title: Hepatic Overexpression of CD36 Improves Glycogen Homeostasis and Attenuates High-Fat Diet-Induced Hepatic Steatosis and Insulin Resistance.
abstract: The common complications in obesity and type 2 diabetes include hepatic steatosis and disruption of glucose-glycogen homeostasis, leading to hyperglycemia. Fatty acid translocase (FAT/CD36), whose expression is inducible in obesity, is known for its function in fatty acid uptake. Previous work by us and others suggested that CD36 plays an important role in hepatic lipid homeostasis, but the results have been conflicting and the mechanisms were not well understood. In this study, by using CD36-overexpressing transgenic (CD36Tg) mice, we uncovered a surprising function of CD36 in regulating glycogen homeostasis. Overexpression of CD36 promoted glycogen synthesis, and as a result, CD36Tg mice were protected from fasting hypoglycemia. When challenged with a high-fat diet (HFD), CD36Tg mice showed unexpected attenuation of hepatic steatosis, increased very low-density lipoprotein (VLDL) secretion, and improved glucose tolerance and insulin sensitivity. The HFD-fed CD36Tg mice also showed decreased levels of proinflammatory hepatic prostaglandins and 20-hydroxyeicosatetraenoic acid (20-HETE), a potent vasoconstrictive and proinflammatory arachidonic acid metabolite. We propose that CD36 functions as a protective metabolic sensor in the liver under lipid overload and metabolic stress. CD36 may be explored as a valuable therapeutic target for the management of metabolic syndrome.
authors.affiliation: Center for Pharmacogenetics and Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
authors.forename: Wojciech G
authors.initials: WG
authors.lastname: Garbacz
authors.affiliation: Center for Pharmacogenetics and Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
authors.forename: Peipei
authors.initials: P
authors.lastname: Lu
authors.affiliation: Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
authors.forename: Tricia M
authors.initials: TM
authors.lastname: Miller
authors.affiliation: Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
authors.forename: Samuel M
authors.initials: SM
authors.lastname: Poloyac
authors.affiliation: School of Biological Sciences, University of Adelaide, Adelaide, Australia.
authors.forename: Nicholas S
authors.initials: NS
authors.lastname: Eyre
authors.affiliation: School of Biological Sciences, University of Adelaide, Adelaide, Australia.
authors.forename: Graham
authors.initials: G
authors.lastname: Mayrhofer
authors.affiliation: Center for Pharmacogenetics and Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
authors.forename: Meishu
authors.initials: M
authors.lastname: Xu
authors.affiliation: Center for Pharmacogenetics and Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
authors.forename: Songrong
authors.initials: S
authors.lastname: Ren
authors.affiliation: Center for Pharmacogenetics and Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, Pennsylvania, USA Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA wex6@pitt.edu.
authors.forename: Wen
authors.initials: W
authors.lastname: Xie
mesh_terms: D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism; D018955:CD36 Antigens / Q000378:metabolism*; D059305:Diet, High-Fat; D005215:Fasting / Q000097:blood; D005234:Fatty Liver / Q000097:blood / Q000378:metabolism*; D006003:Glycogen / Q000378:metabolism*; D006706:Homeostasis; D006893:Hydroxyeicosatetraenoic Acids / Q000378:metabolism; D007003:Hypoglycemia / Q000097:blood / Q000378:metabolism; D007333:Insulin Resistance; D008099:Liver / Q000378:metabolism*; D008822:Mice, Transgenic; D010101:Oxygen Consumption; D011453:Prostaglandins / Q000378:metabolism
chemical_list: D018955:CD36 Antigens; D006893:Hydroxyeicosatetraenoic Acids; D011453:Prostaglandins; D016718:Arachidonic Acid; C055987:20-hydroxy-5,8,11,14-eicosatetraenoic acid; D006003:Glycogen