title: Scavenger receptor CD36 mediates inhibition of cholesterol synthesis via activation of the PPARγ/PGC-1α pathway and Insig1/2 expression in hepatocytes.
abstract: The scavenger receptor CD36 plays a central role in lipid metabolism by promoting macrophage cholesterol efflux with the potential to reduce atherosclerotic lesions. However, the effect of CD36 on de novo cholesterol synthesis is not known. Here, we describe the cellular mechanism by which CD36 activation induces cholesterol depletion in HepG2 cells. Using the CD36 ligand hexarelin, we found a rapid phosphorylation of HMG-CoA reductase Ser-872 in treated cells, resulting in inactivation of the rate-limiting enzyme in sterol synthesis. Degradation of HMG-CoA reductase by the ubiquitin-proteasome pathway was also enhanced by hexarelin, through an increased recruitment of the anchor proteins insulin-induced gene (Insig)-1 and Insig-2. Genes encoding key enzymes involved in cholesterol synthesis and under the control of transcription factor sterol regulatory element-binding protein (SREBP)-2 remained unresponsive to sterol depletion, due to retention of the SREBP-2 escort protein Scap by Insig-1/2. Insig1 and Insig2 gene expression was also increased through activation of nuclear receptor peroxisome-proliferator activating receptor γ (PPARγ) by CD36, which lifted the inhibitory effect of PPARγ1 Ser-84 phosphorylation. Recruitment of coactivator peroxisome proliferator-activated receptor-γ coactivator 1α (PGC1α) to activated AMPKα was also promoted, resulting in PGC-1α transcriptional activation through Sirt1-mediated deacetylation, increased recruitment of PPARγ, and up-regulation of Insig-1/2, revealing a regulatory role of CD36 on PGC-1α signaling. Our data identify CD36 as a novel regulator of HMG-CoA reductase function and Insig-1/2 expression, 2 critical steps regulating cholesterol synthesis in hepatocytes.
authors.affiliation: 1Research Center, Ste-Justine Hospital, 3175 Côte Ste-Catherine, Montréal, QC, Canada, H3T 1C5. andre.tremblay.1@umontreal.ca.
authors.forename: Amélie
authors.initials: A
authors.lastname: Rodrigue-Way
authors.forename: Véronique
authors.initials: V
authors.lastname: Caron
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Bilodeau
authors.forename: Sarah
authors.initials: S
authors.lastname: Keil
authors.forename: Meryl
authors.initials: M
authors.lastname: Hassan
authors.forename: Emile
authors.initials: E
authors.lastname: Lévy
authors.forename: Grant A
authors.initials: GA
authors.lastname: Mitchell
authors.forename: André
authors.initials: A
authors.lastname: Tremblay
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D015153:Blotting, Western; D018955:CD36 Antigens / Q000235:genetics / Q000378:metabolism*; D002784:Cholesterol / Q000096:biosynthesis*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D057809:HEK293 Cells; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D006903:Hydroxymethylglutaryl CoA Reductases / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D009842:Oligopeptides / Q000494:pharmacology; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism*; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D010766:Phosphorylation / Q000187:drug effects; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012694:Serine / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D051782:Sterol Regulatory Element Binding Protein 2 / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: D018955:CD36 Antigens; C108626:INSIG1 protein, human; C467727:INSIG2 protein, human; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D009842:Oligopeptides; D047495:PPAR gamma; C486497:PPARGC1A protein, human; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C497390:SREBF2 protein, human; D051782:Sterol Regulatory Element Binding Protein 2; D014157:Transcription Factors; C086184:hexarelin; D012694:Serine; D002784:Cholesterol; D006903:Hydroxymethylglutaryl CoA Reductases; D055372:AMP-Activated Protein Kinases
keywords: HMG-CoA reductase; Insig-1/2; SREBP-2; hexarelin