title: Liver-Specific Deletion of SRSF2 Caused Acute Liver Failure and Early Death in Mice.
abstract: The liver performs a variety of unique functions critical for metabolic homeostasis. Here, we show that mice lacking the splicing factor SRSF2 but not SRSF1 in hepatocytes have severe liver pathology and biochemical abnormalities. Histological analyses revealed generalized hepatitis with the presence of ballooned hepatocytes and evidence of fibrosis. Molecular analysis demonstrated that SRSF2 governs splicing of multiple genes involved in the stress-induced cell death pathway in the liver. More importantly, SRSF2 also functions as a potent transcription activator, required for efficient expression of transcription factors mainly responsible for energy homeostasis and bile acid metabolism in the liver. Consistent with the effects of SRSF2 in gene regulation, accumulation of total cholesterol and bile acids was prominently observed in the mutant liver, followed by enhanced generation of reactive oxygen species and increased endoplasmic reticulum stress, as revealed by biochemical and ultrastructural analyses. Taking these observations together, inactivation of SRSF2 in liver caused dysregulated splicing events and hepatic metabolic disorders, which trigger endoplasmic reticulum stress, oxidative stress, and finally liver failure.
authors.affiliation: Key Laboratory of Food Safety Research, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
authors.forename: Yuanming
authors.initials: Y
authors.lastname: Cheng
authors.affiliation: Key Laboratory of Food Safety Research, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
authors.forename: Chunling
authors.initials: C
authors.lastname: Luo
authors.affiliation: Key Laboratory of Food Safety Research, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
authors.forename: Wenwu
authors.initials: W
authors.lastname: Wu
authors.affiliation: Key Laboratory of Food Safety Research, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
authors.forename: Zhiqin
authors.initials: Z
authors.lastname: Xie
authors.affiliation: Department of Cell and Molecular Medicine, University of California at San Diego, San Diego, California, USA.
authors.forename: Xiangdong
authors.initials: X
authors.lastname: Fu
authors.affiliation: Key Laboratory of Food Safety Research, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China fengying@sibs.ac.cn.
authors.forename: Ying
authors.initials: Y
authors.lastname: Feng
mesh_terms: D000818:Animals; D001647:Bile Acids and Salts / Q000378:metabolism; D002478:Cells, Cultured; D004195:Disease Models, Animal; D059865:Endoplasmic Reticulum Stress; D004734:Energy Metabolism; D020869:Gene Expression Profiling / Q000379:methods; D005786:Gene Expression Regulation; D055786:Gene Knockout Techniques; D022781:Hepatocytes / Q000378:metabolism*; D017114:Liver Failure, Acute / Q000235:genetics / Q000401:mortality*; D051379:Mice; D018384:Oxidative Stress; D012326:RNA Splicing; D017423:Sequence Analysis, RNA / Q000379:methods*; D000068103:Serine-Arginine Splicing Factors / Q000172:deficiency*; D014157:Transcription Factors / Q000235:genetics*; D015533:Transcriptional Activation
chemical_list: D001647:Bile Acids and Salts; C499372:SRSF2 protein, mouse; D014157:Transcription Factors; D000068103:Serine-Arginine Splicing Factors