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.