title: PPARδ activation attenuates hepatic steatosis in Ldlr-/- mice by enhanced fat oxidation, reduced lipogenesis, and improved insulin sensitivity.
abstract: PPARδ regulates systemic lipid homeostasis and inflammation, but its role in hepatic lipid metabolism remains unclear. Here, we examine whether intervening with a selective PPARδ 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 β-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 AMPKβ1(-/-) hepatocytes. However, FA oxidation was only partially reduced in AMPKβ1(-/-) hepatocytes, suggesting an AMPK-independent contribution to the GW1516 effect. Similarly, PPARδ-mediated attenuation of FA synthesis was partially due to AMPK activation, as GW1516 reduced lipogenesis in WT hepatocytes but not AMPKβ1(-/-) 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, PPARδ agonist treatment inhibits the progression of preestablished hepatic steatosis.
authors.affiliation: Vascular Biology, Robarts Research Institute, The University of Western Ontario, London, Ontario, Canada, N6A 5B7 Departments of Biochemistry, The University of Western Ontario, London, Ontario, Canada, N6A 5B7.
authors.forename: Lazar A
authors.initials: LA
authors.lastname: Bojic
authors.affiliation: Vascular Biology, Robarts Research Institute, The University of Western Ontario, London, Ontario, Canada, N6A 5B7 Medicine, The University of Western Ontario, London, Ontario, Canada, N6A 5B7.
authors.forename: Dawn E
authors.initials: DE
authors.lastname: Telford
authors.affiliation: Division of Endocrinology and Metabolism, Department of Medicine, McMaster University, Hamilton, Ontario, Canada, L8S 4K1.
authors.forename: Morgan D
authors.initials: MD
authors.lastname: Fullerton
authors.affiliation: Division of Endocrinology and Metabolism, Department of Medicine, McMaster University, Hamilton, Ontario, Canada, L8S 4K1.
authors.forename: Rebecca J
authors.initials: RJ
authors.lastname: Ford
authors.affiliation: Vascular Biology, Robarts Research Institute, The University of Western Ontario, London, Ontario, Canada, N6A 5B7.
authors.forename: Brian G
authors.initials: BG
authors.lastname: Sutherland
authors.affiliation: Vascular Biology, Robarts Research Institute, The University of Western Ontario, London, Ontario, Canada, N6A 5B7 Medicine, The University of Western Ontario, London, Ontario, Canada, N6A 5B7.
authors.forename: Jane Y
authors.initials: JY
authors.lastname: Edwards
authors.affiliation: Vascular Biology, Robarts Research Institute, The University of Western Ontario, London, Ontario, Canada, N6A 5B7 Medicine, The University of Western Ontario, London, Ontario, Canada, N6A 5B7.
authors.forename: Cynthia G
authors.initials: CG
authors.lastname: Sawyez
authors.affiliation: Vascular Biology, Robarts Research Institute, The University of Western Ontario, London, Ontario, Canada, N6A 5B7 Physiology, Pharmacology, The University of Western Ontario, London, Ontario, Canada, N6A 5B7.
authors.forename: Robert
authors.initials: R
authors.lastname: Gros
authors.affiliation: St. Vincent's Institute of Medical Research and Department of Medicine, University of Melbourne, Fitzroy, Victoria 3065, Australia.
authors.forename: Bruce E
authors.initials: BE
authors.lastname: Kemp
authors.affiliation: Division of Endocrinology and Metabolism, Department of Medicine, McMaster University, Hamilton, Ontario, Canada, L8S 4K1.
authors.forename: Gregory R
authors.initials: GR
authors.lastname: Steinberg
authors.affiliation: Vascular Biology, Robarts Research Institute, The University of Western Ontario, London, Ontario, Canada, N6A 5B7 Departments of Biochemistry, The University of Western Ontario, London, Ontario, Canada, N6A 5B7 Medicine, The University of Western Ontario, London, Ontario, Canada, N6A 5B7.
authors.forename: Murray W
authors.initials: MW
authors.lastname: Huff
mesh_terms: D000818:Animals; D004041:Dietary Fats / Q000009:adverse effects* / Q000494:pharmacology; D005227:Fatty Acids / Q000096:biosynthesis* / Q000235:genetics; D005234:Fatty Liver / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D007333:Insulin Resistance; D050155:Lipogenesis / Q000187:drug effects* / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D010084:Oxidation-Reduction / Q000187:drug effects; D047494:PPAR delta / Q000235:genetics / Q000378:metabolism*; D011973:Receptors, LDL / Q000235:genetics / Q000378:metabolism*
chemical_list: D004041:Dietary Fats; D005227:Fatty Acids; D047494:PPAR delta; D011973:Receptors, LDL
keywords: adenosine monophosphate-activated protein kinase; energy expenditure; hepatic triglyceride; inflammation; insulin resistance; lipids