title: RGC-32 Deficiency Protects against Hepatic Steatosis by Reducing Lipogenesis.
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.
authors.affiliation: From the Department of Physiology and Pharmacology, University of Georgia, Athens, Georgia 30602 and.
authors.forename: Xiao-Bing
authors.initials: XB
authors.lastname: Cui
authors.affiliation: From the Department of Physiology and Pharmacology, University of Georgia, Athens, Georgia 30602 and.
authors.forename: Jun-Na
authors.initials: JN
authors.lastname: Luan
authors.affiliation: From the Department of Physiology and Pharmacology, University of Georgia, Athens, Georgia 30602 and the Institute of Clinical Medicine and Department of Cardiology, Renmin Hospital, Hubei Medical University, Shiyan, 442000 Hubei, China sc229@uga.edu.
authors.forename: Shi-You
authors.initials: SY
authors.lastname: Chen
mesh_terms: D000818:Animals; D059305:Diet, High-Fat; D000431:Ethanol / Q000633:toxicity; D005234:Fatty Liver / Q000139:chemically induced / Q000235:genetics / Q000517:prevention & control*; D050155:Lipogenesis / Q000235:genetics*; D000071518:Liver X Receptors; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics / Q000502:physiology*; D057093:Orphan Nuclear Receptors / Q000378:metabolism; D015398:Signal Transduction; D051780:Sterol Regulatory Element Binding Protein 1 / Q000378:metabolism
chemical_list: D000071518:Liver X Receptors; D016328:NF-kappa B; D009687:Nuclear Proteins; D057093:Orphan Nuclear Receptors; C520017:Rgc-32 protein, mouse; D051780:Sterol Regulatory Element Binding Protein 1; D000431:Ethanol
keywords: gene expression; hepatic steatosis; lipogenesis; liver; metabolism; response gene to complement 32; stearoyl-CoA desaturase 1; transcription