27-Hydroxycholesterol Inhibits Sterol Regulatory Element-Binding Protein 1 Activation and Hepatic Lipid Accumulation in Mice.

Although 27-hydroxycholesterol (27-HC) has been reported as a potent regulator of lipid homeostasis, its role in hepatic lipogenesis remains obscure. The present study was designed to investigate the impact of 27-HC on sterol regulatory element-binding protein 1 (SREBP-1) and hepatic steatosis. In this study, the 27-HC level in mice was upregulated by overexpressing CYP27A1 or treating primary hepatocytes with 27-HC, and then the hepatic lipid accumulation was detected. 27-HC inhibited hepatic lipid accumulation and decreased the levels of the mature active form of SREBP-1. The expression of lipogenic genes, including acetyl coenzyme A carboxylase, fatty acid synthase, stearoyl-coenzyme A desaturase-1, and glycerol-3-phosphate acyltransferase, were also suppressed after 27-HC intervention. Furthermore, 27-HC induced expression of insulin-induced gene-2 (Insig-2), an endoplasmic reticulum protein that prevents SREBP activation, both in vivo and in vitro. The inhibitory effect of 27-HC on SREBP-1 activation was absent when Insig-2 was silenced. Finally, coimmunoprecipitation showed that 27-HC promoted the binding of Insig-2 to SREBP-1. These studies demonstrated the suppressive effect of 27-HC on hepatic lipid accumulation and revealed a novel mechanism by which 27-HC regulates lipogenesis.