|
|
|
|||||||
|
|||||||||
J. Biol. Chem., Vol. 277, Issue 32, 28795-28802, August 9, 2002
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
From the
Received for publication, May 9, 2002
To determine whether reduction of
insulin resistance could ameliorate fructose-induced very low density
lipoprotein (VLDL) oversecretion and to explore the mechanism of this
effect, fructose-fed hamsters received placebo or rosiglitazone for 3 weeks. Rosiglitazone treatment led to normalization of the blunted
insulin-mediated suppression of the glucose production rate and to a
~2-fold increase in whole body insulin-mediated glucose disappearance
rate (p < 0.001). Rosiglitazone ameliorated the
defect in hepatocyte insulin-stimulated tyrosine phosphorylation of the
insulin receptor, IRS-1, and IRS-2 and the reduced protein mass of
IRS-1 and IRS-2 induced by fructose feeding. Protein-tyrosine
phosphatase 1B levels were increased with fructose feeding and were
markedly reduced by rosiglitazone. Rosiglitazone treatment led to a
~50% reduction of VLDL secretion rates (p < 0.05)
in vivo and ex vivo. VLDL clearance assessed directly in vivo was not significantly different in the FR
(fructose-fed + rosiglitazone-treated) versus F
(fructose-fed + placebo-treated) hamsters, although there was a trend
toward a lower clearance with rosiglitazone. Enhanced stability of
nascent apolipoprotein B (apoB) in fructose-fed hepatocytes was
evident, and rosiglitazone treatment resulted in a significant
reduction in apoB stability. The increase in intracellular mass of
microsomal triglyceride transfer protein seen with fructose feeding was
reduced by treatment with rosiglitazone. In conclusion, improvement of
hepatic insulin signaling with rosiglitazone, a peroxisome
proliferator-activated receptor The typical dyslipidemia of insulin-resistant states and Type 2 diabetes consists of hypertriglyceridemia due to
VLDL1 overproduction, low
high density lipoprotein cholesterol, and small dense low density
lipoprotein particles (1). Elevated plasma free fatty acid (FFA) flux
from peripheral and intra-abdominal adipose tissue depots due to
resistance to the insulin anti-lipolytic and esterification effect in
adipose tissue is felt to play an important role in driving VLDL
assembly and secretion in insulin resistant states (2-4).
Nevertheless, previous studies in humans suggest that insulin also has
an important direct effect on the liver in controlling VLDL secretion
(5-7).
Rat and mouse models of insulin resistance and type 2 diabetes have
provided important insights into the molecular mechanisms of insulin
resistance. These animal models may not, however, be ideal for the
study of human lipoprotein disorders because, unlike humans, their
livers secrete both apoB48 and apoB100-containing VLDL, and they
do not necessarily develop VLDL oversecretion as the basis
for their hypertriglyceridemia (8, 9). Unlike livers from rat or mouse,
the liver of the golden Syrian hamster secretes only apoB100-containing
VLDL, and its lipoprotein metabolism more closely resembles that of
humans (10). We have shown that insulin resistance in the fructose-fed
golden Syrian hamster is associated with mild hypertriglyceridemia,
VLDL-apoB oversecretion, increased intracellular apoB-containing
lipoprotein particle stability, and increased expression of microsomal
triglyceride transfer protein (MTP) (11). The present studies were
conducted to explore the effect of improving insulin sensitivity in
this insulin-resistant animal model by treatment with rosiglitazone, a
peroxisome proliferator-activated receptor Animals and Study Protocols
Male Syrian golden hamsters (Charles River, Quebec, Canada)
were housed in pairs and given free access to food and water. After 7 days acclimatization, animals were placed on a fructose-enriched diet
(hamster diet with 60% fructose, pelleted, Dyets Inc., Bethlehem, PA)
for 5 weeks. After 2 weeks of feeding with the fructose-enriched diet,
the animals were randomized to receive either rosiglitazone (20 µmol/kg/day) (GlaxoSmithKline) diluted in water
versus water only given once daily by gavage for the
remaining 3 weeks of the fructose feeding period. At the end of the 5 weeks, the fructose-fed (F) and fructose-fed + rosiglitazone-treated
(FR) animals underwent either one of the three in vivo
protocols described below or isolation of hepatocytes for the ex
vivo protocols. In addition, some animals remained on regular chow
for 5 weeks to serve as normal controls.
In Vivo Protocols
Euglycemic Hyperinsulinemic Clamp Studies--
Studies were
performed as previously described (11) with the following
modifications. Catheters were kept patent overnight with 4% heparin in
normal saline (Hepalean, Organon Teknica, 1000 IU/ml). At 8:00 a.m. the
morning after insertion of femoral vein and arterial catheters, a
primed (10 µCi) constant (0.1 µCi/min) infusion of high performance
liquid chromatography-purified [3-3H]glucose (PerkinElmer
Life Sciences) was started (time, 90 min) (12).
[3-3H]Glucose was added to the 20% dextrose infusate to
minimize the decline in glucose specific activity during the clamp.
After 75 min of equilibration at time 0 min, a primed (80 milliunits/kg) constant insulin infusion (8 milliunits/kg/min in 0.1%
bovine serum albumin in normal saline) (Humulin R, Eli Lilly, Canada) was started, and a D20% infusion was adjusted at 10-min intervals to
maintain blood glucose at base-line level. Blood samples (0.25 ml) were
taken from the arterial line at times 15, 0, 90, 100, 110, and 120 min
of the clamp for measurement of blood glucose, [3-3H]glucose specific activity (SA), and plasma insulin
levels. There was no significant decline in hematocrit throughout the
study. Endogenous glucose production (Ra) was calculated as the
endogenous rate of appearance measured with [3-3H]glucose
using a modified one-compartment model (13). Insulin-mediated glucose
disappearance ( In Vivo VLDL Secretion Studies--
One day before these
studies, catheters were inserted into the femoral vein and artery of F
(n = 10) and FR animals (n = 9) of
similar weight (134 ± 3 g versus 132 ± 2 g, respectively, p = 0.64) and chow-fed controls
(n = 5) as previously described (11). VLDL-apoB and
VLDL-triglyceride (TG) secretion rates were measured in the fasting
state (12 h) after intravenous injection of Triton WR-1339 (Sigma) as
previously described (11). The total blood volume of the samples drawn
was less than 1.5 ml per animal during the experiment, and there was no
significant decline in hematocrit.
In Vivo VLDL Clearance Studies--
Because the Triton method
does not allow direct assessment of VLDL clearance, the following
studies were performed after a 12-h fast in 7 F and 8 FR animals of
similar weight (129 ± 6 g versus 126 ± 4 g, respectively, p = 0.68). Catheters were
inserted the day before these studies into the femoral vein and artery. A bolus (20 µCi) of [2-3H]glycerol (PerkinElmer Life
Sciences) was injected intravenously, and blood samples were collected
at times 10, 15, 20, 25, 30, 35, 40, and 50 min after the injection to
measure VLDL-TG levels and to determine the rate of decline of VLDL-TG
[3-3H]glycerol SA. The fractional clearance rate of
VLDL-TG (pool/min) was assessed by the slope of the natural logarithm
of VLDL-TG [2-3H] glycerol SA over time, determined by
linear regression over the linear portion of the down-slope, as
previously described (16).
Ex Vivo Protocols
Liver Perfusion and Isolation of Primary Hamster
Hepatocytes--
After an overnight fast, the liver of animals from
the F and FR groups was perfused under anesthesia, and hepatocytes
released from digested liver tissue were transferred into culture
medium and seeded in collagen-coated plates as previously described
(11).
Determination of ex Vivo Tyrosine Phosphorylation of Insulin
Receptor, IRS-1, and IRS-2 in Primary Hamster Hepatocytes--
To
detect tyrosine phosphorylation of insulin receptor Determination of ex Vivo VLDL-apoB Secretion in Primary
Hepatocyte Cultures--
Radiolabeled VLDL-apoB prepared from
collected media by ultracentrifugation was subjected to
immunoprecipitation and SDS-PAGE, and apoB band was quantified by
liquid scintillation counting as described (11).
Pulse-Chase of Primary Hamster Hepatocytes to Assess Nascent ApoB
Particle Stability--
We employed pulse-chase labeling experiments
to assess the stability of apoB in hepatocytes isolated from
fructose-fed hamsters treated with rosiglitazone versus
placebo, as described previously (17).
Chemiluminescent Immunoblotting--
Cell samples were subjected
to chemiluminescent immunoblotting for the protein mass of the MTP
97-kDa subunit, as previously described (11). A similar method was
utilized to measure protein expression levels of IR, IRS-1, IRS-2, and
PTP-1B.
Other Laboratory Methods
Measurement of glucose, insulin, FFA, TG, apoB,
[3-3H]glucose SA, and VLDL isolation were performed as
previously described (7, 11). VLDL-TG [2-3H]glycerol SA
(dpm/mg) was determined as previously described (5).
Statistical Analysis
All the values are reported as mean ± S.E. unless otherwise
stated. For the euglycemic clamp studies, two-way analysis of variance
was used to compare the glucose, insulin, Ra, and Effect of Rosiglitazone Treatment on Body Weight, Plasma Insulin,
FFA, TG, and Glucose (Table I)
Because of constraints imposed by the small blood volume of the
animals, not all variables were measured on each animal undergoing the
various experiments. Fasting plasma insulin was significantly lower
(p = 0.02) in the FR and control chow-fed group than in the F group. Total plasma TG levels tended to be lower (by ~30%, p = 0.16) after rosiglitazone treatment
versus the fructose-fed hamsters and were identical to TG
levels in the control chow-fed hamsters. All other variables were not
significantly different.
Treatment of Fructose-fed Hamsters with Rosiglitazone Ameliorates
Whole-body Insulin Sensitivity and Improves Hepatocyte Insulin
Signaling
Euglycemic Hyperinsulinemic Clamp Studies--
Plasma glucose
(Fig. 1A) was higher in the F
versus FR animals at base line (4.4 ± 0.3 versus 3.2 ± 0.2 mmol/liter, p = 0.03) and during the last 30 min of the clamp (4.0 ± 0.3 mmol/liter versus 3.0 ± 0.1 mmol/liter, p < 0.001) but was kept constant by design throughout the clamp. Hamsters
fed a normal chow diet had intermediate glucose levels at base line
(3.7 ± 0.2 mmol/liter) and during the last 30 min of the clamp
(3.4 ± 0.1 mmol/liter, p < 0.001 versus the F group). The insulin levels (Fig. 1B)
were similar throughout the clamp in the F, FR, and the control
chow-fed group. Glucose SA (not shown) remained constant in the last 30 min of the clamp in the three groups. The endogenous glucose production rate (Ra) (Fig. 1C) was significantly higher in the F
versus FR animals at base line (80.6 ± 12.2 versus 54.0 ± 11.1 µmol/kg/min, p < 0.001) and throughout the clamp (51.9 ± 14.3 versus
10.7 ± 7.0 µmol/kg/min, p < 0.001). Treatment
of the F animals with rosiglitazone resulted in normalization of Ra at
base line and during the clamp (p = NS
versus control chow-fed group) and also led to normalization of the level of suppression of Ra from base line (Ra was suppressed to
64.7 ± 15.6 of base line versus 19.1 ± 11.4 versus 13.1 ± 8.4% of base line level during the
clamp in the F, FR, and control chow-fed group respectively,
p < 0.001 for the difference between F and the two
other groups). The glucose infusion rate (not shown) was significantly
lower in the F versus the FR group during the last 30 min of
the clamp (64.7 ± 8.7 versus 121.7 ± 25.1 µmol/kg/min, p < 0.001). However, rosiglitazone
treatment did not completely correct the glucose infusion rate and
remained lower than the control chow-fed group (glucose infusion rate
of control chow-fed group, 176.2 ± 3.0 µmol/kg/min,
p < 0.001 versus FR group). Consequently, insulin-mediated glucose disappearance rate ( Insulin Signaling in Hamster Primary Hepatocyte Cultures--
In
hepatocytes isolated from F, insulin-stimulated insulin receptor
Interestingly, PTP-1B protein mass increased to 169.9 ± 13.2%
(n = 3, p = 0.0002) that of controls
with fructose feeding. FR had marked reduction of PTP-1B levels to
24.4 ± 12.9% that of control chow-fed animals (n = 3, p = 0.0004 versus F) (Fig. 3D).
Treatment of Fructose-fed Hamsters with Rosiglitazone Ameliorates
VLDL-apoB and VLDL-TG Oversecretion in Vivo and ex Vivo without
Affecting VLDL Clearance
The slope of the increase in VLDL-apoB (Fig.
4A) over time after the
injection of Triton WR-1339 was significantly steeper in the F
versus FR group (2.42 ± 0.51 versus
1.09 ± 0.27 µg/ml/min, p < 0.05) and
versus the control chow-fed group (0.3 ± 0.1 µg/ml/min, p < 0.05). Consequently, the VLDL-apoB
secretion rate was higher in the F versus FR group
(12.4 ± 2.7 versus 5.5 ± 1.4 µg/min, respectively, p < 0.05) and versus the
control chow-fed group (1.3 ± 0.3 µg/min, p < 0.05) (inset of Fig. 4A). Similarly, VLDL-TG increase over time after the injection of Triton WR-1339 (Fig. 4B) was significantly higher in F versus FR
hamsters (0.024 ± 0.004 versus 0.011 ± 0.004 µmol/ml/min, respectively, p < 0.05) and
versus the control chow-fed group (0.009 ± 0.002 µmol/ml/min, p < 0.05). The VLDL-TG secretion rate
(inset of Fig. 4B) was higher in the F than in
the FR group (0.12 ± 0.02 versus 0.06 ± 0.02 µmol/min respectively, p < 0.05) and higher than the
control chow-fed group (0.04 ± 0.01 µmol/min, p < 0.05). As depicted in Fig. 4C, rosiglitazone treatment
significantly reduced ex vivo VLDL-apoB secretion to 38 ± 32% (mean ± S.D., n = 4, p < 0.001) that of fructose-fed hepatocytes, in keeping with the in
vivo findings. In vivo VLDL-TG fractional
clearance rate, as determined from the [2-3H]glycerol
bolus studies, was not significantly different between the F
versus FR animals (0.034 ± 0.008 versus
0.025 ± 0.004 min
Ameliorated Hepatic Insulin Resistance Is Associated with
Normalization of Microsomal Triglyceride Transfer Protein Expression
and Reduction in Very Low Density Lipoprotein Assembly and Secretion in
the Fructose-fed Hamster*
§,,,,
,**
Department of Medicine, Division of
Endocrinology and Metabolism, University Health Network, and
¶ Department of Laboratory Medicine and Pathobiology, Hospital for
Sick Children, University of Toronto, Toronto, Ontario M5G 2C4,
Canada, and GlaxoSmithKline, Clinical Development & Medical
Affairs, New Frontiers Science Park (South),
Harlow, Essex CM19 5AW, United Kingdom
ABSTRACT
TOP
ABSTRACT
INTRODUCTION
EXPERIMENTAL PROCEDURES
RESULTS
DISCUSSION
REFERENCES
agonist, is associated with reduced
hepatic VLDL assembly and secretion due to reduced intracellular apoB stability.
INTRODUCTION
TOP
ABSTRACT
INTRODUCTION
EXPERIMENTAL PROCEDURES
RESULTS
DISCUSSION
REFERENCES
agonist and insulin
sensitizer and to gain further insight into the molecular
mechanisms of VLDL oversecretion in insulin resistant states.
EXPERIMENTAL PROCEDURES
TOP
ABSTRACT
INTRODUCTION
EXPERIMENTAL PROCEDURES
RESULTS
DISCUSSION
REFERENCES
Rd) was the rate of disappearance measured with
[3-3H]glucose during the clamp minus the mean base-line
Rd level. Data were smoothed with the optimal segments routine (14)
using the optimal error algorithm (15). Because euglycemia was not maintained in one hamster of the FR group, this animal was not included
in the analysis of these experiments.
(IR) subunits,
IRS-1 and IRS-2, hepatocytes derived from fructose-fed and fructose-fed
rosiglitazone-treated hamsters were incubated for 5 h in serum and
insulin-free media. Cells were then stimulated with 100 nM
insulin for 10 min at room temperature. Cells were lysed with a buffer
containing phosphatase inhibitor mixture (150 mM NaCl, 10 mM Tris (pH 7.4), 1 mM EDTA, 1 mM
EGTA, 1% Triton X-100, 1% Nonidet P-40, 2 mM
phenylmethylsulfonyl fluoride, 10 µg/ml aprotinin, 10 µg/ml
leupeptin, 100 mM sodium fluoride, 10 mM sodium
pyrophosphate, and 2 mM sodium orthovanadate and subjected to immunoprecipitation with specific polyclonal antibodies (against insulin receptor subunit or IRS-1) or a specific mouse monoclonal antibody against IRS-2. Immunoprecipitates were used for immunoblotting with monoclonal antibody 
PY (1:1000 dilution) using ECL
chemiluminescence system as described below.
Rd curves of the
F, FR, and control chow-fed groups at base line and during the last 30 min of the clamp, and the difference between the three groups was
assessed by post-hoc analysis using Scheffe test. A two-tailed unpaired
homoscedastic t test was used to compare all the other
quantitative parameters between F and FR hamsters and between F and
control chow-fed hamsters. A p value less than 0.05 was
considered to be significant.
RESULTS
TOP
ABSTRACT
INTRODUCTION
EXPERIMENTAL PROCEDURES
RESULTS
DISCUSSION
REFERENCES
Characteristics of F vs. FR vs. chow-fed control hamsters (S.E.)
Rd) (Fig.
1D) during the clamp was also significantly lower in the F
versus FR animals (29.4 ± 8.4 versus
75.3 ± 20.8 µmol/kg/min, p < 0.001) but was not completely normalized by treatment with rosiglitazone (Rd of
control chow-fed group, 119.6 ± 5.1 µmol/kg/min,
p < 0.001 versus FR).
View larger version (22K):
[in a new window]
Fig. 1.
Euglycemic hyperinsulinemic clamp. Shown
are blood glucose levels (A), plasma insulin levels
(B), endogenous glucose appearance rate (Ra)
(C), and insulin-mediated glucose disappearance rate ( Rd)
(D) during euglycemic hyperinsulinemic clamp studies from
time 0 to 120 min in fructose-fed hamsters treated with rosiglitazone
(open circles, n = 5) versus
placebo (closed circles, n = 6)
versus hamsters fed a chow diet (control (open
squares) n = 5). Bars represent the
mean ± S.E. Statistically significant differences between groups
are indicated in the text below.
subunit tyrosine phosphorylation was reduced to 34.1 ± 2.6%
(n = 3, p = 0.033) of that in control
hepatocytes derived from chow-fed hamsters, and this was restored to
the control levels (98.3 ± 0.5%, n = 3, p = 0.01 versus F) after rosiglitazone
treatment, indicating complete restoration of insulin receptor
phosphorylation by the drug (Fig.
2A). Insulin receptor appears
as a doublet on the gel. We have consistently observed this doublet in
hamster hepatocytes. We do not believe that the second band is a result of degradation, since the addition of protease inhibitors does not
prevent the detection of the doublet (data not shown).
Insulin-stimulated IRS-1 phosphorylation versus basal was
184.3 ± 22.6% in the control chow-fed (n = 4, p = 0.002), 130.3 ± 5.3% in F (n = 4, p = 0.007), and 188.9 ± 8.5% in FR
(n = 4, p = 0.001) (Fig. 2B)
groups, indicating improvement of IRS-1 phosphorylation to the control
levels in hepatocytes isolated from FR (p < 0.001 F
versus FR and p = 0.49 for control chow-fed
versus FR groups). The effect of insulin on phosphorylation
of IRS-2 was similar to that of IRS-1, as shown in Fig. 2C,
indicating significant reduction (n = 3, p = 0.01 versus control chow-fed group) in
insulin-stimulated IRS-2 phosphorylation with fructose feeding and a
marked improvement (n = 3, p = 0.004 versus F) after treatment with rosiglitazone. As shown in
Fig. 3A, fructose feeding had
no significant effect on IR protein mass (100 ± 14.1% in the
control chow-fed group versus 88.3 ± 29.6% in F,
n = 4, p = 0.3). However, in FR
hepatocytes, IR protein mass was increased more than 2-fold
versus cells derived from control chow-fed and F animals
(212.6 ± 47% of control chow-fed animals, n = 4, p = 0.001 versus F). Fructose feeding
reduced the protein mass of IRS-1 (Fig. 3B) by 77% from
359.7 ± 23.9 scanning units/mg of total protein in hepatocytes
from control chow-fed animals to 80 ± 11.5 in hepatocytes from F
animals (n = 3, p = 0.0002 versus control chow-fed animals). Rosiglitazone treatment partially restored IRS-1 mass to 52.8 ± 11.1% that in control chow-fed animals (n = 3, p = 0.003 versus F). IRS-2 protein mass in hepatocytes isolated from F
hamsters was reduced to 57.8 ± 7.1% (p = 0.001)
that of the levels in control chow-fed animals, whereas rosiglitazone
treatment increased protein mass to 74.1 ± 8% that of control
hepatocytes (n = 4, p = 0.002 versus F) (Fig. 3C). These data suggest that the
observed change in IR, IRS-1, and IRS-2 phosphorylation in hepatocytes
isolated from FR may be partially due to change in protein
expression levels of these proteins.
View larger version (32K):
[in a new window]
Fig. 2.
Insulin-mediated phosphorylation of the IR,
IRS-1, and IRS-2. Each panel depicts a representative
immunoblot along with combined densitometric quantitation of multiple
experiments performed in duplicate or triplicate. Net intensity of the
bands was normalized for the total protein content of the samples.
Shown are insulin-mediated phosphorylation of the insulin receptor
(n = 3) (A), IRS-1 (n = 3)
(B), and IRS-2 (n = 4) (C) in
hepatocytes from control hamsters fed regular chow and from
fructose-fed hamsters treated with rosiglitazone versus
placebo (n = 3 to 4 per experiment). All data are shown
as the mean ± S.D.
View larger version (24K):
[in a new window]
Fig. 3.
Protein mass of IR, IRS-1, and IRS-2.
Representative immunoblots along with combined densitometric
quantitation of 3-4 experiments performed in duplicate or triplicate
for IR (A), IRS-1 (B), IRS-2 (C), and
PTP-1B (D), respectively. Net intensity of the bands was
normalized for the total protein content of the samples and is either
expressed as scanning unit/mg of total protein (panel B) or
percent of control cells (panels A, C, and
D). Solid, open, and gray
bars represent IR, IRS-1, and IRS-2 protein mass in control
chow-fed, fructose-fed, and fructose-fed + rosiglitazone-treated
hepatocytes, respectively. All data are shown as the mean ± S.D.
1 respectively, p = 0.33), although clearance tended to be slightly delayed in the
latter.
View larger version (16K):
[in a new window]
Fig. 4.
VLDL-apoB and VLDL-TG secretion rates.
Shown are in vivo VLDL-apoB (A) and VLDL-TG
(B) levels over time after intravenous injection of Triton
WR-1339 (600 mg/kg) in fructose-fed hamsters treated with rosiglitazone
(light gray circles, n = 10)
versus placebo (closed circles, n = 9) and control chow-fed hamsters (dark gray squares,
n = 5). Insets in A and
B show VLDL-apoB and VLDL-TG secretion rate, respectively,
in the rosiglitazone (light gray bars), placebo-treated
group (closed bars), and in the control chow-fed group
(dark gray bars). Ex vivo VLDL-apoB secretion
rate (C) in hepatocytes derived from fructose-fed hamsters
treated with rosiglitazone (open bars, n = 4) versus placebo (closed bars, n = 3). Data are shown as the mean ± S.D.
Treatment of Fructose-fed Hamsters with Rosiglitazone Leads to
Intracellular Destabilization of Nascent VLDL Particles and Correction
of Enhanced Expression of MTP--
In pulse-chase labeling
experiments, after a 1-h chase, there was a significant reduction in
the fraction of apoB secreted (Fig.
5A) in hepatocytes from F
versus FR animals (88 ± 3% versus 49 ± 6% respectively, p = 0.001). Decreased secretion
was also accompanied with a significant decrease in total apoB
recovered (Fig. 5B). There was also a significant reduction
in the fraction of labeled apoB secreted in the FR versus F
animals after a 2-h chase (53 ± 7% versus 97 ± 1% in the FR versus F animals, respectively, p = 0.004), and similarly higher levels of total apoB
were recovered, suggesting that rosiglitazone treatment led to
destabilization and increased degradation of nascent apoB-containing
particles. The cellular protein mass of MTP in hepatocytes from F was
153.3 ± 6.6% (n = 4, p = 0.0002)
that of controls (Fig. 5C). Rosiglitazone treatment led to
normalization of cellular protein mass of MTP in fructose-fed hamsters
to 107.0 ± 9.4% that of controls (n = 4, p < 0.005 versus F).
|
| |
DISCUSSION |
|---|
|
TOP
ABSTRACT
INTRODUCTION
EXPERIMENTAL PROCEDURES
RESULTS
DISCUSSION
REFERENCES
|
|---|
In the present study we have demonstrated that treatment of
fructose-fed insulin-resistant hamsters with rosiglitazone, a member of
the thiazolidinedione class of insulin sensitizers with specific
peroxisome proliferator-activated receptor agonist activity,
improved whole body and liver insulin sensitivity in vivo
and insulin signaling in the liver and reduced VLDL secretion in
vivo and ex vivo. Furthermore, rosiglitazone treatment
was associated with a reversal of the increased expression of MTP seen
with fructose feeding and with de-stabilization of intracellular nascent apoB-containing lipoproteins, indicating potential molecular mechanisms by which insulin sensitization led to reduction of VLDL
secretion in this insulin-resistant animal model.
Treatment with rosiglitazone has been shown to improve glucose metabolism at least in part by improving skeletal muscle insulin sensitivity in insulin-resistant humans (18) and animals (19). This is consistent with the demonstration of increased whole-body glucose disposal rate with treatment of fructose-fed hamsters in the present study. Rosiglitazone treatment has also resulted in insulin sensitization of adipose tissue (20) and has often led to a reduction of plasma FFA levels and flux (21, 22). Although rosiglitazone treatment did not result in a significant reduction in fasting plasma FFA in the present study, we cannot rule out that rosiglitazone treatment in this model may have resulted in lower postprandial FFA levels and lower overall FFA flux to the liver. If this were the case, reduced FFA flux to the liver could have accounted in part for the reduced VLDL secretion with rosiglitazone treatment. More studies will be required to evaluate this possibility.
Reduction of TG secretion with thiazolidinedione treatment has also been found in sucrose-fed and obese Zucker rats by other investigators (22, 23). Nevertheless, most published studies in rats or mice did not show an inhibitory effect of thiazolidinediones on VLDL secretion, thereby concluding that the lowering of plasma TG resulted in total or in part from increased VLDL clearance (22, 24, 25). Unlike the fructose-fed hamster and insulin resistant humans, the rodent models used in the latter studies display impaired plasma TG clearance as the major mechanism of their hypertriglyceridemia when they become insulin-resistant (8). This perhaps explains the discrepancy between our results and those of the latter studies. Also, unlike the present study, previous studies did not directly assess VLDL clearance. Whether rosiglitazone and other thiazolidinediones can affect lipoprotein lipase expression and activity in animals and humans is controversial, with some studies showing increased expression and activity (24, 26) but others showing either no effect (27) or even reduced expression and activity in adipose tissue (28).
A limitation of the tritiated glycerol method used in the present study to assess VLDL clearance is that any change in de novo lipogenesis induced by treatment with rosiglitazone in the present study could result in a change in the relative contribution of glycerol-derived palmitate synthesis to VLDL-TG turnover, resulting in some error in the assessment of VLDL-TG glycerol turnover. To our knowledge, no previous study has addressed whether treatment with a thiazolidinedione results in alteration of fructose-induced elevation of in vivo hepatic de novo lipogenesis. Although a putative effect of rosiglitazone on the induction of hepatic de novo lipogenesis (29) may be expected to somewhat alter VLDL-TG glycerol turnover, de novo lipogenesis contributes less than 20% of total VLDL-TG turnover in fructose-fed rodents (30). Because only a fraction of hepatic de novo lipogenesis is derived from glycerol, it is unlikely that any effect of rosiglitazone on de novo lipogenesis would significantly alter total VLDL-TG glycerol turnover.
Treatment with thiazolidinediones has resulted in either no significant reduction or, at best, a modest lowering of plasma TGs in clinical trials in humans with insulin resistance and Type 2 diabetes (31), despite their documented insulin sensitizing effects (21, 32, 33). This is consistent with our observation that treatment with rosiglitazone resulted in a non-significant reduction in fasting plasma TG levels in the fructose-fed hamster, an animal model of mild hypertriglyceridemia associated with VLDL oversecretion. A marked reduction of plasma TG levels after treatment with thiazolidinediones has been more consistently shown in various mouse and rat models of insulin resistance and type 2 diabetes, animal models that display a much more pronounced fasting hypertriglyceridemia than the one usually found in insulin-resistant humans (23, 34, 35) and in our hamster model. In the present study, the reduction of VLDL secretion in the fructose-fed hamster accounted for the reduction of plasma TG levels associated with rosiglitazone treatment, since VLDL-TG clearance was not different with rosiglitazone treatment. In fact, the VLDL clearance rate was slightly lower with rosiglitazone treatment versus fructose alone, which could explain why the 50% reduction of VLDL secretion observed both in vivo and ex vivo with rosiglitazone treatment did not translate into a significant reduction in fasting plasma TG levels. To our knowledge, the effect of treatment with rosiglitazone on VLDL production and clearance in humans has not been reported.
In the present study, we documented definite improvement in the insulin-signaling cascade in hepatocytes isolated from fructose-fed hamsters treated with rosiglitazone as well as a significant reduction of endogenous glucose production in vivo. Whether the improved hepatic insulin sensitization in the present study resulted from a direct hepatic effect of rosiglitazone or from an indirect effect, secondary to the action of rosiglitazone on extrahepatic tissues, is unclear. We showed that primary hepatocytes from fructose-fed hamsters display a significant increase in PTP-1B expression, which was markedly reduced with rosiglitazone treatment. PTP-1B has been shown to dephosphorylate the insulin receptor and perhaps also IRS-1 and plays a very important role in the regulation of insulin signaling (36). Increased PTP-1B expression in skeletal muscle, adipose tissue, and liver has also been found in other animal models of insulin resistance and diabetes (37-39) and in humans with obesity or diabetes (40, 41). Knock-out mice for this enzyme are very sensitive to insulin, are resistant to fat-induced insulin resistance, and display an increased phosphorylation of liver and muscle insulin receptor after insulin injection (42, 43). We have recently shown that increased expression of PTP-1B precedes the reduction of insulin-mediated tyrosine phosphorylation of IRS-1 and IRS-2 observed in primary hamster hepatocytes with prolonged ex vivo exposure to high concentrations of insulin (44). We have also shown that incubation with vanadate, a general phosphatase inhibitor, leads to a dose-dependent reduction in cellular and secreted apoB (44), a finding that has also been reported in primary rat hepatocytes (45). To our knowledge, this is the first report of the effect of treatment with a thiazolidinedione on PTP-1B expression. Clearly, this PTP-1B-lowering effect of rosiglitazone could be a very important potential mechanism for the liver insulin-sensitizing effect of this drug observed in our study. Further studies are needed to address whether this occurs as a direct effect at the liver or secondary to changes induced in extra-hepatic tissues and whether these findings are specific to the fructose-fed hamster model or can be generalized to humans.
The reduction in MTP levels with rosiglitazone treatment may have been implicated in the reduction of VLDL secretion in the present study. MTP plays an important role in VLDL assembly and intracellular stabilization of apoB (46), although it may not be required for the late lipidation of the particle (47). The promoter region of the MTP gene contains a negative insulin-response element (48), and insulin, acting through its receptor, can lower MTP expression in HepG2 cells (49). Therefore, it is likely that the reduction in MTP levels induced by rosiglitazone treatment was a consequence of improvements in insulin signaling at the liver. However, the precise molecular-signaling pathway involved in insulin-mediated modulation of MTP expression is currently unclear. Given the complexity of insulin regulation of VLDL secretion, it is unlikely that modulation of MTP levels in the liver associated with insulin sensitization is the sole explanation for the rosiglitazone-induced reduction of intracellular apoB-containing particle stability and consequent VLDL secretion.
We have previously shown that fructose feeding results in increased apoB stability and VLDL assembly in the Syrian Golden hamster (11). An important finding in the present study was the reduction in nascent apoB stability with rosiglitazone treatment. We have recently shown that ~40% of nascent apoB is degraded intracellularly in hamster hepatocytes (10). Posttranslational apoB degradation is felt to be an important regulatory mechanism controlling the rate of VLDL secretion (50). The factors regulating apoB degradation are complex, but hepatocyte lipid availability, insulin action, and MTP activity are three important factors (50). Rosiglitazone treatment could have reduced apoB stability in the fructose-fed hamster by any one of these mechanisms, i.e. by reducing FFA flux to the liver and, hence, reducing hepatocyte triglycerides, by improving insulin action and, hence, increasing apoB degradation, or by reducing MTP activity and, hence, reducing nascent VLDL particle assembly.
In conclusion, we have shown that whole-body and hepatic insulin
sensitization with rosiglitazone treatment is associated with a
reduction in hepatic MTP expression, apoB stability, and VLDL secretion
in the fructose-fed insulin-resistant hamster. Our findings suggest
that therapeutic measures that effectively ameliorate hepatic insulin
sensitivity or that reduce MTP overexpression in insulin resistant
states could be part of the strategy to correct the VLDL oversecretion
associated with insulin resistance.
| |
FOOTNOTES |
|---|
* These studies were supported in part by operating grants from the Canadian Institutes of Health Research, Heart and Stroke Foundation of Ontario and GlaxoSmithKline.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
§ Supported by a Heart and Stroke Foundation of Canada/Medical Research Council cardiovascular research fellowship and currently a New Investigator of the Canadian Institutes of Health Research.
** Holds a Canada Research Chair in Diabetes and a Scientist of the Heart and Stroke Foundation of Canada. To whom correspondence should be addressed: Division of Endocrinology and Metabolism, Toronto General Hospital, 200 Elizabeth St., Room EN11-229, Toronto, Ontario M5G 2C4, Canada. Tel.: 416-340-4270; Fax: 416-340-3314; E-mail: gary.lewis@uhn.on.ca.
Published, JBC Papers in Press, June 4, 2002, DOI 10.1074/jbc.M204568200
| |
ABBREVIATIONS |
|---|
The abbreviations used are:
VLDL, very low
density lipoprotein;
apoB, apolipoprotein B;
F, fructose-fed + placebo-treated hamsters;
FFA, free fatty acids;
FR, fructose-fed + rosiglitazone-treated hamsters;
MTP, microsomal triglyceride transfer
protein;
IR, insulin receptor;
IRS-1, insulin receptor substrate-1;
PTP-1B, protein-tyrosine phosphatase 1B;
Ra, endogenous glucose
appearance rate;
Rd, insulin-mediated glucose disappearance rate;
SA, specific activity;
TG, triglyceride;
FFA, free fatty acid.
| |
REFERENCES |
|---|
|
TOP
ABSTRACT
INTRODUCTION
EXPERIMENTAL PROCEDURES
RESULTS
DISCUSSION
REFERENCES
|
|---|
| 1. | Lewis, G. F., and Steiner, G. (1996) Diabetes Metab. Rev. 12, 37-56[CrossRef][Medline] [Order article via Infotrieve] |
| 2. | Ginsberg, H. N. (2000) J. Clin. Invest. 106, 453-458[Medline] [Order article via Infotrieve] |
| 3. |
Lewis, G. F.,
Carpentier, A.,
Adeli, K.,
and Giacca, A.
(2002)
Endocr. Rev.
23,
201-229 |
| 4. | Lewis, G. F. (1997) Curr. Opin. Lipidol. 8, 146-153[Medline] [Order article via Infotrieve] |
| 5. | Lewis, G. F., Uffelman, K. D., Szeto, L. W., Weller, B., and Steiner, G. (1995) J. Clin. Invest. 95, 158-166[Medline] [Order article via Infotrieve] |
| 6. | Malmstrom, R., Packard, C. J., Caslake, M., Bedford, D., Stewart, P., YkiJarvinen, H., Shepherd, J., and Taskinen, M. R. (1998) Diabetes 47, 779-787[Abstract] |
| 7. |
Carpentier, A.,
Patterson, B. W.,
Uffelman, K.,
Giacca, A.,
Vranic, M.,
Cattral, M. S.,
and Lewis, G. F.
(2001)
Diabetes
50,
1402-1413 |
| 8. | Hirano, T., Mamo, J., Poapst, M., and Steiner, G. (1988) Am. J. Physiol. 255, E236-E240[Medline] [Order article via Infotrieve] |
| 9. | Li, X., Grundy, S. M., and Patel, S. B. (1997) J. Lipid Res. 38, 1277-1288[Abstract] |
| 10. |
Taghibiglou, C.,
Rudy, D.,
VanIderstine, S. C.,
Aiton, A.,
Cavallo, D.,
Cheung, R.,
and Adeli, K.
(2000)
J. Lipid Res.
41,
499-513 |
| 11. |
Taghibiglou, C.,
Carpentier, A.,
Rudy, D.,
Aiton, A.,
Lewis, G. F.,
and Adeli, K.
(2000)
J. Biol. Chem.
275,
8416-8425 |
| 12. | Schwenk, W. F., Butler, P. C., Haymond, M. W., and Rizza, R. A. (1990) Am. J. Physiol. 258, E228-E233[Medline] [Order article via Infotrieve] |
| 13. | Finegood, D. T., Bergman, R. N., and Vranic, M. (1987) Diabetes 36, 914-924[Abstract] |
| 14. | Finegood, D. T., and Bergman, R. N. (1983) Am. J. Physiol. 244, E472-E479[Medline] [Order article via Infotrieve] |
| 15. | Bradley, D. C., Steil, G. M., and Bergman, R. N. (1993) Am. J. Physiol. 264, E902-E911[Medline] [Order article via Infotrieve] |
| 16. |
Lemieux, S.,
Patterson, B. W.,
Carpentier, A.,
Lewis, G. F.,
and Steiner, G.
(1999)
J. Lipid Res.
40,
2111-2117 |
| 17. |
Adeli, K.
(1994)
J. Biol. Chem.
269,
9166-9175 |
| 18. |
Fonseca, V.,
Rosenstock, J.,
Patwardhan, R.,
and Salzman, A.
(2000)
J. Am. Med. Assoc.
283,
1695-1702 |
| 19. | Oakes, N. D., Kennedy, C. J., Jenkins, A. B., Laybutt, D. R., Chisholm, D. J., and Kraegen, E. W. (1994) Diabetes 43, 1203-1210[Abstract] |
| 20. | Steppan, C. M., Bailey, S. T., Bhat, S., Brown, E. J., Banerjee, R. R., Wright, C. M., Patel, H. R., Ahima, R. S., and Lazar, M. A. (2001) Nature 409, 307-312[CrossRef][Medline] [Order article via Infotrieve] |
| 21. | Raskin, P., Rappaport, E. B., Cole, S. T., Yan, Y., Patwardhan, R., and Freed, M. I. (2000) Diabetologia 43, 278-284[CrossRef][Medline] [Order article via Infotrieve] |
| 22. |
Oakes, N. D.,
Thalen, P. G.,
Jacinto, S. M.,
and Ljung, B.
(2001)
Diabetes
50,
1158-1165 |
| 23. | Chicco, A., Basabe, J. C., Karabatas, L., Ferraris, N., Fortino, A., and Lombardo, Y. B. (2000) Metabolism 49, 1346-1351[CrossRef][Medline] [Order article via Infotrieve] |
| 24. |
Lefebvre, A. M.,
Peinado-Onsurbe, J.,
Leitersdorf, I.,
Briggs, M. R.,
Paterniti, J. R.,
Fruchart, J. C.,
Fievet, C.,
Auwerx, J.,
and Staels, B.
(1997)
Arterioscler. Thromb. Vasc. Biol.
17,
1756-1764 |
| 25. | Oakes, N. D., Camilleri, S., Furler, S. M., Chisholm, D. J., and Kraegen, E. W. (1997) Metabolism 46, 935-942[CrossRef][Medline] [Order article via Infotrieve] |
| 26. | Schoonjans, K., Peinado-Onsurbe, J., Lefebvre, A. M., Heyman, R. A., Briggs, M., Deeb, S., Staels, B., and Auwerx, J. (1996) EMBO J. 15, 5336-5348[Medline] [Order article via Infotrieve] |
| 27. | Rieusset, J., Auwerx, J., and Vidal, H. (1999) Biochem. Biophys. Res. Commun. 265, 265-271[CrossRef][Medline] [Order article via Infotrieve] |
| 28. |
Ranganathan, S.,
and Kern, P. A.
(1998)
J. Biol. Chem.
273,
26117-26122 |
| 29. | Park, J., Lemieux, S., Lewis, G. F., Kuksis, A., and Steiner, G. (1997) J. Lipid Res. 38, 2529-2536[Abstract] |
| 30. | Park, O. J., Cesar, D., Faix, D., Wu, K., Shackleton, C. H., and Hellerstein, M. K. (1992) Biochem. J. 282, 753-757[Medline] [Order article via Infotrieve] |
| 31. | Kumar, S., Boulton, A. J., Beck, N. H., Berthezene, F., Muggeo, M., Persson, B., Spinas, G. A., Donoghue, S., Lettis, S., and Stewart, L. P. (1996) Diabetologia 39, 701-709[Medline] [Order article via Infotrieve] |
| 32. |
Maggs, D. G.,
Buchanan, T. A.,
Burant, C. F.,
Cline, G.,
Gumbiner, B.,
Hsueh, W. A.,
Inzucchi, S.,
Kelley, D.,
Nolan, J.,
Olefsky, J. M.,
Polonsky, K. S.,
Silver, D.,
Valiquett, T. R.,
and Shulman, G. I.
(1998)
Ann. Intern. Med.
128,
176-185 |
| 33. | Sunayama, S., Watanabe, Y., Ohmura, H., Sawano, M., Shimada, K., Mokuno, H., Daida, H., and Yamaguchi, H. (1999) Atherosclerosis 146, 187-193[CrossRef][Medline] [Order article via Infotrieve] |
| 34. | Murakami, K., Tobe, K., Ide, T., Mochizuki, T., Ohashi, M., Akanuma, Y., Yazaki, Y., and Kadowaki, T. A (1998) Diabetes 47, 1841-1847[Abstract] |
| 35. |
Edvardsson, U.,
Bergstrom, M.,
Alexandersson, M.,
Bamberg, K.,
Ljung, B.,
and Dahllof, B.
(1999)
J. Lipid Res.
40,
1177-1184 |
| 36. | Kennedy, B. P., and Ramachandran, C. (2000) Biochem. Pharmacol. 60, 877-883[CrossRef][Medline] [Order article via Infotrieve] |
| 37. | Ahmad, F., and Goldstein, B. J. (1995) Metabolism 44, 1175-1184[CrossRef][Medline] [Order article via Infotrieve] |
| 38. | Sredy, J., Sawicki, D. R., Flam, B. R., and Sullivan, D. (1995) Metabolism 44, 1074-1081[CrossRef][Medline] [Order article via Infotrieve] |
| 39. | Meyerovitch, J., Backer, J. M., and Kahn, C. R. (1989) J. Clin. Invest. 84, 976-983[Medline] [Order article via Infotrieve] |
| 40. | Ahmad, F., Considine, R. V., Bauer, T. L., Ohannesian, J. P., Marco, C. C., and Goldstein, B. J. (1997) Metabolism 46, 1140-1145[CrossRef][Medline] [Order article via Infotrieve] |
| 41. | Ahmad, F., Azevedo, J. L., Cortright, R., Dohm, G. L., and Goldstein, B. J. (1997) J. Clin. Invest. 100, 449-458[Medline] [Order article via Infotrieve] |
| 42. |
Elchebly, M.,
Payette, P.,
Michaliszyn, E.,
Cromlish, W.,
Collins, S.,
Loy, A. L.,
Normandin, D.,
Cheng, A.,
Himms-Hagen, J.,
Chan, C. C.,
Ramachandran, C.,
Gresser, M. J.,
Tremblay, M. L.,
and Kennedy, B. P.
(1999)
Science
283,
1544-1548 |
| 43. |
Klaman, L. D.,
Boss, O.,
Peroni, O. D.,
Kim, J. K.,
Martino, J. L.,
Zabolotny, J. M.,
Moghal, N.,
Lubkin, M.,
Kim, Y. B.,
Sharpe, A. H.,
Stricker-Krongrad, A.,
Shulman, G. I.,
Neel, B. G.,
and Kahn, B. B.
(2000)
Mol. Cell. Biol.
20,
5479-5489 |
| 44. |
Taghibiglou, C.,
Rashid-Kolvear, F.,
Van Iderstine, S. C., Le,
Tien, H.,
Fantus, I. G.,
Lewis, G. F.,
and Adeli, K.
(2002)
J. Biol. Chem.
277,
793-803 |
| 45. | Jackson, T. K., Salhanick, A. I., Sparks, J. D., Sparks, C. E., Bolognino, M., and Amatruda, J. M. (1988) Diabetes 37, 1234-1240[Abstract] |
| 46. | Gordon, D. A., and Jamil, H. (2000) Biochim. Biophys. Acta 1486, 72-83[Medline] [Order article via Infotrieve] |
| 47. |
Pan, M.,
Liang Js, J. S.,
Fisher, E. A.,
and Ginsberg, H. N.
(2002)
J. Biol. Chem.
277,
4413-4421 |
| 48. |
Hagan, D. L.,
Kienzle, B.,
Jamil, H.,
and Hariharan, N.
(1994)
J. Biol. Chem.
269,
28737-28744 |
| 49. | Lin, M. C., Gordon, D., and Wetterau, J. R. (1995) J. Lipid Res. 36, 1073-1081[Abstract] |
| 50. | Yao, Z., Tran, K., and McLeod, R. S. (1997) J. Lipid Res. 38, 1937-1953[Abstract] |
Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
CiteULike 
Complore 
Connotea 
Del.icio.us 
Digg 
Reddit 
Technorati What's this?
This article has been cited by other articles:
|
|
 |
|
  W. Huang, A. Metlakunta, N. Dedousis, H. K. Ortmeyer, M. Stefanovic-Racic, and R. M. O'Doherty Leptin Augments the Acute Suppressive Effects of Insulin on Hepatic Very Low-Density Lipoprotein Production in Rats Endocrinology, May 1, 2009; 150(5): 2169 - 2174. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Laplante, W. T. Festuccia, G. Soucy, P.-G. Blanchard, A. Renaud, J. P. Berger, G. Olivecrona, and Y. Deshaies Tissue-specific postprandial clearance is the major determinant of PPAR{gamma}-induced triglyceride lowering in the rat Am J Physiol Regulatory Integrative Comp Physiol, January 1, 2009; 296(1): R57 - R66. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Z. Chen, E. P. Newberry, J. Y. Norris, Y. Xie, J. Luo, S. M. Kennedy, and N. O. Davidson ApoB100 is required for increased VLDL-triglyceride secretion by microsomal triglyceride transfer protein in ob/ob mice J. Lipid Res., September 1, 2008; 49(9): 2013 - 2022. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Duez, B. Lamarche, K. D. Uffelman, R. Valero, L. Szeto, S. Lemieux, J. S. Cohn, and G. F. Lewis Dissociation between the Insulin-Sensitizing Effect of Rosiglitazone and Its Effect on Hepatic and Intestinal Lipoprotein Production J. Clin. Endocrinol. Metab., May 1, 2008; 93(5): 1722 - 1729. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. Qin, R. A. Anderson, and K. Adeli Tumor necrosis factor-{alpha} directly stimulates the overproduction of hepatic apolipoprotein B100-containing VLDL via impairment of hepatic insulin signaling Am J Physiol Gastrointest Liver Physiol, May 1, 2008; 294(5): G1120 - G1129. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Laplante, W. T. Festuccia, G. Soucy, Y. Gelinas, J. Lalonde, and Y. Deshaies Involvement of adipose tissues in the early hypolipidemic action of PPAR{gamma} agonism in the rat Am J Physiol Regulatory Integrative Comp Physiol, April 1, 2007; 292(4): R1408 - R1417. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Qu, D. Su, J. Altomonte, A. Kamagate, J. He, G. Perdomo, T. Tse, Y. Jiang, and H. H. Dong PPAR{alpha} mediates the hypolipidemic action of fibrates by antagonizing FoxO1 Am J Physiol Endocrinol Metab, February 1, 2007; 292(2): E421 - E434. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Duez, B. Lamarche, K. D. Uffelman, R. Valero, J. S. Cohn, and G. F. Lewis Hyperinsulinemia Is Associated With Increased Production Rate of Intestinal Apolipoprotein B-48-Containing Lipoproteins in Humans Arterioscler. Thromb. Vasc. Biol., June 1, 2006; 26(6): 1357 - 1363. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. Burgermeister, A. Schnoebelen, A. Flament, J. Benz, M. Stihle, B. Gsell, A. Rufer, A. Ruf, B. Kuhn, H. P. Marki, et al. A Novel Partial Agonist of Peroxisome Proliferator-Activated Receptor-{gamma} (PPAR{gamma}) Recruits PPAR{gamma}-Coactivator-1{alpha}, Prevents Triglyceride Accumulation, and Potentiates Insulin Signaling in Vitro Mol. Endocrinol., April 1, 2006; 20(4): 809 - 830. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Adiels, J. Boren, M. J. Caslake, P. Stewart, A. Soro, J. Westerbacka, B. Wennberg, S.-O. Olofsson, C. Packard, and M.-R. Taskinen Overproduction of VLDL1 Driven by Hyperglycemia Is a Dominant Feature of Diabetic Dyslipidemia Arterioscler. Thromb. Vasc. Biol., August 1, 2005; 25(8): 1697 - 1703. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. M. Allister, N. M. Borradaile, J. Y. Edwards, and M. W. Huff Inhibition of Microsomal Triglyceride Transfer Protein Expression and Apolipoprotein B100 Secretion by the Citrus Flavonoid Naringenin and by Insulin Involves Activation of the Mitogen-Activated Protein Kinase Pathway in Hepatocytes Diabetes, June 1, 2005; 54(6): 1676 - 1683. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J.-P. F. Morand, J. Macri, and K. Adeli Proteomic Profiling of Hepatic Endoplasmic Reticulum-associated Proteins in an Animal Model of Insulin Resistance and Metabolic Dyslipidemia J. Biol. Chem., May 6, 2005; 280(18): 17626 - 17633. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Ameen, U. Edvardsson, A. Ljungberg, L. Asp, P. Akerblad, A. Tuneld, S.-O. Olofsson, D. Linden, and J. Oscarsson Activation of Peroxisome Proliferator-activated Receptor {alpha} Increases the Expression and Activity of Microsomal Triglyceride Transfer Protein in the Liver J. Biol. Chem., January 14, 2005; 280(2): 1224 - 1229. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. F. Lewis, K. Uffelman, M. Naples, L. Szeto, M. Haidari, and K. Adeli Intestinal Lipoprotein Overproduction, a Newly Recognized Component of Insulin Resistance, Is Ameliorated by the Insulin Sensitizer Rosiglitazone: Studies in the Fructose-Fed Syrian Golden Hamster Endocrinology, January 1, 2005; 146(1): 247 - 255. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. Qiu, R. K. Avramoglu, N. Dube, T. M. Chong, M. Naples, C. Au, K. G. Sidiropoulos, G. F. Lewis, J. S. Cohn, M. L. Tremblay, et al. Hepatic PTP-1B Expression Regulates the Assembly and Secretion of Apolipoprotein B-Containing Lipoproteins: Evidence From Protein Tyrosine Phosphatase-1B Overexpression, Knockout, and RNAi Studies Diabetes, December 1, 2004; 53(12): 3057 - 3066. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. F. Lewis, S. Murdoch, K. Uffelman, M. Naples, L. Szeto, A. Albers, K. Adeli, and J. D. Brunzell Hepatic Lipase mRNA, Protein, and Plasma Enzyme Activity Is Increased in the Insulin-Resistant, Fructose-Fed Syrian Golden Hamster and Is Partially Normalized by the Insulin Sensitizer Rosiglitazone Diabetes, November 1, 2004; 53(11): 2893 - 2900. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. F. Lewis, M. Naples, K. Uffelman, N. Leung, L. Szeto, and K. Adeli Intestinal Lipoprotein Production Is Stimulated by an Acute Elevation of Plasma Free Fatty Acids in the Fasting State: Studies in Insulin-Resistant and Insulin-Sensitized Syrian Golden Hamsters Endocrinology, November 1, 2004; 145(11): 5006 - 5012. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Berthiaume, H. Sell, J. Lalonde, Y. Gelinas, A. Tchernof, D. Richard, and Y. Deshaies Actions of PPAR{gamma} agonism on adipose tissue remodeling, insulin sensitivity, and lipemia in absence of glucocorticoids Am J Physiol Regulatory Integrative Comp Physiol, November 1, 2004; 287(5): R1116 - R1123. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Alam, M. Stolinski, C. Pentecost, M. A. Boroujerdi, R. H. Jones, P. H. Sonksen, and A. M. Umpleby The Effect of a Six-Month Exercise Program on Very Low-Density Lipoprotein Apolipoprotein B Secretion in Type 2 Diabetes J. Clin. Endocrinol. Metab., February 1, 2004; 89(2): 688 - 694. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. Morel, S. Demignot, D. Chateau, J. Chambaz, M. Rousset, and F. Delers Lipid-dependent Bidirectional Traffic of Apolipoprotein B in Polarized Enterocytes Mol. Biol. Cell, January 1, 2004; 15(1): 132 - 141. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W.-S. Au, H.-f. Kung, and M. C. Lin Regulation of Microsomal Triglyceride Transfer Protein Gene by Insulin in HepG2 Cells: Roles of MAPKerk and MAPKp38 Diabetes, May 1, 2003; 52(5): 1073 - 1080. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| All ASBMB Journals | Molecular and Cellular Proteomics |
| Journal of Lipid Research | ASBMB Today |