title: Clusterin decreases hepatic SREBP-1c expression and lipid accumulation.
abstract: Hepatic steatosis is emerging as the most important cause of chronic liver disease and is associated with the increasing incidence of obesity with insulin resistance. Sterol regulatory binding protein-1c (SREBP-1c) is a master regulator of lipogenic gene expression in the liver. Hyperinsulinemia induces SREBP-1c transcription through liver X receptor (LXR), specificity protein 1, and SREBP-1c itself. Clusterin, an 80-kDa disulfide-linked heterodimeric protein, has been functionally implicated in several physiological processes including lipid transport; however, little is known about its effect on hepatic lipogenesis. The present study examined whether clusterin regulates SREBP-1c expression and lipid accumulation in the liver. Adenovirus-mediated overexpression of clusterin inhibited insulin- or LXR agonist-stimulated SREBP-1c expression in cultured liver cells. In reporter assays, clusterin inhibited SREBP-1c promoter activity. Moreover, adenovirus-mediated overexpression of clusterin in the livers of mice fed a high-fat diet inhibited hepatic steatosis through the inhibition of SREBP-1c expression. Reporter and gel shift assays showed that clusterin inhibits SREBP-1c expression via the repression of LXR and specificity protein 1 activity. This study shows that clusterin inhibits hepatic lipid accumulation through the inhibition of SREBP-1c expression and suggests that clusterin is a negative regulator of SREBP-1c expression and hepatic lipogenesis.
authors.affiliation: Department of Internal Medicine, Kyungpook National University School of Medicine, 50 Samduk-2ga, Jung-gu, Daegu 700-721, South Korea.
authors.forename: Hye-Young
authors.initials: HY
authors.lastname: Seo
authors.forename: Mi-Kyung
authors.initials: MK
authors.lastname: Kim
authors.forename: Yun-A
authors.initials: YA
authors.lastname: Jung
authors.forename: Byoung Kuk
authors.initials: BK
authors.lastname: Jang
authors.forename: Eun-Kyung
authors.initials: EK
authors.lastname: Yoo
authors.forename: Keun-Gyu
authors.initials: KG
authors.lastname: Park
authors.forename: In-Kyu
authors.initials: IK
authors.lastname: Lee
mesh_terms: D000818:Animals; D051152:Clusterin / Q000235:genetics / Q000494:pharmacology / Q000502:physiology*; D005786:Gene Expression Regulation / Q000187:drug effects; D056945:Hep G2 Cells; D006801:Humans; D050356:Lipid Metabolism / Q000187:drug effects* / Q000235:genetics; D050155:Lipogenesis / Q000187:drug effects / Q000235:genetics; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D051381:Rats; D051780:Sterol Regulatory Element Binding Protein 1 / Q000235:genetics* / Q000378:metabolism; D014407:Tumor Cells, Cultured
chemical_list: D051152:Clusterin; D051780:Sterol Regulatory Element Binding Protein 1