RGC-32 deficiency protects against hepatic steatosis by reducing lipogenesis [Metabolism]

July 1st, 2015 by Cui, X.-B., Luan, J.-N., Chen, S.-Y.

Hepatic steatosis is associated with insulin resistance and metabolic syndrome due to the increased hepatic triglyceride content. We previously reported that deficiency of response gene to complement 32 (RGC-32) prevents high-fat diet (HFD)-induced obesity and insulin resistance in mice. The present study was conducted to determine the role of RGC-32 in the regulation of hepatic steatosis. We observed that hepatic RGC-32 was dramatically induced by both HFD challenge and ethanol administration. RGC-32 knockout (RGC32-/-) mice were resistant to HFD- and ethanol-induced hepatic steatosis. Hepatic triglyceride contents of RGC32-/- mice were significantly decreased compared with wild-type (WT) controls even under normal chow conditions. Moreover, RGC-32 deficiency decreased expression of lipogenesis-related genes, sterol regulatory element (SRE) binding protein (SREBP)-1c, fatty acid synthase (FAS), and stearoyl-CoA desaturase-1 (SCD1). RGC-32 deficiency also decreased SCD1 activity, indicated by decreased desaturase indices of the liver and serum. Mechanistically, insulin and ethanol induced RGC-32 expression through nuclear factor (NF)-κB signaling pathway, which in turn increased SCD1 expression in a SREBP-1c-dependent manner. RGC-32 also promoted SREBP-1c expression through activating liver X receptor (LXR). These results demonstrate that RGC-32 contributes to the development of hepatic steatosis by facilitating de novo lipogenesis through activating LXR, leading to the induction of SREBP-1c and its target genes. Therefore, RGC-32 may be a potential novel drug target for the treatment of hepatic steatosis and its related diseases.