Arteriosclerosis, Thrombosis, and Vascular Biology. 1995;15:1688-1694
(Arteriosclerosis, Thrombosis, and Vascular Biology. 1995;15:1688-1694.)
© 1995 American Heart Association, Inc.
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.
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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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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
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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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Table 1. Activities of LPL in Postheparin Plasma and
Skeletal and Cardiac Muscles in Mice Before and After Induction of
Diabetes Mellitus
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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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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 1 . 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).
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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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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.
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Discussion
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Intravenous injection of STZ induced diabetes
mellitus
25 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 al
42 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-100rich lipoproteins to cell-surface proteoglycans,
resulting in increased cellular uptake of those lipoproteins through
the LDL receptorindependent pathway.56 57 58 The rapid
clearance of lipolyzed VLDL through both the LDL
receptordependent and the LDL receptorindependent 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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Selected Abbreviations and Acronyms
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| FFA |
= |
free fatty acid(s) |
| HL |
= |
hepatic triglyceride lipase |
| LPL |
= |
lipoprotein lipase |
| STZ |
= |
streptozotocin |
|
Received January 11, 1995;
accepted August 2, 1995.
 |
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