coronary artery disease J. Lipid Res., December 1, 2003; 44(12): 2374 - 2381. [Abstract] [Full Text] [PDF]
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S. Vega-Lopez, H. C. Freake, and M. L. Fernandez Sex and Hormonal Status Modulate the Effects of Psyllium on Plasma Lipids and Monocyte Gene Expression in Humans J. Nutr., January 1, 2003; 133(1): 67 - 70. [Abstract] [Full Text] [PDF]
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E. Raspe, H. Duez, A. Mansen, C. Fontaine, C. Fievet, J.-C. Fruchart, B. Vennstrom, and B. Staels Identification of Rev-erb{alpha} as a physiological repressor of apoC-III gene transcription J. Lipid Res., December 1, 2002; 43(12): 2172 - 2179. [Abstract] [Full Text] [PDF]
|
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H. N. Ginsberg New Perspectives on Atherogenesis: Role of Abnormal Triglyceride-Rich Lipoprotein Metabolism Circulation, October 15, 2002; 106(16): 2137 - 2142. [Full Text] [PDF]
|
|
|
|
|
|
J. S. Cohn, M. Tremblay, R. Batal, H. Jacques, L. Veilleux, C. Rodriguez, L. Bernier, O. Mamer, and J. Davignon Plasma kinetics of VLDL and HDL apoC-I in normolipidemic and hypertriglyceridemic subjects J. Lipid Res., October 1, 2002; 43(10): 1680 - 1687. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
O. Olivieri, C. Stranieri, A. Bassi, B. Zaia, D. Girelli, F. Pizzolo, E. Trabetti, S. Cheng, M. A. Grow, P. F. Pignatti, et al. ApoC-III gene polymorphisms and risk of coronary artery disease J. Lipid Res., September 1, 2002; 43(9): 1450 - 1457. [Abstract] [Full Text] [PDF]
|
|
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|
|
|
T. Gautier, D. Masson, M. C. Jong, L. Duverneuil, N. Le Guern, V. Deckert, J.-P. P. de Barros, L. Dumont, A. Bataille, Z. Zak, et al. Apolipoprotein CI Deficiency Markedly Augments Plasma Lipoprotein Changes Mediated by Human Cholesteryl Ester Transfer Protein (CETP) in CETP Transgenic/ApoCI-knocked Out Mice J. Biol. Chem., August 23, 2002; 277(35): 31354 - 31363. [Abstract] [Full Text] [PDF]
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 |
|
 L. Lins, C. Flore, L. Chapelle, P.J. Talmud, A. Thomas, and R. Brasseur Lipid-interacting properties of the N-terminal domain of human apolipoprotein C-III Protein Eng. Des. Sel., June 1, 2002; 15(6): 513 - 520. [Abstract] [Full Text] [PDF]
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|
 C. C. Pritchard, L. Hsu, J. Delrow, and P. S. Nelson Project normal: Defining normal variance in mouse gene expression PNAS, November 6, 2001; 98(23): 13266 - 13271. [Abstract] [Full Text] [PDF]
|
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 |
|
 H. R. Kast, C. M. Nguyen, C. J. Sinal, S. A. Jones, B. A. Laffitte, K. Reue, F. J. Gonzalez, T. M. Willson, and P. A. Edwards Farnesoid X-Activated Receptor Induces Apolipoprotein C-II Transcription: a Molecular Mechanism Linking Plasma Triglyceride Levels to Bile Acids Mol. Endocrinol., October 1, 2001; 15(10): 1720 - 1728. [Abstract] [Full Text] [PDF]
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T. Hirano, T. Takahashi, S. Saito, H. Tajima, T. Ebara, and M. Adachi Apoprotein C-III deficiency markedly stimulates triglyceride secretion in vivo: comparison with apoprotein E Am J Physiol Endocrinol Metab, October 1, 2001; 281(4): E665 - E669. [Abstract] [Full Text] [PDF]
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W. R. Oliver Jr., J. L. Shenk, M. R. Snaith, C. S. Russell, K. D. Plunket, N. L. Bodkin, M. C. Lewis, D. A. Winegar, M. L. Sznaidman, M. H. Lambert, et al. A selective peroxisome proliferator-activated receptor delta agonist promotes reverse cholesterol transport PNAS, April 12, 2001; (2001) 91021198. [Abstract] [Full Text]
|
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|
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M. Dahim, W. E. Momsen, M. M. Momsen, and H. L. Brockman Specificity of the lipid-binding domain of apoC-II for the substrates and products of lipolysis J. Lipid Res., April 1, 2001; 42(4): 553 - 562. [Abstract] [Full Text]
|
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S. Barlage, D. Fröhlich, A. Böttcher, M. Jauhiainen, H. P. Müller, F. Noetzel, G. Rothe, C. Schütt, R. P. Linke, K. J. Lackner, et al. ApoE-containing high density lipoproteins and phospholipid transfer protein activity increase in patients with a systemic inflammatory response J. Lipid Res., February 1, 2001; 42(2): 281 - 290. [Abstract] [Full Text]
|
|
|
|
 |
|
 P. J. A. Davies, S. A. Berry, G. L. Shipley, R. H. Eckel, N. Hennuyer, D. L. Crombie, K. M. Ogilvie, J. Peinado-Onsurbe, C. Fievet, M. D. Leibowitz, et al. Metabolic Effects of Rexinoids: Tissue-Specific Regulation of Lipoprotein Lipase Activity Mol. Pharmacol., February 1, 2001; 59(2): 170 - 176. [Abstract] [Full Text]
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D. M. Waterworth, J. A. Hubacek, J. Pitha, J. Kovar, R. Poledne, S. E. Humphries, and P. J. Talmud Plasma levels of remnant particles are determined in part by variation in the APOC3 gene insulin response element and the APOCI;-APOE cluster J. Lipid Res., July 1, 2000; 41(7): 1103 - 1109. [Abstract] [Full Text]
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E. Raspe, H. Duez, P. Gervois, C. Fievet, J.-C. Fruchart, S. Besnard, J. Mariani, A. Tedgui, and B. Staels Transcriptional Regulation of Apolipoprotein C-III Gene Expression by the Orphan Nuclear Receptor RORalpha J. Biol. Chem., January 19, 2001; 276(4): 2865 - 2871. [Abstract] [Full Text] [PDF]
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P. Medstrand, J.-R. Landry, and D. L. Mager Long Terminal Repeats Are Used as Alternative Promoters for the Endothelin B Receptor and Apolipoprotein C-I Genes in Humans J. Biol. Chem., January 12, 2001; 276(3): 1896 - 1903. [Abstract] [Full Text] [PDF]
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W. R. Oliver Jr., J. L. Shenk, M. R. Snaith, C. S. Russell, K. D. Plunket, N. L. Bodkin, M. C. Lewis, D. A. Winegar, M. L. Sznaidman, M. H. Lambert, et al. A selective peroxisome proliferator-activated receptor delta agonist promotes reverse cholesterol transport PNAS, April 24, 2001; 98(9): 5306 - 5311. [Abstract] [Full Text] [PDF]
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