title: Deficiency of liver Comparative Gene Identification-58 causes steatohepatitis and fibrosis in mice.
abstract: Triglyceride (TG) accumulation in hepatocytes (hepatic steatosis) preludes the development of advanced nonalcoholic fatty liver diseases (NAFLDs) such as steatohepatitis, fibrosis, and cirrhosis. Mutations in human Comparative Gene Identification-58 (CGI-58) cause cytosolic TG-rich lipid droplets to accumulate in almost all cell types including hepatocytes. However, it is unclear if CGI-58 mutation causes hepatic steatosis locally or via altering lipid metabolism in other tissues. To directly address this question, we created liver-specific CGI-58 knockout (LivKO) mice. LivKO mice on standard chow diet displayed microvesicular and macrovesicular panlobular steatosis, and progressed to advanced NAFLD stages over time, including lobular inflammation and centrilobular fibrosis. Compared with CGI-58 floxed control littermates, LivKO mice showed 8-fold and 52-fold increases in hepatic TG content, which was associated with 40% and 58% decreases in hepatic TG hydrolase activity at 16 and 42 weeks, respectively. Hepatic cholesterol also increased significantly in LivKO mice. At 42 weeks, LivKO mice showed increased hepatic oxidative stress, plasma aminotransferases, and hepatic mRNAs for genes involved in fibrosis and inflammation, such as α-smooth muscle actin, collagen type 1 α1, tumor necrosis factor α, and interleukin-1β. In conclusion, CGI-58 deficiency in the liver directly causes not only hepatic steatosis but also steatohepatitis and fibrosis.
authors.affiliation: Departments of Biochemistry and Wake Forest University School of Medicine, Winston-Salem, NC.
authors.forename: Feng
authors.initials: F
authors.lastname: Guo
authors.affiliation: Departments of Biochemistry and Wake Forest University School of Medicine, Winston-Salem, NC; Department of Animal and Avian Sciences, University of Maryland, College Park, MD.
authors.forename: Yinyan
authors.initials: Y
authors.lastname: Ma
authors.affiliation: Department of Animal and Avian Sciences, University of Maryland, College Park, MD.
authors.forename: Anil K G
authors.initials: AKG
authors.lastname: Kadegowda
authors.affiliation: Department of Pathology, Section on Lipid Sciences, Wake Forest University School of Medicine, Winston-Salem, NC.
authors.forename: Jenna L
authors.initials: JL
authors.lastname: Betters
authors.affiliation: Departments of Biochemistry and Wake Forest University School of Medicine, Winston-Salem, NC.
authors.forename: Ping
authors.initials: P
authors.lastname: Xie
authors.affiliation: Institute of Cardiovascular Sciences and Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education, Peking University Health Science Center, Beijing, China.
authors.forename: George
authors.initials: G
authors.lastname: Liu
authors.affiliation: Department of Anatomic Pathology, Cleveland Clinic, Cleveland, OH.
authors.forename: Xiuli
authors.initials: X
authors.lastname: Liu
authors.affiliation: Department of Animal and Avian Sciences, University of Maryland, College Park, MD.
authors.forename: Hongming
authors.initials: H
authors.lastname: Miao
authors.affiliation: Department of Animal and Avian Sciences, University of Maryland, College Park, MD.
authors.forename: Juanjuan
authors.initials: J
authors.lastname: Ou
authors.affiliation: Nutritional Sciences and Departments of Medicine, Cell Biology, and Physiology, Washington University School of Medicine, St. Louis, MO.
authors.forename: Xiong
authors.initials: X
authors.lastname: Su
authors.affiliation: Plastic Surgery, Wake Forest University School of Medicine, Winston-Salem, NC.
authors.forename: Zhenlin
authors.initials: Z
authors.lastname: Zheng
authors.affiliation: Department of Biology, Georgia State University, Atlanta, GA; and.
authors.forename: Bingzhong
authors.initials: B
authors.lastname: Xue
authors.affiliation: Department of Biology, Georgia State University, Atlanta, GA; and.
authors.forename: Hang
authors.initials: H
authors.lastname: Shi
authors.affiliation: Departments of Biochemistry and Wake Forest University School of Medicine, Winston-Salem, NC; Department of Animal and Avian Sciences, University of Maryland, College Park, MD. Electronic address: lyu123@umd.edu.
authors.forename: Liqing
authors.initials: L
authors.lastname: Yu
mesh_terms: D051103:1-Acylglycerol-3-Phosphate O-Acyltransferase / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D005234:Fatty Liver / Q000378:metabolism* / Q000473:pathology; D005260:Female; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D008103:Liver Cirrhosis / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout
chemical_list: D051103:1-Acylglycerol-3-Phosphate O-Acyltransferase; C492986:Abhd5 protein, mouse
keywords: CGI-58; fatty liver; lipase; triglyceride hydrolysis