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Hepatic insulin signaling regulates VLDL secretion and atherogenesis in mice.

ABSTRACT: Type 2 diabetes is associated with accelerated atherogenesis, which may result from a combination of factors, including dyslipidemia characterized by increased VLDL secretion, and insulin resistance. To assess the hypothesis that both hepatic and peripheral insulin resistance contribute to atherogenesis, we crossed mice deficient for the LDL receptor (Ldlr-/- mice) with mice that express low levels of IR in the liver and lack IR in peripheral tissues (the L1B6 mouse strain). Unexpectedly, compared with Ldlr-/- controls, L1B6Ldlr-/- mice fed a Western diet showed reduced VLDL and LDL levels, reduced atherosclerosis, decreased hepatic AKT signaling, decreased expression of genes associated with lipogenesis, and diminished VLDL apoB and lipid secretion. Adenovirus-mediated hepatic expression of either constitutively active AKT or dominant negative glycogen synthase kinase (GSK) markedly increased VLDL and LDL levels such that they were similar in both Ldlr-/- and L1B6Ldlr-/- mice. Knocking down expression of hepatic IR by adenovirus-mediated shRNA decreased VLDL triglyceride and apoB secretion in Ldlr-/- mice. Furthermore, knocking down hepatic IR expression in either WT or ob/ob mice reduced VLDL secretion but also resulted in decreased hepatic Ldlr protein. These findings suggest a dual action of hepatic IR on lipoprotein levels, in which the ability to increase VLDL apoB and lipid secretion via AKT/GSK is offset by upregulation of Ldlr.

SUBMITTER: Han S

PROVIDER: S-EPMC2662550 | biostudies-literature | 2009 Apr

REPOSITORIES: biostudies-literature

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Hepatic insulin signaling regulates VLDL secretion and atherogenesis in mice.

Han Seongah S Liang Chien-Ping CP Westerterp Marit M Senokuchi Takafumi T Welch Carrie L CL Wang Qizhi Q Matsumoto Michihiro M Accili Domenico D Tall Alan R AR

The Journal of clinical investigation 20090309 4

Type 2 diabetes is associated with accelerated atherogenesis, which may result from a combination of factors, including dyslipidemia characterized by increased VLDL secretion, and insulin resistance. To assess the hypothesis that both hepatic and peripheral insulin resistance contribute to atherogenesis, we crossed mice deficient for the LDL receptor (Ldlr-/- mice) with mice that express low levels of IR in the liver and lack IR in peripheral tissues (the L1B6 mouse strain). Unexpectedly, compar ...[more]

PMID: 19273907

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Project description:ContextThe exact mechanisms responsible for increased plasma triglyceride (TG) concentration in obese people are unclear, and it is not known whether excess energy intake per se is involved in the pathophysiology of this abnormality.ObjectiveThe purpose of our study was to examine how excess energy intake from a balanced diet for 1 day affects very-low-density lipoprotein (VLDL)-TG kinetics and its putative regulators hepatic insulin sensitivity and plasma free fatty acid availability.Subjects and designWe used stable isotope-labeled tracer methods to evaluate glucose and lipid kinetics in 8 overweight and obese men (age, 38 ± 3 years; body mass index, 33.7 ± 1.7 kg/m(2); means ± SEM) on 2 occasions (randomized crossover design): once, the day after they consumed a balanced diet that provided an amount of energy that matched their energy expenditure, and another time, the day after they consumed a balanced diet that provided 30% excess calories. Eight healthy, lean men (34 ± 1 years; 22.5 ± 0.6 kg/m(2)) were studied under isocaloric conditions only to provide a reference for normal lipid kinetics.ResultsVLDL-TG and VLDL-apolipoprotein B-100 (apoB-100) concentrations and secretion rates were significantly greater (P < .01) in overweight/obese compared with lean men. Hypercaloric, compared with isocaloric, feeding in overweight/obese men increased glucose rate of appearance in plasma (904 ± 21 vs 873 ± 26 μmol/min), the hepatic insulin resistance index (10.9 ± 2.2 vs 8.3 ± 1.8), and VLDL-apoB-100 concentration and secretion rate (1.91 ± 0.24 vs. 1.53 ± 0.13 nmol/min), whereas VLDL-apoB-100 plasma clearance rate, VLDL-TG secretion and plasma clearance rates, and free fatty acid rate of appearance in plasma were not affected by overfeeding.ConclusionOne day of moderate overfeeding (30% excess energy intake) stimulates hepatic glucose and VLDL-apo B-100 secretion rates but has no effect on hepatic and adipose tissue fatty acid metabolism in overweight/obese men.

Project description:BackgroundPPARs (?,?,?) are a family of ligand-activated transcription factors that regulate energy balance, including lipid metabolism. Despite these critical functions, the integration between specific pathways of lipid metabolism and distinct PPAR responses remains obscure. Previous work has revealed that lipolytic pathways can activate PPARs. Whether hepatic lipase (HL), an enzyme that regulates VLDL and HDL catabolism, participates in PPAR responses is unknown.Methods/principal findingsUsing PPAR ligand binding domain transactivation assays, we found that HL interacted with triglyceride-rich VLDL (>HDL?LDL, IDL) to activate PPAR? preferentially over PPAR? or PPAR?, an effect dependent on HL catalytic activity. In cell free ligand displacement assays, VLDL hydrolysis by HL activated PPAR? in a VLDL-concentration dependent manner. Extended further, VLDL stimulation of HL-expressing HUVECs and FAO hepatoma cells increased mRNA expression of canonical PPAR? target genes, including adipocyte differentiation related protein (ADRP), angiopoietin like protein 4 and pyruvate dehydrogenase kinase-4. HL/VLDL regulated ADRP through a PPRE in the promoter region of this gene. In vivo, adenoviral-mediated hepatic HL expression in C57BL/6 mice increased hepatic ADRP mRNA levels by 30%. In ob/ob mice, a model with higher triglycerides than C57BL/6 mice, HL overexpression increased ADRP expression by 70%, demonstrating the importance of triglyceride substrate for HL-mediated PPAR? activation. Global metabolite profiling identified HL/VLDL released fatty acids including oleic acid and palmitoleic acid that were capable of recapitulating PPAR? activation and ADRP gene regulation in vitro.ConclusionsThese data define a novel pathway involving HL hydrolysis of VLDL that activates PPAR? through generation of specific monounsaturated fatty acids. These data also demonstrate how integrating cell biology with metabolomic approaches provides insight into specific lipid mediators and pathways of lipid metabolism that regulate transcription.

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Hepatic insulin signaling regulates VLDL secretion and atherogenesis in mice.

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Hepatic insulin signaling regulates VLDL secretion and atherogenesis in mice.

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