© 1997 American Heart Association, Inc.
Articles |
Adipose Tissue Lipoprotein Lipase and Hormone-Sensitive Lipase
Contrasting Findings in Familial Combined Hyperlipidemia and Insulin Resistance Syndrome
From the Lipid Laboratory (S.R., P.A.) and Metabolism Unit (B.A., M.E.), Center for Metabolism and Endocrinology, Department of Medicine and Research Center, Karolinska Institute at Huddinge University Hospital, Huddinge, Sweden, the Institute of Geriatrics, Uppsala University, Uppsala, Sweden (H.L.), the Department of Cell and Molecular Biology (C.H.), Lund University, Lund, Sweden, and INSERM UnitÈ 317 (D.L), Institut Louis Bugnard, FacultÈ de MÈdecine, Hôpital Rangueil, Toulouse, France.
Correspondence to Peter Arner, MD, Department of Medicine, Huddinge University Hospital, S-141 86, Huddinge, Sweden.
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Abstract |
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Abstract The metabolism of free fatty acids (FFA) is altered in two common atherosclerosis-promoting disorders: familial combined hyperlipidemia (FCHL) and insulin resistance syndrome (IRS). It has been suggested that these two conditions may have a common etiology. The enzymes lipoprotein lipase (LPL) and hormone-sensitive lipase (HSL) are rate-limiting steps for the turnover of fatty acids in adipose tissue, because they hydrolyze extracellular triglycerides in lipoproteins (LPL) and intracellular triglycerides in adipocytes (HSL). The present study was undertaken to simultaneously determine the activities of LPL and HSL in subcutaneous adipose tissue from male patients with FCHL and IRS. LPL and HSL activity was investigated in 10 nonobese FCHL patients and compared with 10 matched healthy nonobese subjects, and in 8 essentially normolipidemic IRS patients (who did not have overt diabetes mellitus) and compared with 9 nonobese matched control subjects. LPL activity was 43% lower in patients with IRS (P<.0005), as compared with control subjects, but HSL activity was not significantly different in the two groups. On the other hand, HSL activity was decreased by 45% in FCHL patients (P<.01), as compared with control subjects, but LPL activity was not significantly different in FCHL patients and the control group. In conclusion, triglyceride metabolism in adipose tissue is altered in both FCHL and IRS. However, the abnormalities observed involve impaired function of LPL in IRS and impaired function of HSL in FCHL, suggesting separate etiologies for the altered lipolysis in these conditions, at least in male subjects.
Key Words: lipolysis • free fatty acids • lipoproteins • fat cells • atherosclerosis • familial combined hyperlipidemia • insulin resistance syndrome
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Introduction |
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FFA are key intermediates in lipid metabolism and are stored as triglycerides in adipose tissue (for review, see references 1 and 2). Although circulating FFA can be directly taken up and released by adipose tissue, the major source of adipose fatty acids is plasma TG. These lipids are transported to adipose tissue in chylomicrons and VLDL. Through the action of LPL, which is synthesized within the fat cell and then transported to the endothelial stroma of adipose tissue, where TG is hydrolyzed to FFA and glycerol. FFA are subsequently taken up by fat cells and esterified to new TG. When needed, these TG are hydrolyzed inside the fat cells through the action of HSL, which results in the formation of FFA and glycerol. FFA are then released from fat cells and transported, bound to albumin, in the circulation for utilization by other tissues. Thus, adipose tissue turnover of fatty acids is to a large extent regulated by extracellular and intracellular lipolysis of TG through the action of different lipases.1 2
FCHL is a common inherited disorder of lipid metabolism and is strongly linked to premature coronary heart disease.3 4 5 6 With no specific biological markers for this disorder, the diagnosis is generally based on family studies: if multiple lipoprotein phenotypes (IIA, IIB, and IV) can be demonstrated among the relatives of a family, and also within a single individual over time, FCHL is considered to be present.6 Genetic linkage of FCHL to the LPL gene7 and to the apolipoprotein (apo) AI-CIII-AIV gene cluster8 9 has been suggested, but no definite metabolic defect has yet been defined. Overproduction of VLDL apo B is a frequent finding,10 11 12 13 and delayed clearance of chylomicron remnants, together with prolonged postprandial elevations of plasma FFA, has called attention to the possible importance of disturbances of TG and FFA metabolism in the pathogenesis of FCHL.14 15 We recently reported marked resistance to the lipolytic effect of catecholamines in subcutaneous fat cells from patients with FCHL, possibly related to reduced HSL activity.16
IRS is another common disorder associated with an increased risk of atherosclerotic cardiovascular disease.2 17 18 19 This disease is characterized by truncal obesity, insulin resistance and hyperinsulinemia that is often accompanied by hyperglycemia or glucose intolerance, dyslipidemia, abnormal blood coagulation and hypertension in various combinations. As with FCHL, the mechanism for IRS is not known. However, IRS has also been linked to altered metabolism of FFA1 17 18 19 20 and to impaired reactivity of adipose lipolysis in response to catecholamine stimulation.21 Whether the lipolysis defect is related to HSL has not been investigated.
The obvious similarities between FCHL and IRS, and the frequent interaction of insulin resistance and glucose intolerance in FCHL,3 6 22 23 24 have led to the suggestion that the two conditions may share a common mechanism that results in disturbed FFA and TG metabolism.15 23 24 To study this question, we analyzed the capacity of adipose tissue to store and release FFA in patients with FCHL and IRS. We measured the enzyme activities of LPL and HSL in subcutaneous adipose samples obtained in the overnight fasting state from male patients with (non-obese) FCHL or IRS (with no overt signs of diabetes) and compared the values with those in samples obtained from matched control subjects. The results showed distinctly contrasting enzyme patterns between the two diseases, with low HSL activity and normal LPL activity in FCHL and reduced LPL activity and normal HSL activity in IRS.
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Methods |
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Subjects
Two groups of patients with matched control subjects were studied (Table 1
). The first group was
recruited among 72-year-old men, identified as
described.21 Eight subjects with IRS were selected for the
study. The following inclusion criteria were used: BMI >27
kg/m2, waist-hip ratio >0.95, and insulin
resistance as determined with an euglycemic
hyperinsulinemic clamp, with an M/I value (insulin
sensitivity index; mg/kg/min/mU/L) of <4.0, indicating a
low degree of glucose uptake in response to insulin. None had received
any form of antidiabetic therapy before the study. All were drug-free
with the exception of the antihypertensive treatment. All had normal
fasting blood glucose levels (range: 5.0 to 6.0 mmol/L).
With regard to oral glucose tolerance, serum glucose values were in
three categories based on age-matched outcome of the 2-hour value:
normal, values (<8.9 mmol/L) in 4 subjects; diabetic,
values (>10.5 mmol/L) in 2 subjects; and glucose
intolerance, (intermediate values) in 2 subjects. Diabetic values in
the 2 subjects were 10.9 and 12.3 mmol/L, respectively. Six
of the 8 subjects had hypertension (3 were treated with a
calcium-channel blocker and 3 were untreated), and 3 of the 8 subjects
had untreated hypertriglyceridemia (fasting
TG values: 2.4, 2.6, and 3.0 mmol/L, respectively). Nine
age-matched, nonobese, drug-free, healthy subjects with normal insulin
sensitivity and normal tolerance to an oral glucose load served as
control subjects. The M/I value in these subjects was >5.5 and the BMI
<24 kg/m2.
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The second group of subjects included 10 nonobese male patients with FCHL who had been followed as outpatients for several years.16 The patients were drug-free except for 5 who were receiving lipid-lowering therapy with fibrates. The patients were in stable metabolic condition, and secondary hyperlipidemia had been excluded. The diagnosis of FCHL was based on the finding of hyperlipidemia in first-degree relatives, among which at least 1 relative had a lipoprotein phenotype that differed from that of the proband.6 25 In addition, variable lipoprotein phenotypes had generally been observed during clinical follow-up of these patients. Individual clinical characteristics and pedigrees of these patients have been published previously.16 Ten healthy, nonobese, drug-free normolipidemic volunteers, matched for BMI and age, served as control subjects. Data from these subjects have not been published previously.
All subjects were examined at 8 am after an overnight fast. First, venous samples for analysis of hormones, metabolites, and lipid profiles were collected. The analyses were performed by the hospital's routine chemistry laboratory, except for insulin, which was determined by a radioimmunoassay kit (Pharmacia). Blood pressure was measured with subjects in the supine position. Thereafter, a subcutaneous fat biopsy was surgically obtained from the paraumbilical region. The tissue was placed in saline solution, and immediately transported to the laboratory. Determination of fat cell size was done on the same day. Remaining pieces of adipose tissue were frozen in liquid nitrogen for analysis of HSL and LPL activity, which was performed on 1 occasion within 6 months.
All subjects had given informed consent before entering the study, which had been approved by the ethics committees of the Karolinska Institute and Uppsala University.
Determination of Fat Cell Size
Fat cell size was determined as described.21 In
brief, isolated fat cells were prepared. The diameter of 100 cells was
determined, and mean fat cell volume was calculated.
HSL Assay
The assay of total intracellular HSL activity was performed as
described previously.26 First, pieces of adipose tissue
(
100 mg), which had been stored in liquid nitrogen, were
homogenized at 4°C. The homogenate
was centrifuged and the fat cake removed. The fat-free
infranatant was recovered for analysis of HSL activity in
triplicate samples, using 1(3)-mono-[3H]-oleyl-2-oleoyl
glycerol (obtained from the Department of Cell and Molecular Biology,
Lund University, Lund, Sweden) as substrate.27 All samples
could not be analyzed on the same occasion. Therefore, the
samples obtained from IRS patients and the corresponding control
subjects were analyzed simultaneously together. On
another occasion, the samples obtained from FCHL patients and the
corresponding control subjects were analyzed together (using
another batch of substrate). Methodological experiments have not
revealed any significant decrease in enzymatic activity during storage
of tissue at -70°C for 9 months (data not shown). One mU
of enzyme activity equaled 1 nmol of fatty acid produced per minute at
37°C. Enzyme activity was related to total protein
concentration in the sample.
LPL Activity
LPL activity was determined exactly as
described,28 29 using tissue that had been stored in
liquid nitrogen. In brief, about 25 mg of adipose tissue was incubated
in a glycine buffer containing heparin. A [3H]triolein
(New England Nuclear) emulsion, with purified egg lecithin as
emulsifier, was used as substrate. One nmol of fatty acid released per
minute equaled 1 mU enzyme activity. Three determinations were made on
each tissue sample, and samples from all subjects were assayed on 1
occasion. LPL activity was expressed per gram of tissue. This procedure
was compared in fresh tissue and tissue that had been frozen and
thawed. There was no change in LPL activity, indicating that the
contribution of intracellular LPL due to lysis caused by the handling
of the samples was negligible and therefore the results mainly
represented extracellular LPL.29 In
methodological experiments LPL activity was measured within 1 week
after tissue removal and 6 months thereafter in tissue pieces obtained
from the same individuals. No significant differences between the two
measures were found.
Statistical Analysis
All values are expressed as mean±SEM. Student's two-tailed
t test was used for comparison of data on patients and
control subjects. In some cases, simple regression analysis was
performed. All statistics were performed with the aid of a software
statistical package (Stat View II; Abacus Concepts Inc).
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Results |
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The clinical characteristics of the two different patient groups and their respective control subjects (new subjects in this study) are summarized in Table 1
. As expected,
plasma TG and cholesterol levels were increased in the
patients with FCHL, but fasting plasma insulin and blood glucose as
well as blood pressure were not elevated in FCHL. Patients with IRS
had, as expected, elevated plasma insulin and glucose levels, enlarged
fat cells and increased blood pressure in comparison with the matched
control subjects. However, despite the distinct changes in body fat and
insulin sensitivity, mean plasma lipid levels were not significantly
altered in IRS (only 3 subjects had values slightly above the normal
range).
The findings from the determinations of adipose HSL enzyme activity are
shown in Table 2 and Fig 1.
HSL activity was decreased by 45% in
FCHL patients as compared with control subjects (P <.01),
but there was no significant difference in HSL activity in the IRS
group compared with the control group. Like the FCHL patients, the
matched control subjects of the FCHL group had a wide age range (28 to
-72 yrs), but age did not correlate with HSL activity in this group
when data were examined by linear regression analysis (data not
shown). The mean HSL enzyme activity differed somewhat between the two
control groups, presumably because assays were conducted on different
occasions and with different batches of substrate.
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LPL activity determinations are summarized in Table 2. The enzyme activity was decreased by
43% in patients with IRS as compared with control subjects
(P<.0005), but there was no difference in LPL activity in
patients with FCHL compared with matched controls subjects. Five of the
10 FCHL patients were receiving lipid-lowering drugs (fibrates), which
have known stimulatory effects on LPL activity in muscle but no effect
on adipose tissue LPL activity.30 Accordingly, a separate
analysis of the results of LPL activity was performed in the
non-treated subjects only, which gave the same results. LPL activity
did not differ significantly between the two control groups, and thus
there was no significant correlation between these
parameters and age in the combined control groups.
Furthermore, since fat cell volume was larger in patients with IRS than
in control subjects, it is important to note that no significant
relationship between fat cell volume and LPL activity was observed.
Two of the IRS patients had a diabetic glucose tolerance test (despite normal fasting blood glucose levels). A separate analysis of LPL and HSL activity, excluding these two patients, gave the same results as those for the whole group. Three IRS patients were receiving calcium-channel blockers. The values for LPL and HSL were not altered in a significant way when these patients were omitted from the analyses.
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Discussion |
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HSL and LPL are key enzymes that govern the release and deposition of fatty acids in adipose tissue. HSL is the rate-limiting step for lipolysis of TG in fat cells, and LPL regulates the hydrolysis of circulating TG, which delivers fatty acids to adipose sites. With the presently used enzymatic techniques, LPL activity28 29 and HSL activity26 could be determined in the same adipose tissue sample. A change in the relative activity between these two lipases could result in an alteration of FFA metabolism. Since FFA metabolism is disturbed in both FCHL and IRS,1 14 15 17 18 19 20 it was of considerable interest to compare adipose HSL and LPL in these two conditions. Both FCHL and IRS are frequently occurring diseases, and it is thus highly likely that they are frequently co-expressed in the general population. To examine the influence of each condition on lipase function individually, we studied nonobese FCHL patients and IRS patients without obvious disturbances in plasma lipoprotein levels. By examining well-matched control subjects in each case, we were able to clearly demonstrate contrasting patterns of lipase activity in FCHL and IRS.
As far as we know, LPL and HSL in adipose tissue have not been previously investigated simultaneously in FCHL and IRS. Simple obesity is accompanied by normal LPL activity (when expressed per tissue weight), whereas Type 2 (non-insulin-dependent) diabetes is associated with decreased LPL activity.31 Diabetes was not a confounding factor in this study, because all IRS subjects had normal fasting blood glucose levels and only 2 had a diabetic 2-hour glucose tolerance value. In the IRS subjects, there was a 43% decrease in the enzymatic activity of LPL as compared with the control group, whereas HSL activity was normal. The latter does not, however, exclude lipolysis defects at earlier steps in the lipolytic cascade. We have previously demonstrated decreased ß2-adrenoceptor expression and impaired cyclic AMP function in elderly men with IRS, (i.e., in the same cohort as presently studied).21
Decreased HSL activity has recently been demonstrated in subcutaneous adipose tissue of patients with FCHL.16 This finding was confirmed in the present study upon reinvestigation of the same patients. HSL activity was 45% lower in nonobese male subjects with FCHL compared with a new control group, matched for age, sex, and BMI. Decreased HSL maximum enzymatic activity may have physiological relevance for lipolysis regulation as a major rate-limiting step, since there is a significant correlation between HSL activity (as measured in this study) and the lipolytic capacity of intact human fat cells.32
The possible role of LPL activity in FCHL is more uncertain.33 Babirak et al.34 reported decreased activity of post-heparin LPL in about one third of patients with FCHL; no data on the influence of obesity were given in that report, however. None of these patients had evidence of mutations affecting the function of the enzyme,35 although 1 patient was found to have an abnormal promoter region of the gene.36 A lack of association between the LPL gene and FCHL has been confirmed by others as well.37 38 The relative contribution of different types of tissue (muscle, fat, liver) to post-heparin LPL activity is unknown in FCHL and IRS. In a review, Taskinen39 reported low enzymatic activity in adipose tissue of FCHL subjects, but no details about patients and methods were given in this report. The frequent occurrence of obesity in FCHL may be a confounding factor, affecting results derived from adipose tissue, as discussed above. Our study included only normal-weight FCHL patients with waist/hip ratios similar to those of matched control subjects, and we observed normal LPL activity in subcutaneous fat from these patients. However, other defects may occur with respect to the capacity of adipocytes to store FFA by the esterification process.33 A decreased ability of acylation-stimulating protein to stimulate TG synthesis has been shown in hyperapobetalipoproteinemia, a condition apparently related to FCHL.40 41
When the present data are considered together, it appears that both FCHL and IRS are accompanied by lipolysis defects in adipose tissue, which could be of importance in conjunction with disturbed FFA metabolism, according to the following theory: the abnormalities in adipose lipolysis involve two distinct lipase defects—an LPL defect in IRS and an HSL defect in FCHL. These alterations, together with other reported abnormalities in the regulation of the synthesis and breakdown of TG in adipose tissue,16 21 40 41 42 may explain why circulating FFA levels are elevated in both FCHL and IRS.
In FCHL the breakdown of VLDL-TG (and of TG in chylomicrons) by adipose tissue is normal because LPL is not changed (as demonstrated by the present findings). However, the action of acylation-stimulating protein which stimulates esterification of FFA to TG in adipocytes, is decreased.39 40 41 Therefore, less FFA is liberated by hydrolysis of VLDL-TG and taken up by fat tissue. Instead FFA re-enter the bloodstream, causing high circulating FFA. At the same time, release of FFA from adipose tissue is decreased, perhaps as a compensatory phenomenon or as a primary phenomenon when the acylation-stimulating protein defect is compensatory. The lipolysis defect seems to be due to impaired maximum HSL activity.16 Since many FCHL patients (at least our patients) are normal-weight and have normal fat cell size, an HSL defect must be accompanied by an adipocyte defect in TG storage.
In IRS, LPL is defective (as demonstrated by the present findings), so that less VLDL-TG (and TG in chylomicrons) is taken up by fat tissue. These particles will instead be hydrolyzed at an accelerated rate in non-fat tissues, resulting in excess delivery of FFA to the bloodstream as a result of the lipolysis of TG in VLDL-TG and chylomicrons. At the same time mobilization of FFA from adipose tissue is decreased due to a low rate of lipolysis of intracellular TG in adipocytes. The low lipolysis rate seems to be due to decreased ability of cyclic AMP to activate HSL,21 although maximal enzyme activity is normal (as demonstrated by the present findings). The LPL defect could be primary and the lipolysis defect secondary, or vice versa. An isolated LPL defect without an accompanying adipocyte lipolysis defect is highly unlikely in IRS, since most of these patients are obese. It is not currently known whether the action of acylation-stimulating protein is altered in IRS.
We admit that our theory is based entirely on studies in two groups of subjects (our own and those of Sniderman and Cianflone) and needs to be confirmed by independent investigations. However, both IRS and FCHL appear to be accompanied by decreased turnover of TG in adipose tissue, which might lead to compensatory changes in other routes of FFA metabolism. An increased flux of FFA into the liver could contribute to the enhanced secretion of VLDL apo B observed in both conditions.43 Of course, combinations of the two abnormalities would result in a more pronounced clinical phenotype.
Notably, the speculation above is based on in vitro findings. It is currently not possible to investigate fatty acid turnover in human adipose tissue in vivo. Although net fluxes of lipids over abdominal subcutaneous adipose tissue can be estimated in vivo by arteriovenous cannulation,23 this method does not allow an estimation of the simultaneous uptake, storage, and release of lipids, which is necessary for the calculation of turnover. It is also important to note that our discussion is based on measurements performed in subcutaneous adipose tissue obtained after an overnight fast. It is quite possible that the turnover of lipids in other fat depots, such as visceral fat, and the influence of feeding may be different in FCHL and IRS. Marked regional variations in adipose tissue lipolysis have been reported by several authors.1
In conclusion, this study demonstrated the presence of abnormal adipose tissue lipase action in male patients with FCHL and IRS. The molecular mechanisms responsible for the abnormalities are not known, but they seem to differ markedly between the two conditions. An LPL defect is present in IRS, and an HSL abnormality is present in FCHL. Several investigators have speculated that FCHL and IRS may have a common etiology.15 23 24 The present data, showing contrasting results for LPL and HSL in the two conditions, would strongly argue against such a hypothesis, but would instead suggest that the discrepancies of previous reports may be explained by the frequent coexistence of the two conditions.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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Three of the laboratories involved in this study (Lipid Laboratory of Karolinska Institute at Huddinge University Hospital, Department of Cell and Molecular Biology of Lund University, and INSERM UnitÈ 317 of Hôpital Rangueil) participate in the EUROLIP network supported by the European Union (Biomed I). This study was supported by grants from the Swedish Medical Research Council (19X-1034, 03X-7137, 19X-5446 and 19X11284), the Swedish Diabetes Association, the Karolinska Institute, the Foundations of Osterman, Novo Nordic, Golje, King Gustaf V and Queen Victoria, the Swedish Heart and Lung Foundation and Institute National de la SantÈ et de la Recherche MÈdicale. The excellent clinical assistance of Eva Sjàlin, Kerstin WåhlÈn, Catharina Sjàberg, and Britt-Marie Leijonhufvud is greatly appreciated.
Received July 1, 1996; accepted December 3, 1996.
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References |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
1. Kissebah AH, Krakower GR. Regional adiposity and morbidity. Physiol Rev. 1994;74:761-809.
2. Frayn KN. Studies of human adipose tissue in vivo. In: Kinney JM, Tucker HN, eds. Energy Metabolism: Tissue Determinants and Cellular Corollaries. New York, NY: Raven Press, 1992: 267-295.
3. Goldstein JL, Schrott HG, Hazzard WR, Bierman EL, Motulsky AG. Hyperlipidemia in coronary heart disease. II. Genetic analysis in 176 families and delineation of a new inherited disorder, familial combined hyperlipidemia. J Clin Invest. 1973;52:1544-1568.
4. Nikkilä EA, Aro A. Family study of serum lipids and lipoproteins in coronary heart disease. Lancet. 1973;i:954-958.
5. Brunzell JD, Schrott HG, Motulsky AG, Bierman EL. Myocardial infarction in the familial forms of hypertriglyceridemia. Metabolism. 1976;25:313-320.[Medline] [Order article via Infotrieve]
6. Grundy SM, Chait A, Brunzell JD. Familial combined hyperlipidemia workshop. Arteriosclerosis. 1987;7:203-207.
7.
Babirak SP, Iverius P-H, Fujimoto WY, Brunzell
JD. Detection and characterization of the heterozygote state for
lipoprotein lipase deficiency.
Arteriosclerosis. 1989;9:326-334.
8. Hayden MR, Kirk H, Clark C, et al. DNA polymorphisms in and around the apo A I-C III gene and genetic hyperlipidemias. Am J Hum Genet. 1987;40:421-430.[Medline] [Order article via Infotrieve]
9. Wojciechowski AP, Farrall M, Cullen P, et al. Familial combined hyperlipidemia linked to the apolipoprotein AI-CIII-AIV gene cluster on chromosome 11q23-q24. Nature (Lond). 1991;349:161-164.[Medline] [Order article via Infotrieve]
10. Chait A, Albers JJ, Brunzell D. Very low density lipoprotein overproduction in genetic forms of hypertriglyceridaemia. Eur J Clin Invest. 1980;10:17-22.[Medline] [Order article via Infotrieve]
11. Janus ED, Nicoll AM, Turner PR, Magill P, Lewis B. Kinetic basis of the primary hyperlipidaemias: studies of apolipoprotein-B turnover in genetically defined subjects. Eur J Clin Invest. 1980;10:161-172.[Medline] [Order article via Infotrieve]
12. Kissebah AH, Alfarsi S, Adams PW. Integrated regulation of very low density lipoprotein triglyceride and apolipoprotein-B kinetics in man: normolipemic subjects, familial hypertriglyceridemia and familial combined hyperlipidemia. Metab Clin Exp. 1981;30:856-868.
13. Cortner JA, Coates PM, Bennett MJ, Cryer DR, Le NA. Familial combined hyperlipidemia: Use of stable isotopes to demonstrate overproduction of very low-density lipoprotein apolipoprotein B by the liver. J Inherited Metab Dis. 1991;14:915.[Medline] [Order article via Infotrieve]
14. Castro Cabezas M, de Bruin TWA, et al. Simvastatin improves chylomicron remnant removal in familial combined hyperlipidemia without changing chylomicron conversion. Metab Clin Exp. 1993;42:497-503.
15. Castro Cabezas M, de Bruin TWA, de Valk HW, Shoulders CC, Jansen H, Erklens DW. Impaired fatty acid metabolism in familial combined hyperlipidemia. A mechanism associating hepatic apolipoprotein B overproduction and insulin resistance. J Clin Invest. 1993;92:160-168.
16. Reynisdottir S, Eriksson M, Angelin B, Arner P. Impaired activation of adipocyte lipolysis in familial combined hyperlipidemia. J Clin Invest. 1995;95:2161-2169.
17. Lemieux S, DeprÈs JP. Metabolic complications of visceral obesity: contribution to the aetiology of type 2 diabetes and implications for prevention and treatment. Diabete & MÈtabolisme. 1994;20:375-393.
18. Frayn KN, Coppack SW. Insulin resistance, adipose tissue and coronary heart disease. Clin Sci. 1992;82:1-8.[Medline] [Order article via Infotrieve]
19. Abat N, Garg A. Heterogeneity in adipose tissue metabolism: causes, implications and management of regional adiposity. Prog Lipid Res. 1995;34:53-70.[Medline] [Order article via Infotrieve]
20. Roust LR, Jensen MD. Postprandial free fatty acid kinetics are abnormal in upper body obesity. Diabetes. 1993;42:1567-1573.[Abstract]
21. Reynisdottir S, Ellerfeldt K, Wahrenberg H, Lithell H, Arner P. Multiple lipolysis defects in the insulin resistance (metabolic) syndrome. J Clin Invest. 1994;93:2590-2599.
22. Rose HG, Kranz P, Weinstock M, Juliano J, Haft JI. Inheritance of combined hyperlipoproteinemia: evidence for a new lipoprotein phenotype. Am J Med. 1972;54:148-160.
23.
Williams RR, Hunt SC, Hopkins PN, et al. Familial
dyslipidemic hypertension: evidence from 58 Utah families
for a syndrome present in approximately 12% of families with
essential hypertension. JAMA. 1988;259:3579-3585.
24.
Hunt SC, Wu LL, Hopkins PN, et al. Apolipoprotein, low
density lipoprotein subfraction, and insulin associations with familial
combined hyperlipidemia. Study of Utah patients with
familial dyslipidemic hypertension.
Arteriosclerosis. 1989;9:335-344.
25. Ericsson S, Eriksson M, Berglund L, Angelin B. Metabolism of plasma low density lipoproteins in familial combined hyperlipidemia: effect of acipimox therapy. J Intern Med. 1992;232:313-320.[Medline] [Order article via Infotrieve]
26. Frayn KN, Langin D, Holm C, Belfrage P. Hormone-sensitive lipase: quantitation of enzyme activity and mRNA in small biopsies of human adiopse tissue. Clin Chim Acta. 1993;216:183-189.[Medline] [Order article via Infotrieve]
27. Tàrnqvist H, Bjàrgell P, Krabisch L, Belfrage P. Monoacyl monoalkylglycerol as a substrate for acylglycerolhydrolase activity in adipose tissue. J Lipid Res. 1978;19:654-656.[Abstract]
28. Lithell H, Boberg J. The lipoprotein lipase activity of adipose tissue from different sites in obese women and the relationship to the cell size. Int J Obes. 1978;2:47-52.[Medline] [Order article via Infotrieve]
29. Lithell H, Boberg J. A method of determining lipoprotein-lipase activity in human adipose tissue. J Clin Lab Invest. 1977;37:551-561.[Medline] [Order article via Infotrieve]
30. Vessby B, Lithell H, Ledermann H. Elevated lipoprotein lipase activity in skeletal muscle tissue during treatment of hypertriglyceridaemic patients with bezafibrate. Atherosclerosis. 1982;44:113-118.[Medline] [Order article via Infotrieve]
31. Taskinen MR. Lipoprotein lipase in diabetes. Diabetes/Metabolism Rev. 1987;3:551-570.[Medline] [Order article via Infotrieve]
32. Hellstràm L, Langin D, Reynisdottir S, Danzats M, Arner P. Adipocyte lipolysis in normla weight subjects with obesity among first-degree relatives. Diabetologia. 1996;39:921-928.[Medline] [Order article via Infotrieve]
33. Kwiterovich PO Jr. Genetics and molecular biology of familial combined hyperlipidemia. Curr Opin Lipidol. 1993;4:133-143.
34. Babirak SP, Brown BG, Brunzell JD. Familial combined hyperlipidemia and abnormal lipoprotein lipase. Arterioscler Thromb. 1992;12:1176-1183.[Abstract]
35.
Nevin DN, Brunzell JD, Deeb SS. The LPL gene in
individuals with familial combined hyperlipidemia and
decreased LPL activity. Arterioscler Thromb. 1994;14:869-873.
36.
Yang W-S, Nevin DN, Peng R, Brunzell JD, Deeb
SS. A mutation in the promoter of the lipoprotein lipase (LPL)
gene in a patient with familial combined hyperlipidemia
and low LPL activity. Proc Natl Acad Sci USA. 1995;92:4462-4466.
37.
GagnÈ G, Genest J Jr, Zhang H, Clarke LA, Hayden
MA. Analysis of DNA changes in the LPL gene in patients
with familial combined hyperlipidemia.
Arterioscler Thromb. 1994;14:1250-1257.
38. Wilson DE, Emi M, Iverius PH, et al. Phenotypic expression of heterozygous lipoprotein lipase deficiency in the extended pedigree of a proband homozygous for a missense mutation. J Clin Invest. 1990;86:735-750.
39. Taskinen MR. Lipoprotein lipase in hypertriglyceridemias. In: Borensztajn J, ed. Lipoprotein Lipase. Chicago: Evener, 1987: 201-228.
40. Teng B, Forse A, Rodriguez A, Kwiterovich PO, Sniderman AD. Adipose tissue triglyceride synthesis in patients with hyperapobetalipoproteinemia. J Physiol Pharmacol. 1988,66:239-242.
41. Cianflone K, Maslowska MH, Sniderman AD. Impaired response of fibroblasts from patients with hyperapobetalipoproteinemia to acylation-stimulating protein. J Clin Invest. 1990;85:722-730.
42. Baldo A, Sniderman AD, St.-Luce S, et al. The adipsin-acylation stimulating protein system and regulation of intracellular triglyceride synthesis. J Clin Invest. 1993;92:1543-1547.
43.
Sniderman AD, Cianflone K. Substrate delivery as
a determinant of hepatic apo B secretion. Arterioscler
Thromb. 1993;13:629-636.
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