title: Uric acid induces fat accumulation via generation of endoplasmic reticulum stress and SREBP-1c activation in hepatocytes.
abstract: Non-alcoholic fatty liver disease (NAFLD) is currently one of the most common types of chronic liver injury. Elevated serum uric acid is a strong predictor of the development of fatty liver as well as metabolic syndrome. Here we demonstrate that uric acid induces triglyceride accumulation by SREBP-1c activation via induction of endoplasmic reticulum (ER) stress in hepatocytes. Uric acid-induced ER stress resulted in an increase of glucose-regulated protein (GRP78/94), splicing of the X-box-binding protein-1 (XBP-1), the phosphorylation of protein kinase RNA-like ER kinase (PERK), and eukaryotic translation initiation factor-2α (eIF-2α) in cultured hepatocytes. Uric acid promoted hepatic lipogenesis through overexpression of the lipogenic enzyme, acetyl-CoA carboxylase 1 (ACC1), fatty acid synthase (FAS), and stearoyl-CoA desaturase 1 (SCD1) via activation of SREBP-1c, which was blocked by probenecid, an organic anion transport blocker in HepG2 cells and primary hepatocytes. A blocker of ER stress, tauroursodeoxycholic acid (TUDCA), and an inhibitor of SREBP-1c, metformin, blocked hepatic fat accumulation, suggesting that uric acid promoted fat synthesis in hepatocytes via ER stress-induced activation of SREBP-1c. Uric acid-induced activation of NADPH oxidase preceded ER stress, which further induced mitochondrial ROS production in hepatocytes. These studies provide new insights into the mechanisms by which uric acid stimulates fat accumulation in the liver.
authors.affiliation: Department of Internal Medicine, Ewha Womans University School of Medicine, Ewha Medical Research Center, Seoul, Republic of Korea.
authors.forename: Yea-Jin
authors.initials: YJ
authors.lastname: Choi
authors.affiliation: Department of Internal Medicine, Ewha Womans University School of Medicine, Ewha Medical Research Center, Seoul, Republic of Korea.
authors.forename: Hyun-Soo
authors.initials: HS
authors.lastname: Shin
authors.affiliation: Department of Internal Medicine, Ewha Womans University School of Medicine, Ewha Medical Research Center, Seoul, Republic of Korea.
authors.forename: Hack Sun
authors.initials: HS
authors.lastname: Choi
authors.affiliation: Department of Biochemistry, Ewha Womans University School of Medicine, Ewha Medical Research Center, Seoul, Republic of Korea.
authors.forename: Joo-Won
authors.initials: JW
authors.lastname: Park
authors.affiliation: Department of Molecular Medicine, Ewha Womans University School of Medicine, Ewha Medical Research Center, Seoul, Republic of Korea.
authors.forename: Inho
authors.initials: I
authors.lastname: Jo
authors.affiliation: Department of Life Sciences, Division of Life and Pharmaceutical Sciences, Ewha Womans University, Seoul, Republic of Korea.
authors.forename: Eok-Soo
authors.initials: ES
authors.lastname: Oh
authors.affiliation: College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Republic of Korea.
authors.forename: Kang-Yo
authors.initials: KY
authors.lastname: Lee
authors.affiliation: College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Republic of Korea.
authors.forename: Byung-Hoon
authors.initials: BH
authors.lastname: Lee
authors.affiliation: The Division of Renal Diseases and Hypertension, University of Colorado Denver, Aurora, Colorado, USA.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Johnson
authors.affiliation: Department of Internal Medicine, Ewha Womans University School of Medicine, Ewha Medical Research Center, Seoul, Republic of Korea.
authors.forename: Duk-Hee
authors.initials: DH
authors.lastname: Kang
mesh_terms: D000103:Acetyl-CoA Carboxylase / Q000378:metabolism; D000818:Animals; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress; D064429:Fatty Acid Synthases / Q000378:metabolism; D005234:Fatty Liver / Q000209:etiology*; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D050155:Lipogenesis; D051379:Mice; D013230:Stearoyl-CoA Desaturase / Q000378:metabolism; D051780:Sterol Regulatory Element Binding Protein 1 / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism; D014280:Triglycerides / Q000378:metabolism; D014527:Uric Acid / Q000378:metabolism*
chemical_list: D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; C000717248:Hspa5 protein, mouse; D051780:Sterol Regulatory Element Binding Protein 1; D014157:Transcription Factors; D014280:Triglycerides; D014527:Uric Acid; C523776:SCD1 protein, human; D013230:Stearoyl-CoA Desaturase; D064429:Fatty Acid Synthases; C000588423:ACACA protein, human; D000103:Acetyl-CoA Carboxylase
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