© 1995 American Heart Association, Inc.
Articles |
Overexpression of Human Lipoprotein Lipase Protects Diabetic Transgenic Mice From Diabetic Hypertriglyceridemia and Hypercholesterolemia
From the Third Department of Internal Medicine, University of Tokyo, Hongo, Tokyo, Japan.
Correspondence to Nobuhiro Yamada, Third Department of Internal Medicine, University of Tokyo, Hongo, Tokyo, Japan, 113.
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Abstract |
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Abstract We investigated the role of the overexpression of lipoprotein lipase (LPL) in lipoprotein abnormalities in transgenic mice with streptozotocin-induced diabetes mellitus. Before the induction of diabetes, LPL activity was 4.6-fold in skeletal muscle and 2.0-fold higher in the heart in transgenic mice than in their nontransgenic littermates. LPL activity in skeletal muscles in diabetic nontransgenic mice and cardiac LPL activity in diabetic nontransgenic and transgenic mice were decreased. Body weights were similarly reduced, and no appreciable amount of adipose tissue was observed in diabetes in both groups. The plasma triglyceride level was lower in diabetic transgenic mice than in diabetic nontransgenic mice (33.2±22.5 versus 185.3±57.4 mg/dL). Induction of diabetes was associated with a significant increase in the plasma cholesterol level in nontransgenic mice (90.0±11.1 versus 163.9±39.3 mg/dL) but much less in transgenic mice. Our results indicate that overexpression of LPL in transgenic mice inhibited diabetes-associated hypertriglyceridemia and hypercholesterolemia but did not affect the loss of body weight induced by diabetes.
Key Words: diabetes mellitus • insulin • body weight • triglycerides • cholesterol
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Introduction |
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LPL is a rate-limiting enzyme that hydrolyzes circulating triglycerides, leading to the generation of FFA, which store triglycerides in adipose tissue and serve as energy sources in skeletal muscle and the heart.1 LPL activity changes dramatically in various tissues in response to energy requirements. In animals that have been fed, for instance, high adipose LPL activity and low muscle LPL activity lead to the preferential uptake of hydrolyzed triglycerides by adipose tissues for storage. In the fasting state, high muscle LPL activity and low adipose tissue LPL activity utilize plasma triglycerides as primary energy sources.2 3 LPL activity also changes in response to physiological requirements associated with lactation,4 5 development,6 cold acclimation,7 8 exercise,9 10 and obesity.3 11 These changes in LPL activity are under direct and/or indirect hormonal control.12 13 14 15 16 Hormonal control of LPL has been studied mainly in adipose tissue, skeletal muscle, and the heart. Insulin has a profound effect on adipose tissue, suppressing fat mobilization from adipose tissue and increasing LPL activity by promoting LPL synthesis and secretion.17 18 19 20
Atherosclerotic disorders, including ischemic heart disease and cerebrovascular disease, are major complications of diabetes mellitus.21 Plasma lipoprotein abnormalities such as hypertriglyceridemia and hypercholesterolemia frequently result from impaired insulin action and play an important role in the progression of diabetic atherosclerosis.3 22 Several mechanisms of diabetic hyperlipidemia have been suggested, including increased intestinal absorption of dietary cholesterol,23 24 increased VLDL production, and decreased removal of VLDL and LDL from plasma.25 26 LPL activity has been extensively studied in tissues to clarify the mechanism of decreased removal of VLDL. LPL activity in adipose tissue is highly sensitive to a decrease in plasma insulin, which is not affected by feeding in diabetes.11 22 27 Conflicting results have been obtained in studies of LPL activity in the heart and skeletal muscles in diabetes mellitus: decreased activity,28 no change in activity,29 30 and increased activity have been observed.27 We and other groups recently established a strain of transgenic mice that overexpresses human LPL.31 32 33 We found that LPL mediated the lipolytic conversion of VLDL to LDL as well as hydrolysis of triglyceride-rich lipoproteins and that overexpression of LPL prevented the development of diet-induced hypertriglyceridemia and hypercholesterolemia in this transgenic strain. In the present study, we investigated the pathophysiological role of LPL in diabetic hyperlipidemia in heterozygous transgenic mice with overexpression of the human LPL gene in which diabetes mellitus was induced by injection of streptozotocin.
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Methods |
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Materials and Animals
Glycerol-tri[9,10-3H]oleate and rat insulin were purchased from Amersham International Corp. The radioimmunoassay kit for human insulin was purchased from Shionogi Chemical Co. All reagents used were of analytical grade.
Transgenic mice with overexpression of lipoprotein lipase regulated by the CMV IE enhancer/chicken ß-actin promoter,34 line 6-2, were established as described previously.31 Age-matched heterozygotes (BDF2xC57bl/6) and sibling mice lacking the transgene were used as controls. Mice used in this study weighed between 20 and 30 g and were fed a standard chow. Diabetes mellitus was induced by a single intravenous injection of 100 mg/kg STZ dissolved in a 50 mmol/L citrate buffer (pH 4.5). We used animals for experiments 3 weeks after injection of STZ. After evaluation of plasma lipoprotein levels in diabetic mice, insulin therapy was performed by human lente insulin (Penfile N-40) twice a day for 2 weeks.
Animal Treatment Procedure
Blood samples were drawn from the retro-orbital plexus by
heparin-coated capillaries into ice-cold tubes after animals
fasted for 5 hours (from 11 AM to 4 PM) to
measure plasma level of triglycerides. Our preliminary
experiments demonstrated that plasma triglyceride levels
after 5 hours of fasting showed the significant difference among animal
groups better than those after 16 hours of fasting. For determination
of plasma glucose levels, 5-hour fasting blood samples (10 µL) were
obtained in tubes containing 0.5 mg of sodium fluoride. To
determine plasma levels of cholesterol and insulin, blood
samples were obtained after a 16-hour fast (from 6 PM to
10 AM). Plasma was isolated by
centrifugation. Animals were fed either a standard
chow, a chow containing 10% glucose (high glucose diet), or a chow
containing 15% saturated fat in the form of cocoa butter (high fat
diet) to study the effect of LPL overexpression on body weight.
LPL Activity in Postheparin Plasma and
Tissues
Sixteen-hour fasting postheparin plasma was
obtained 3 minutes after a bolus dose of heparin (100 U/kg) was
injected into the tail vein. Heart and muscle samples taken after the
16-hour fast (50 mg) were homogenized with the use of a
glass homogenizer (Iwaki Glass Co Ltd) in 1 mL of a
solution containing 1 mol/L ethylene glycol, 50 mmol/L Tris-HCl, 3
mmol/L deoxycholate, 100 U/mL heparin, and 5% (vol/vol) aprotinin
(Trasylol, Miles Pharmaceuticals), pH 7.4. The homogenates
were centrifuged at 800g at 4°C for 10 minutes,
and the supernatants were used in experiments. Plasma, skeletal muscle,
and heart samples were quickly stored at -80°C until used for
determinations of LPL activity. The protein content was determined by
the Lowry method.35 LPL activity was assayed by the method
of Nilsson-Ehle and Schotz,36 37 as described
previously.31 LPL and HL activities in
postheparin plasma were measured in the presence and
absence of 1 mol/L NaCl. Lipase activity in the presence of 1 mol/L
NaCl represented HL activity. LPL activity was calculated
by subtracting HL activity from lipase activity measured in the absence
of 1 mol/L NaCl.
Plasma Levels of Glucose, Insulin, and Lipids
Plasma glucose levels were determined by the
glucose-oxidase method. Plasma insulin levels were measured by a
double-antibody radioimmunoassay (Shionogi Co Ltd) with the use of
rat insulin as standard.38 The plasma concentrations of
triglycerides, cholesterol, and FFA were
determined enzymatically.31
Gel Filtration Chromatography
Pooled fasting plasma (10 µL) from nondiabetic (n=5) and
diabetic transgenic mice (n=5) and nondiabetic (n=8) and diabetic
nontransgenic siblings (n=8) was applied to a combined column system
composed of TSK G3000SW + G5000PW (Tosoh) in sequence and eluted with
0.15 mol/L NaCl/0.01% EDTA at a rate of 0.4 mL/min. The effluent was
mixed with an enzymatic reagent to measure levels of
triglycerides and cholesterol. The
high-performance liquid chromatography
system showed three distinct elution peaks identifying the three major
lipoprotein classes (VLDL, LDL, and HDL).39
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Results |
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Plasma Glucose and Insulin Levels
Plasma glucose levels were 4.0-fold and 3.3-fold higher in diabetic nontransgenic and transgenic mice compared with nondiabetic nontransgenic and transgenic mice (417.7±57.5 versus 102.3±20.8 mg/dL in 12 nontransgenic mice and 389.4±54.4 versus 118.3±34.9 mg/dL in 7 transgenic mice). Plasma insulin levels were below 0.5 µU/mL in diabetic mice. After insulin therapy, plasma glucose levels were significantly reduced to 154.3±56.6 and 169.6±51.6 mg/dL in nontransgenic and transgenic mice, respectively (Table 2
).
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LPL Activity in Fasting Plasma Samples and Tissues
Before injection of STZ, LPL activity was 1.9-fold higher in
postheparin plasma, 4.6-fold higher in skeletal muscle, and
2.0-fold higher in the heart in transgenic mice than in controls. After
induction of diabetes and insulin therapy, the postheparin
plasma LPL activity was not changed significantly in nontransgenic and
transgenic mice. After induction of diabetes, plasma glucose levels
were above 300 mg/dL, and adipose tissue was barely detectable by
macroscopic observation in both diabetic groups. LPL activity in
skeletal muscle in diabetic control mice was 43.8% of the level in
nondiabetic controls (3.9±2.9 versus 8.9±3.0 µmol FFA/h per gram).
LPL activity in the heart in diabetic transgenic mice was 63.5% of the
level in nondiabetic transgenic mice (10.6±2.6 versus 16.7±3.9 µmol
FFA/h per gram). There were no significant differences in LPL activity
in skeletal muscle in transgenic mice and in the heart in nontransgenic
mice before and after induction of diabetes mellitus (Table 1).
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Plasma Lipoprotein Levels
Plasma triglyceride levels increased from 89.1±44.5
to 185.3±57.4 mg/dL in nontransgenic mice and from 35.7±18.9 to
33.2±22.5 mg/dL in transgenic mice after induction of diabetes. After
insulin therapy, plasma triglyceride levels decreased
significantly in nontransgenic controls. There was no significant
difference in the plasma cholesterol level between
transgenic and nontransgenic mice before induction of diabetes. After
injection of STZ, plasma cholesterol levels showed a
1.8-fold increase in control mice but did not increase significantly in
transgenic mice. Plasma cholesterol levels returned to
normal after insulin therapy. The results indicating that plasma
triglyceride and cholesterol levels in diabetic
nontransgenic mice were significantly reduced after insulin treatment
are in accord with the fact that insulin deficiency caused lipid
abnormalities in diabetic mice. Plasma levels of FFA were lower in the
diabetic than in the nondiabetic condition in both nontransgenic and
transgenic mice (Table 2
).
The peak of VLDL triglycerides was 2.0-fold higher in
diabetic control mice than in nondiabetic controls, as determined by
gel filtration chromatography. The
VLDL-triglyceride peak was significantly reduced in
transgenic mice before and after injection of STZ (Fig 1). VLDL- and LDL-cholesterol fractions
increased significantly in diabetic control mice compared with
nondiabetic controls. The LDL-cholesterol peak height did
not significantly change in transgenic mice before and after induction
of diabetes. The HDL-cholesterol fractions showed 1.6-fold
and 1.3-fold increase in diabetic nontransgenic and transgenic mice
(Fig 2).
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Body Weight Change
In transgenic mice, diabetes did not cause a statistically
significant decrease in body weight (Table 2). LPL overexpression had
no effect on body weight in any of the diet groups including normal,
high fat, and high glucose diets (Fig 3).
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Discussion |
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Intravenous injection of STZ induced diabetes mellitus25 27 40 41 in both nontransgenic and transgenic mice. LPL activities in skeletal muscle and heart were 4.6-fold and 2.0-fold higher in transgenic mice compared with nontransgenic mice respectively and did not change significantly after induction of diabetes mellitus in transgenic mice. Postheparin LPL activity was reduced after induction of diabetes in transgenic mice. LPL activity in postheparin plasma did not differ in nontransgenic mice before and after induction of diabetes. Postheparin LPL activity is not necessarily consistent with tissue LPL activity: We previously found that postheparin LPL activity was smaller than that expected from tissue LPL activity in transgenic mice.31 LPL activity in tissue more directly reflects the effect of diabetes than LPL activity in postheparin plasma because plasma LPL activity represents only the heparin-induced release of LPL activity from various tissues. In the present study, LPL activity in skeletal muscles was suppressed in nontransgenic mice, and cardiac LPL activity decreased in both nontransgenic and transgenic mice by insulin deficiency, suggesting that regulation of LPL activity in diabetes is tissue specific. LPL activity in skeletal muscles may be more sensitive to insulin than LPL activity in the heart (Table 1
).
Ben-Zeev et al42 have suggested that LPL activity in the
heart and adipose tissue is under independent genetic
control.
LPL is believed to play a role in the process of fat
deposition1 2 3 : LPL hydrolyzes triglycerides on
the capillary endothelium and mediates the uptake of
FFA by adipose tissue, resulting in accumulation of
triglycerides in adipose tissue. However, the decrease in
body weight after induction of diabetes was similar in transgenic and
nontransgenic mice (Table 2). Insulin deficiency may cause a
significant loss of adipose tissue by enhancing the lipolytic
process.25 We observed a marked loss of adipose tissue in
diabetic mice, suggesting that overexpression of LPL did not increase
the uptake of hydrolyzed FFA in the presence of diabetes.
Overexpression of LPL had no significant effect on body weight gain in
transgenic mice in any of the diet groups (Fig 3). Although LPL may be
involved in the process of delivery of FFA to adipose
tissue,43 44 45 46 the overproduction of human LPL
mainly in adipose tissue, skeletal muscle, and the heart does not cause
obesity.
Hypertriglyceridemia3 22 and
increased levels of FFA are common clinical findings in
diabetes.47 48 The VLDL triglyceride fraction
increased 2.0-fold in control mice after induction of diabetes mellitus
(Fig 1). There was little change in the lipoprotein elution profiles
after induction of diabetes mellitus in transgenic mice (Fig 1). There
are two possible mechanisms of the diabetes-associated increase in
VLDL triglycerides in control mice:
overproduction of VLDL in the liver and decreased clearance
of VLDL.25 26 Impaired insulin action not only stimulates
lipolysis, increasing delivery of FFA to the liver and consequently
increasing production of triglycerides, but also
reduces LPL activity. We found no significant difference in LPL
activity in the heart between diabetic and nondiabetic control mice.
However, adipose tissue was not observed, and LPL activity in muscle
was decreased in diabetic control mice, suggesting that lipolysis was
enhanced in adipose tissue after induction of diabetes, resulting in
increased delivery of FFA to the liver and decreased hydrolysis of VLDL
triglycerides in muscle. Therefore,
hypertriglyceridemia in diabetic mice may
have been caused by both increased production of hepatic
triglycerides and defective hydrolysis of plasma
triglycerides. In our previous study, we observed marked
acceleration of turnover of chylomicrons and VLDL in transgenic
mice.31 Because LPL activities in skeletal muscle and
heart in transgenic mice were higher than those in nondiabetic control
mice (Table 1), plasma triglycerides were rapidly removed
from the blood and maintained at a low level (Table 2). Plasma FFA
levels did not increase in control mice and showed a decrease in
transgenic mice after induction of diabetes. Plasma FFA levels are
regulated by the transfer of FFA between plasma and adipose
tissue,49 50 in which LPL and hormone-sensitive lipase
are involved.51 Adipose tissue disappeared within a few
weeks of induction of diabetes in the present study, suggesting
that the lipolytic process in the adipose tissue by
hormone-sensitive lipase may have been reduced in mice 3 weeks
after induction of diabetes.
The plasma cholesterol level was significantly higher in
control mice than in transgenic mice after induction of diabetes
mellitus (Table 2). Studies have shown that cholesterol
absorption is increased and can be corrected by insulin
treatment.31 34 A defect in the removal of lipoproteins
containing apolipoprotein (apo)B through LDL receptors is another
possible mechanism of hypercholesterolemia.
Alterations in the lipoprotein composition, such as the increase in
large triglyceride-rich lipoproteins observed in the
present study, may influence the removal of lipoproteins containing
apoB in diabetic mice by reducing their binding affinity to LDL
receptors in diabetic mice. The role of LPL in
hypercholesterolemia associated with diabetes
mellitus has received less attention than its role in
hypertriglyceridemia. VLDL- and
LDL-cholesterol fractions increased in diabetic
nontransgenic mice but not in diabetic transgenic mice in the
present study (Fig 2), suggesting that LPL overexpression prevented
the progression of diabetic
hypercholesterolemia. LPL-induced inhibition of
hypercholesterolemia may have been related to
the increased removal of lipolyzed VLDL before lipolytic conversion of
VLDL to LDL. Studies have shown that LPL enhances cellular uptake of
triglyceride-rich lipoproteins.52 53 54 55
Recent studies have suggested that LPL promotes binding of
apoB-100–rich lipoproteins to cell-surface proteoglycans,
resulting in increased cellular uptake of those lipoproteins through
the LDL receptor–independent pathway.56 57 58 The rapid
clearance of lipolyzed VLDL through both the LDL
receptor–dependent and the LDL receptor–independent pathways
in transgenic mice overexpressing LPL may explain the reduction in the
production of LDL from VLDL even in the presence of diabetes.
The present results confirmed the findings of our previous study in
which plasma cholesterol levels were decreased in LPL
transgenic mice after cholesterol loading.31
These findings suggest that LPL plays an important role in determining
plasma cholesterol levels.
Diabetes mellitus is an important risk factor for atherosclerotic disorders such as ischemic heart disease and cerebrovascular disease.21 Transgenic animal models are useful for studying the functions of certain genes in vivo.31 32 33 59 60 61 We believe that our transgenic mouse provides a good model for the study of the role of LPL in diabetic atherosclerosis and its effect on lipid metabolism.
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Received January 11, 1995; accepted August 2, 1995.
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References |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
1. Garfinkel AS, Schotz MC. Lipoprotein lipase. In: Gotto AM Jr, ed. Lipoproteins. Amsterdam, Netherlands: Elsevier; 1987:335-354.
2. Cryer A. Tissue lipoprotein lipase activity and its action in lipoprotein lipase metabolism. Int J Biochem. 1981;13:525-541. [Medline] [Order article via Infotrieve]
3. Eckel RH. Lipoprotein lipase: a multifunctional enzyme relevant to common metabolic diseases. N Engl J Med. 1989;320:1060-1068. [Abstract]
4. Robinson DS. Lipid metabolism. In: Florkin M, Stotz EH, eds. Compr. Biochem. Amsterdam, Netherlands: Elsevier; 1970:18:51-116.
5. Scow RO, Chermick SS. Role of lipoprotein lipase during lactation. In: Borensztajn J, ed. Lipoprotein Lipase. Chicago, Ill: Evener: 1987:149-185.
6.
Tavangar K, Murata Y, Patel S, Kalinyak JE, Pedersen
ME, Goers JF, Hoffman AR, Kraemer FB. Developmental regulation
of lipoprotein lipase in rats. Am J Physiol. 1992;262:E330-E337.
7.
Smith RE, Roberts JC. Thermogenesis of brown
adipose tissue in cold-accliminated rats. Am J
Physiol. 1964;206:143-148.
8.
Carneheim C, Nedergaard J, Cannon B.
Beta-adrenergic stimulation of lipoprotein lipase in rat
brown adipose tissue during acclimination to cold. Am J
Physiol. 1984;246:E327-E333.
9. Kiens B, Lithell H. Lipoprotein metabolism influenced by training-induced changes in human skeletal muscle. J Clin Invest. 1989;83:458-564.
10. Kuwajima M, Foster DW, Mcgarry JD. Regulation of lipoprotein lipase in different rat tissues. Metab Clin Exp. 1988;37:597-601.
11. Eckel RH. Adipose tissue lipoprotein lipase. In: Borensztajn J, ed. Lipoprotein Lipase. Chicago, Ill: Evener; 1987:79-132.
12.
Steingrimsdottir L, Brasel J, Greenwood MRC.
Hormonal modulation of adipose tissue lipoprotein lipase may
alter food intake in rats. Am J Physiol. 1980;239:E162-E167.
13. Gavin LA, McMahon F, Moeller M. Modulation of adipose lipoprotein lipase by thyroid hormone and diabetes: the significance of the low T3 state. Diabetes. 1985;34:1266-1271. [Abstract]
14. Lithell H, Boberg J, Hellsing K, Ljunghall S, Lundqvist G, Vessby B, Wide L. Serum lipoprotein and apolipoprotein concentrations and tissue lipoprotein-lipase activity in overt and subclinical hypothyroidism: the effect of substitution therapy. Eur J Clin Invest. 1981;11:3-10. [Medline] [Order article via Infotrieve]
15.
Inoue S, Satoh S, Tanaka K, Takamura Y, Murase T.
Determinants of fasting
hypertriglyceridemia in ventromedial
hypothalamic obesity in rats. Am J Physiol. 1993;265:R786-R791.
16.
Richelsen B, Pedersen SB, Børglum JD,
Møller-Pedersen
T, Jørgensen J, Jørgensen JO. Growth hormone treatment of
obese women for 5 weeks: effect on body composition and adipose tissue
LPL activity. Am J Physiol. 1994;266:E211-E216.
17.
Spooner PM, Chernick SS, Garrison MM, Scow RO.
Development of lipoprotein lipase activity and accumulation of
triacylglycerol in differentiating 3T3-L1
adipocytes: effects of prostaglandin
F2a, 1-methyl-3-isobutylxanthine, prolactin, and
insulin. J Biol Chem. 1979;254:1305-1311.
18.
Ong JM, Kirchgessner TG, Schotz MC, Kern PA.
Insulin increases the synthetic rate and messenger RNA level of
lipoprotein lipase in isolated rat adipocytes. J
Biol Chem. 1988;263:12933-12938.
19.
Appel B, Fried SK. Effects of insulin and
dexamethasone on lipoprotein lipase in human adipose
tissue. Am J Physiol. 1992;262:E695-E699.
20. Fried SK, Russell CD, Grauso NL, Brolin RE. Lipoprotein lipase regulation by insulin and glucocorticoid in subcutaneous and omental adipose tissues of obese women and men. J Clin Invest. 1993;92:2191-2198.
21. Després J-P, Marette A. Relation of components of insulin resistance syndrome to coronary disease risk. Curr Opin Lipidol. 1994;5:274-289.[Medline] [Order article via Infotrieve]
22. O'Looney PA, Vahouny GV. Diabetes and lipoprotein lipase activity. In: Borensztajn J, ed. Lipoprotein Lipase. Chicago, Ill: Evener; 1987:229-246.
23. Jiao S, Matsuzawa Y, Matsubara K, Kihara S, Nakamura T, Tokunaga K, Kubo M, Tarui S. Increased activity of intestinal acyl-CoA:cholesterol acyltransferase in rats with streptozotocin-induced diabetes and restoration by insulin supplementation. Diabetes. 1988;37:342-346. [Abstract]
24. Maechler P, Wollheim CB, Bentzen CL, Niesor E. Role of the intestinal acyl-CoA:cholesterol acyltransferase activity in the hyperresponse of diabetic rats to dietary cholesterol. J Lipid Res. 1992;33:1475-1484. [Abstract]
25. Reaven EP, Reaven GM. Mechanisms for development of diabetic hypertriglyceridemia in streptozotocin-treated rats: effect of diet and duration of insulin deficiency. J Clin Invest. 1974;54:1167-1178.
26.
O'Looney P, Irwin D, Briscoe P, Vahouny GV.
Lipoprotein composition as a component in the lipoprotein
clearance defect in experimental diabetes. J
Biol Chem. 1985;260:428-432.
27. Rauramaa R, Kuusela P, Hietanen E. Adipose, muscle and lung tissue lipoprotein lipase activities in young streptozotocin treated rats. Horm Metab Res. 1980;12:591-595. [Medline] [Order article via Infotrieve]
28. Aktin E, Meng HC. Release of clearing factor lipase (lipoprotein lipase) in vivo and from isolated perfused hearts of alloxan diabetic rats. Diabetes. 1972;21:149-156. [Medline] [Order article via Infotrieve]
29.
Linder C, Chernick SS, Fleck TR, Scow RO.
Lipoprotein lipase and uptake of chylomicron
triglyceride by skeletal muscle of rats. Am J
Physiol. 1976;231:860-864.
30. Elkeles RS, Williams E. Post-heparin lipolytic activity and tissue lipoprotein lipase activity in the alloxan-diabetic rat. Clin Sci Mol Med. 1974;46:661-664. [Medline] [Order article via Infotrieve]
31.
Shimada M, Shimano H, Gotoda T, Yamamoto K, Kawamura M,
Inaba T, Yazaki Y, Yamada N. Overexpression of human lipoprotein
lipase in transgenic mice: resistance to diet-induced
hypertriglyceridemia and
hypercholesterolemia. J
Biol Chem. 1993;268:17924-17929.
32.
Liu M-S, Jirik FR, LeBoeuf RC, Henderson H, Castellani
LW, Lusis AJ, Ma Y, Forsythe IJ, Zhang H, Kirk E, Brunzell JD, Hayden
MR. Alteration of lipid profiles in plasma of transgenic mice
expressing human lipoprotein lipase. J Biol
Chem. 1994;269:11417-11424.
33.
Zsigmond E, Scheffler E, Forte TM, Potenz R, Wu W, Chan
L. Transgenic mice expressing human lipoprotein lipase driven by
the mouse metallothionein promoter: a
phenotype associated with increased perinatal mortality and
reduced plasma very low density lipoprotein of normal size.
J Biol Chem. 1994;269:18757-18766.
34. Niwa H, Yamamura K, Miyazaki J. Efficient selection for high-expression transfectants with a novel eukaryotic vector. Gene. 1991;108:193-200. [Medline] [Order article via Infotrieve]
35.
Lowry OH, Rosebrough NJ, Farr AL, Randall RJ.
Protein measurement with the folin phenol reagent.
J Biol Chem. 1951;193:265-275.
36. Nilsson-Ehle P, Schotz MC. A stable radioactive substrate emulsion for assay of lipoprotein lipase. J Lipid Res. 1976;17:536-541. [Abstract]
37. Gotoda T, Yamada N, Kawamura M, Kozaki K, Mori N, Ishibashi S, Shimano H, Takaku F, Yazaki Y, Furuichi Y, Murase T. Heterogenous mutations in the human lipoprotein lipase gene in patients with familial lipoprotein lipase deficiency. J Clin Invest. 1991;88:1856-1864.
38. Hales CN, Randle PJ. Immunoassay of insulin with insulin antibody precipitate. Biochem J. 1963;88:137-146. [Medline] [Order article via Infotrieve]
39. Shimano H, Yamada N, Katsuki M, Yamamoto K, Gotoda T, Harada K, Shimada M, Yazaki Y. Plasma lipoprotein metabolism in transgenic mice overexpressing apolipoprotein E: accelerated clearance of lipoproteins containing apolipoprotein B. J Clin Invest. 1992;90:2084-2091.
40. Nakai T, Oida K, Tamai T, Yamada S, Kobayashi T, Hayashi T, Kutsumi Y, Takeda R. Lipoprotein lipase activities in heart muscle of streptozotocin-induced diabetic rats. Horm Metab Res. 1984;16:67-70.
41.
O'Looney P, Vander-Maten M, Vahouny GV.
Insulin-mediated modifications of myocardial lipoprotein
lipase and lipoprotein metabolism. J
Biol Chem. 1983;258:12994-13001.
42.
Ben-Zeev O, Lusis AJ, LeBoeuf RC, Nakazy J, Schotz MC.
Evidence for independent genetic regulation of heart and adipose
lipoprotein lipase activity. J Biol Chem. 1983;258:13632-13636.
43. Dugail I, Quignard-Boulange A, Brigant L, Etienne J, Noe L, Lavau M. Increased lipoprotein lipase content in the adipose tissue of suckling and weaning obese Zucker rats. Biochem J. 1988;249:45-49. [Medline] [Order article via Infotrieve]
44. Gruen R, Hietanen E, Greenwood MR. Increased adipose tissue lipoprotein lipase activity during the development of the genetically obese rat (fa/fa). Metab Clin Exp. 1978;27(suppl 2):1955-1966.
45. Ong JM, Kern PA. Effect of feeding and obesity on lipoprotein lipase activity, immunoreactive protein, and messenger RNA levels in human adipose tissue. J Clin Invest. 1989;84:305-311.
46. Pykalisto OJ, Smith PH, Brunzell JD. Determinants of human adipose tissue lipoprotein lipase: effect of diabetes and obesity on basal- and diet-induced activity. J Clin Invest. 1975;56:1108-1117.
47. Bierman EL, Dole VP, Roberts TN. An abnormality of non-esterified fatty acid metabolism in diabetes mellitus. Diabetes. 1957;6:475-479.
48. Bagdade JD, Porte D Jr, Bierman EL. The interaction of diabetes and obesity on regulation of fat mobilization in man. Diabetes. 1969;18:759-772. [Medline] [Order article via Infotrieve]
49.
Ruderman NB, Toews CJ, Shafrir E. Role of free
fatty acids in glucose homeostasis. Arch Intern Med. 1969;123:299-313.
50. Pelkonen R, Miettinen TA, Taskinen MR, Nikkila EA. Effect of acute elevation of plasma glycerol, triglyceride and FFA levels on glucose utilization and plasma insulin. Diabetes. 1968;17:76-82.[Medline] [Order article via Infotrieve]
51. Coppack SW, Evans RD, Fisher RM, Frayn KN, Gibbons GF, Humphreys SM, Kirk ML, Potts JL, Hockaday TDR. Adipose tissue metabolism in obesity: lipase action in vivo before and after a mixed meal. Metabolism. 1992;41:264-272. [Medline] [Order article via Infotrieve]
52.
Khoo JC, Mahoney EM, Witztum JL. Secretion of
lipoprotein lipase by macrophages in culture.
J Biol Chem. 1981;256:7105-7108.
53. Chait A, Iverius P, Brunzell JD. Lipoprotein lipase secretion by human monocyte-derived macrophages. J Clin Invest. 1982;69:490-493.
54.
Mahoney EM, Khoo JC, Steinberg D. Lipoprotein
lipase secretion by human monocytes and rabbit alveolar
macrophages in culture. Proc Natl Acad Sci
U S A. 1982;79:1639-1642.
55.
Ishibashi S, Yamada N, Shimano H, Mori N, Mokuno H,
Gotohda T, Kawakami M, Murase T, Takaku F. Apolipoprotein E and
lipoprotein lipase secreted from human monocyte-derived
macrophages modulate very low density lipoprotein
uptake. J Biol Chem. 1990;265:3040-3047.
56.
Saxena U, Klein MG, Goldberg IJ.
Metabolism of endothelial cell-bound
lipoprotein lipase: evidence for heparan sulfate
proteoglycan-mediated internalization and recycling.
J Biol Chem. 1990;265:12880-12886.
57.
Williams KJ, Fless GM, Petrie KA, Snyder ML, Brocia RW,
Swenson TL. Mechanisms by which lipoprotein lipase alters
cellu-lar metabolism of lipoprotein (a), low density
lipoprotein receptors and heparan sulfate proteoglycans.
J Biol Chem. 1992;267:13284-13292.
58.
Mulder M, Lombardi P, Jansen H, van Berkel TJ, Frants
RR, Havekes LM. Low density lipoprotein receptor internalizes
low density and very low density lipoproteins that are bound to heparan
sulfate proteoglycans via lipoprotein lipase. J
Biol Chem. 1993;268:9369-9375.
59. Ishibashi S, Brown MS, Goldstein JL, Gerard RD, Hammer RE, Herz J. Hypercholesterolemia in low density lipoprotein receptor knockout mice and its reversal by adenovirus-mediated gene delivery. J Clin Invest. 1993;92:883-893.
60. Plump AS, Smith JD, Hayek T, Aalto-Setala K, Walsh A, Verstuyft JG, Rubin EM, Breslow JL. Severe hypercholesterolemia and atherosclerosis in apolipoprotein E-deficient mice created by homologous recombination in ES cells. Cell. 1992;71:343-353. [Medline] [Order article via Infotrieve]
61.
Zhang SH, Reddick RL, Piedrahita JA, Maeda N.
Spontaneous hypercholesterolemia and
arterial lesions in mice lacking apolipoprotein E.
Science. 1992;258:468-471.
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