Deficiency of liver Comparative Gene Identification-58 causes steatohepatitis and fibrosis in mice

Feng Guo, Yinyan Ma, Anil K.G. Kadegowda, Jenna L. Betters, Ping Xie, George Liu, Xiuli Liu, Hongming Miao, Juanjuan Ou, Xiong Su, Zhenlin Zheng, Bingzhong Xue, Hang Shi, Liqing Yu

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46 Scopus citations

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 α 1, tumor necrosis factor , and interleukin-1 β . In conclusion, CGI-58 deficiency in the liver directly causes not only hepatic steatosis but also steatohepatitis and fibrosis.

Original languageEnglish
Pages (from-to)2109-2120
Number of pages12
JournalJournal of lipid research
Volume54
Issue number8
DOIs
StatePublished - Aug 2013

Keywords

  • CGI-58
  • Fatty liver
  • Lipase
  • Triglyceride hydrolysis

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    Guo, F., Ma, Y., Kadegowda, A. K. G., Betters, J. L., Xie, P., Liu, G., Liu, X., Miao, H., Ou, J., Su, X., Zheng, Z., Xue, B., Shi, H., & Yu, L. (2013). Deficiency of liver Comparative Gene Identification-58 causes steatohepatitis and fibrosis in mice. Journal of lipid research, 54(8), 2109-2120. https://doi.org/10.1194/jlr.M035519