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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.

SUBMITTER: Cheng Y

PROVIDER: S-EPMC4959313 | biostudies-literature | 2016 Jun

REPOSITORIES: biostudies-literature

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Liver-Specific Deletion of SRSF2 Caused Acute Liver Failure and Early Death in Mice.

Cheng Yuanming Y Luo Chunling C Wu Wenwu W Xie Zhiqin Z Fu Xiangdong X Feng Ying Y

Molecular and cellular biology 20160516 11

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 ...[more]

PMID: 27022105

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Project description:BACKGROUND & AIMS:Acute liver failure (ALF) caused by hepatitis B virus (HBV) infection can occur after immunosuppressive treatment and be fatal, although it might be preventable. We aimed to characterize the causes, clinical course, and short-term outcomes of HBV-associated ALF after immune-suppressive therapy, compared with patients with HBV-associated ALF without immunosuppression (control subjects). METHODS:We performed a retrospective multicenter study of 156 consecutive patients diagnosed with HBV-associated ALF (22 with a solid or blood malignancy) enrolled in the Acute Liver Failure Study Group registry from January 1998 through April 2015. We collected data on results of serologic and hepatic biochemistry analyses, grade of hepatic encephalopathy, Model for End-Stage Liver Disease score, and King's College criteria. We also collected data on clinical features, medical therapies, and complications in the first 7 days following study enrollment. Logistic regression was used to identify factors associated with transplant-free survival at 21 days in HBV-associated ALF (the primary outcome). RESULTS:Among patients with HBV-associated ALF, 28 cases (18%) occurred after immunosuppressive therapy (15 patients received systemic corticosteroids and 21 received chemotherapy); and 128 cases did not (control subjects, 82%). Significantly greater proportions of patients with HBV-associated ALF after immunosuppression were nonwhite persons, and had anemia or thrombocytopenia than controls (P < .02 for all). The serologic profile of HBV infection, severity of liver failure (based on MELD score), and complications (hepatic encephalopathy or need for mechanical ventilation, vasopressors, or renal replacement therapy) were similar between the groups (P > .17 for all). Factors associated with 21 day transplant-free survival were increased MELD score (odds ratio ?OR, 0.894 (95% confidence interval 0.842-0.949 per increment), requirement for mechanical ventilation (OR 0.111(0.041-0.300), and immunosuppressive therapy (OR 0.274(0.082-0.923)). CONCLUSIONS:Within a cohort study of patients with HBV-associated ALF, 18% had received immunosuppressive therapy. Significantly smaller proportions of patients with HBV-associated ALF after immunosuppression survive beyond 21 days than patients with HBV-associated ALF who did not receive immunosuppression. Patients undergoing chemotherapy should be screened for HBV infection and given appropriate antiviral therapies to reduce preventable mortality.

Dataset Information

Liver-Specific Deletion of SRSF2 Caused Acute Liver Failure and Early Death in Mice.

Publications

Liver-Specific Deletion of SRSF2 Caused Acute Liver Failure and Early Death in Mice.

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