Abstract
Hepatic steatosis is associated with insulin resistance and metabolic syndrome because of increased hepatic triglyceride content. We have reported previously that deficiency of response gene to complement 32 (RGC-32) prevents high-fat diet (HFD)-induced obesity and insulin resistance in mice. This study was conducted to determine the role of RGC-32 in the regulation of hepatic steatosis. We observed that hepatic RGC-32 was induced dramatically by both HFD challenge and ethanol administration. RGC-32 knockout (RGC32(-/-)) mice were resistant to HFD- and ethanol-induced hepatic steatosis. The hepatic triglyceride content of RGC32(-/-) mice was decreased significantly compared with WT controls even under normal chow conditions. Moreover, RGC-32 deficiency decreased the expression of lipogenesis-related genes, sterol regulatory element binding protein 1c (SREBP-1c), fatty acid synthase, and stearoyl-CoA desaturase 1 (SCD1). RGC-32 deficiency also decreased SCD1 activity, as indicated by decreased desaturase indices of the liver and serum. Mechanistically, insulin and ethanol induced RGC-32 expression through the 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. These results demonstrate that RGC-32 contributes to the development of hepatic steatosis by facilitating de novo lipogenesis through activating liver X receptor, 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.
Highlights
Hepatic steatosis is an increasing health concern associated with metabolic syndrome
response gene to complement 32 (RGC-32) Deficiency Prevented high-fat diet (HFD)-induced Hepatic Steatosis— Our previous studies have shown that RGC-32 expression in adipose tissue was induced by HFD challenge, and RGC-32 deficiency prevented HFD-induced obesity and insulin resistance [20]
To test whether RGC-32 affects liver during HFD-induced obesity, we first detected RGC-32 expression in liver tissues from WT mice fed normal chow or a 12-week HFD. We found that both mRNA and protein expression of RGC-32 was dramatically up-regulated by the HFD challenge (Fig. 1, A and B)
Summary
Hepatic steatosis is an increasing health concern associated with metabolic syndrome. Results: RGC-32 deficiency protects mice from HFD- and ethanol-induced hepatic steatosis by decreasing hepatic lipogenic gene expression. We have reported previously that deficiency of response gene to complement 32 (RGC-32) prevents high-fat diet (HFD)-induced obesity and insulin resistance in mice. RGC-32 deficiency decreased the expression of lipogenesis-related genes, sterol regulatory element binding protein 1c (SREBP-1c), fatty acid synthase, and stearoyl-CoA desaturase 1 (SCD1). Mice with a global or liver-specific knockout of SCD1 are protected from diet-induced obesity, hepatic steatosis, and insulin resistance (9 –11). We found recently that RGC-32 deficiency (RGC32Ϫ/Ϫ) protected mice from high-fat diet (HFD)-induced obesity and insulin resistance through alleviating inflammation and increasing energy expenditure of adipose tissue [20]. Our results indicate that RGC-32 is potentially a novel regulator of hepatic lipid metabolism
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