Noncanonical farnesoid X receptor signaling inhibits apoptosis and impedes liver fibrosisResearch in context
Background: Hepatocyte is particularly vulnerable to apoptosis, a hallmark of many liver diseases. Although pro-apoptotic mechanisms have been extensively explored, less is known about the hepatocyte-specific anti-apoptotic molecular events and it lacks effective approach to combat hepatocyte apopto...
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| Format: | Article |
| Language: | English |
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Elsevier
2018-11-01
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| Series: | EBioMedicine |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2352396418304468 |
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Article |
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DOAJ |
| language |
English |
| format |
Article |
| sources |
DOAJ |
| author |
Hong Wang Chaoliang Ge Jiyu Zhou Yitong Guo Shuang Cui Ningning Huang Tingting Yan Lijuan Cao Yuan Che Qiuling Zheng Xiao Zheng Frank J. Gonzalez Guangji Wang Haiping Hao |
| spellingShingle |
Hong Wang Chaoliang Ge Jiyu Zhou Yitong Guo Shuang Cui Ningning Huang Tingting Yan Lijuan Cao Yuan Che Qiuling Zheng Xiao Zheng Frank J. Gonzalez Guangji Wang Haiping Hao Noncanonical farnesoid X receptor signaling inhibits apoptosis and impedes liver fibrosisResearch in context EBioMedicine |
| author_facet |
Hong Wang Chaoliang Ge Jiyu Zhou Yitong Guo Shuang Cui Ningning Huang Tingting Yan Lijuan Cao Yuan Che Qiuling Zheng Xiao Zheng Frank J. Gonzalez Guangji Wang Haiping Hao |
| author_sort |
Hong Wang |
| title |
Noncanonical farnesoid X receptor signaling inhibits apoptosis and impedes liver fibrosisResearch in context |
| title_short |
Noncanonical farnesoid X receptor signaling inhibits apoptosis and impedes liver fibrosisResearch in context |
| title_full |
Noncanonical farnesoid X receptor signaling inhibits apoptosis and impedes liver fibrosisResearch in context |
| title_fullStr |
Noncanonical farnesoid X receptor signaling inhibits apoptosis and impedes liver fibrosisResearch in context |
| title_full_unstemmed |
Noncanonical farnesoid X receptor signaling inhibits apoptosis and impedes liver fibrosisResearch in context |
| title_sort |
noncanonical farnesoid x receptor signaling inhibits apoptosis and impedes liver fibrosisresearch in context |
| publisher |
Elsevier |
| series |
EBioMedicine |
| issn |
2352-3964 |
| publishDate |
2018-11-01 |
| description |
Background: Hepatocyte is particularly vulnerable to apoptosis, a hallmark of many liver diseases. Although pro-apoptotic mechanisms have been extensively explored, less is known about the hepatocyte-specific anti-apoptotic molecular events and it lacks effective approach to combat hepatocyte apoptosis. We investigated the anti-apoptotic effect and mechanism of farnesoid X receptor (FXR), and strategies of how to target FXR for inhibiting apoptosis implicated in liver fibrosis. Methods: Sensitivity to apoptosis was compared between wild type and Fxr−/− mice and in cultured cells. Cell-based and cell-free assays were employed to identify the binding protein of FXR and to uncover the mechanism of its anti-apoptotic effect. Overexpression of FXR by adenovirus-FXR was employed to determine its anti-fibrotic effect in CCl4-treated mice. Specimens from fibrotic patients were collected to validate the relevance of FXR on apoptosis/fibrosis. Findings: FXR deficiency sensitizes hepatocytes to death receptors (DRs)-engaged apoptosis. FXR overexpression, but not FXR ligands, inhibits apoptosis both in vitro and in vivo. Apoptotic stimuli lead to drastic reduction of FXR protein levels, a prerequisite for DRs-engaged apoptosis. Mechanistically, FXR interacts with caspase 8 (CASP8) in the cytoplasm, thus preventing the formation of death-inducing signaling complex (DISC) and activation of CASP8. Adenovirus-FXR transfection impedes liver fibrosis in CCl4-treated mice. Specimens from fibrotic patients are characterized with reduced FXR expression and compromised FXR/CASP8 colocalization. Interpretation: FXR represents an intrinsic apoptosis inhibitor in hepatocytes and can be targeted via restoring its expression or strengthening FXR/CASP8 interaction for inhibiting hepatocytes apoptosis in liver fibrosis. Fund: National Natural Science Foundation of China. Keywords: Apoptosis, Liver fibrosis, FXR, Caspase 8, Transactivation independent |
| url |
http://www.sciencedirect.com/science/article/pii/S2352396418304468 |
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doaj-d33de32aab2047ff956f4e8cc2e98ea32020-11-25T01:44:20ZengElsevierEBioMedicine2352-39642018-11-0137322333Noncanonical farnesoid X receptor signaling inhibits apoptosis and impedes liver fibrosisResearch in contextHong Wang0Chaoliang Ge1Jiyu Zhou2Yitong Guo3Shuang Cui4Ningning Huang5Tingting Yan6Lijuan Cao7Yuan Che8Qiuling Zheng9Xiao Zheng10Frank J. Gonzalez11Guangji Wang12Haiping Hao13State Key Laboratory of Natural Medicines, Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing 210009, ChinaState Key Laboratory of Natural Medicines, Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing 210009, China; Department of Pharmacy, The First Affiliated Hospital of Anhui Medical University, Hefei 230022, ChinaState Key Laboratory of Natural Medicines, Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing 210009, ChinaState Key Laboratory of Natural Medicines, Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing 210009, ChinaState Key Laboratory of Natural Medicines, Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing 210009, ChinaState Key Laboratory of Natural Medicines, Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing 210009, ChinaLaboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USAState Key Laboratory of Natural Medicines, Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing 210009, ChinaState Key Laboratory of Natural Medicines, Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing 210009, ChinaState Key Laboratory of Natural Medicines, Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing 210009, ChinaState Key Laboratory of Natural Medicines, Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing 210009, ChinaLaboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USAState Key Laboratory of Natural Medicines, Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing 210009, China; Corresponding authors.State Key Laboratory of Natural Medicines, Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing 210009, China; Corresponding authors.Background: Hepatocyte is particularly vulnerable to apoptosis, a hallmark of many liver diseases. Although pro-apoptotic mechanisms have been extensively explored, less is known about the hepatocyte-specific anti-apoptotic molecular events and it lacks effective approach to combat hepatocyte apoptosis. We investigated the anti-apoptotic effect and mechanism of farnesoid X receptor (FXR), and strategies of how to target FXR for inhibiting apoptosis implicated in liver fibrosis. Methods: Sensitivity to apoptosis was compared between wild type and Fxr−/− mice and in cultured cells. Cell-based and cell-free assays were employed to identify the binding protein of FXR and to uncover the mechanism of its anti-apoptotic effect. Overexpression of FXR by adenovirus-FXR was employed to determine its anti-fibrotic effect in CCl4-treated mice. Specimens from fibrotic patients were collected to validate the relevance of FXR on apoptosis/fibrosis. Findings: FXR deficiency sensitizes hepatocytes to death receptors (DRs)-engaged apoptosis. FXR overexpression, but not FXR ligands, inhibits apoptosis both in vitro and in vivo. Apoptotic stimuli lead to drastic reduction of FXR protein levels, a prerequisite for DRs-engaged apoptosis. Mechanistically, FXR interacts with caspase 8 (CASP8) in the cytoplasm, thus preventing the formation of death-inducing signaling complex (DISC) and activation of CASP8. Adenovirus-FXR transfection impedes liver fibrosis in CCl4-treated mice. Specimens from fibrotic patients are characterized with reduced FXR expression and compromised FXR/CASP8 colocalization. Interpretation: FXR represents an intrinsic apoptosis inhibitor in hepatocytes and can be targeted via restoring its expression or strengthening FXR/CASP8 interaction for inhibiting hepatocytes apoptosis in liver fibrosis. Fund: National Natural Science Foundation of China. Keywords: Apoptosis, Liver fibrosis, FXR, Caspase 8, Transactivation independenthttp://www.sciencedirect.com/science/article/pii/S2352396418304468 |