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.