Journal
JOURNAL OF LIPID RESEARCH
Volume 55, Issue 7, Pages 1254-1266Publisher
ELSEVIER
DOI: 10.1194/jlr.M046037
Keywords
hepatic triglyceride; lipids; adenosine monophosphate-activated protein kinase; insulin resistance; inflammation; energy expenditure
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Funding
- Canadian Institutes of Health Research [MOP-126045]
- Heart and Stroke Foundation of Canada [PRG-5967]
- University of Western Ontario, Department of Medicine Grant POEM
- Canadian Diabetes Association
- Canadian Foundation for Innovation
- National Health and Medical Research Council
- Victorian Government's Operational Infrastructure Support Program
- Ontario Graduate Scholarship
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PPAR delta regulates systemic lipid homeostasis and inflammation, but its role in hepatic lipid metabolism remains unclear. Here, we examine whether intervening with a selective PPAR delta agonist corrects hepatic steatosis induced by a high-fat, cholesterol-containing (HFHC) diet. Ldlr(-/-) mice were fed a chow or HFHC diet (42% fat, 0.2% cholesterol) for 4 weeks. For an additional 8 weeks, the HFHC group was fed HFHC or HFHC plus GW1516 (3 mg/kg/day). GW1516-intervention significantly attenuated liver TG accumulation by induction of FA beta-oxidation and attenuation of FA synthesis. In primary mouse hepatocytes, GW1516 treatment stimulated AMP-activated protein kinase (AMPK) and acetyl-CoA carboxylase (ACC) phosphorylation in WT hepatocytes, but not AMPK beta 1(-/-) hepatocytes. However, FA oxidation was only partially reduced in AMPK beta 1(-/-) hepatocytes, suggesting an AMPK-independent contribution to the GW1516 effect. Similarly, PPAR delta-mediated attenuation of FA synthesis was partially due to AMPK activation, as GW1516 reduced lipogenesis in WT hepatocytes but not AMPK beta 1(-/-) hepatocytes. HFHC-fed animals were hyperinsulinemic and exhibited selective hepatic insulin resistance, which contributed to elevated fasting FA synthesis and hyperglycemia. GW1516 intervention normalized fasting hyperinsulinemia and selective hepatic insulin resistance and attenuated fasting FA synthesis and hyperglycemia. The HFHC diet polarized the liver toward a proinflammatory M1 state, which was reversed by GW1516 intervention. Thus, PPAR delta agonist treatment inhibits the progression of preestablished hepatic steatosis.
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