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Arteriosclerosis, Thrombosis, and Vascular Biology. 1995;15:1688-1694

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(Arteriosclerosis, Thrombosis, and Vascular Biology. 1995;15:1688-1694.)
© 1995 American Heart Association, Inc.

Articles

Overexpression of Human Lipoprotein Lipase Protects Diabetic Transgenic Mice From Diabetic Hypertriglyceridemia and Hypercholesterolemia

Masako Shimada; Shun Ishibashi; Takanari Gotoda; Masako Kawamura; Koji Yamamoto; Toshimori Inaba; Kenji Harada; Junichi Ohsuga; Stephane Perrey; Yoshio Yazaki; Nobuhiro Yamada

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.


*    Abstract
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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


*    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.


*    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


*    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 2Down).


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  		Table 2. Effects of Overexpression of Human LPL on Concentrations of Plasma Glucose, Insulin, Triglyceride, Cholesterol, and Free Fatty Acid Levels and Body Weight in Mice Before and After Induction of Diabetes Mellitus

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 1Down).


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  		Table 1. Activities of LPL in Postheparin Plasma and Skeletal and Cardiac Muscles in Mice Before and After Induction of Diabetes Mellitus

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 2Up).

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 1Down). 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 2Down).



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  		Figure 1. Gel filtration chromatography profiles of fasting plasma lipoproteins in transgenic mice before and after induction of diabetes mellitus. Pooled fasting plasma (10 µL) from transgenic mice and nontransgenic siblings was applied to a combined column system composed of TSK G3000SW + G5000PW (Tosoh) in sequence. Data show the elution peaks of VLDL, LDL, and HDL for triglycerides (TG) before (A) and after (B) injection of STZ.32 A, Nondiabetic (controls; n=8, TG=89.1 mg/dL vs transgenic mice; n=5, TG=35.7 mg/dL); B, diabetic (controls; n=8, TG=185.3 mg/dL vs transgenic mice; n=5, TG=33.2 mg/dL).



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  		Figure 2. Gel filtration chromatography profiles of fasting plasma lipoproteins in transgenic mice before and after induction of diabetes mellitus in cholesterol monitor. Pooled fasting plasma (10 µL) was applied to a combined column system in the same way as described in Fig 1Up. Data show the elution peaks of VLDL, LDL, and HDL for cholesterol (TC) before (a) and after (b) induction of diabetes mellitus. a, Nondiabetic (controls; n=8, TC=90.0 mg/dL vs transgenic mice; n=7, TC=83.6 mg/dL); b, diabetic (controls; n=8, TC=163.9 mg/dL vs transgenic mice; n=7, TC=104.9 mg/dL).

Body Weight Change
In transgenic mice, diabetes did not cause a statistically significant decrease in body weight (Table 2Up). LPL overexpression had no effect on body weight in any of the diet groups including normal, high fat, and high glucose diets (Fig 3Down).



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  		Figure 3. Effects of overexpression of LPL on body weight in nondiabetic control and transgenic mice. A, Body weights of control and transgenic mice in normal chow from 6 to 22 weeks after birth (controls; n=7, transgenic mice; n=7); B, 6 control and 6 transgenic mice were given 10% glucose diet for 135 days; 5 control and 4 transgenic mice were administered 15% saturated fat diet in the form of cocoa butter for 90 days.


*    Discussion
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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 1Up). 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 2Up). 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 3Up). 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 1Up). There was little change in the lipoprotein elution profiles after induction of diabetes mellitus in transgenic mice (Fig 1Up). 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 1Up), plasma triglycerides were rapidly removed from the blood and maintained at a low level (Table 2Up). 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 2Up). 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 2Up), 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.


*    Selected Abbreviations and Acronyms
 
FFA = free fatty acid(s)
HL = hepatic triglyceride lipase
LPL = lipoprotein lipase
STZ = streptozotocin

Received January 11, 1995; accepted August 2, 1995.


*    References
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 *References
 

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