Abstract
Hepatic steatosis is associated with obesity due to the increased lipogenesis. Previously, we have found that RGC-32 (response gene to complement 32) deficiency prevents the mice from high-fat diet (HFD)-induced obesity and insulin resistance. The present study was conducted to determine the role of RGC-32 in the control of hepatic steatosis. We observed that hepatic RGC-32 expression was dramatically induced by HFD challenge. RGC-32 knockout (RGC32-/-) mice were resistant to HFD-induced hepatic steatosis. More importantly, hepatic triglyceride contents of RGC32-/- mice were significantly decreased compared with wild-type (WT) controls on both normal chow and HFD. Mechanistically, 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). Our in vitro study showed that RGC-32 knockdown decreased while RGC-32 overexpression increased SCD1 expression in hepatocytes. Deletion or mutation of SRE in the SCD1 promoter abolished the function of RGC-32. These data demonstrate that RGC-32 contributes to HFD-induced hepatic steatosis by facilitating de novo lipogenesis in a SREBP-1c dependent manner. Therefore, RGC-32 may be a novel drug target in the treatment of hepatic steatosis and its related diseases.
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