1. Academic Validation
  2. Noncanonical farnesoid X receptor signaling inhibits apoptosis and impedes liver fibrosis

Noncanonical farnesoid X receptor signaling inhibits apoptosis and impedes liver fibrosis

  • EBioMedicine. 2018 Nov;37:322-333. doi: 10.1016/j.ebiom.2018.10.028.
Hong Wang 1 Chaoliang Ge 2 Jiyu Zhou 1 Yitong Guo 1 Shuang Cui 1 Ningning Huang 1 Tingting Yan 3 Lijuan Cao 1 Yuan Che 1 Qiuling Zheng 1 Xiao Zheng 1 Frank J Gonzalez 3 Guangji Wang 4 Haiping Hao 5
Affiliations

Affiliations

  • 1 State Key Laboratory of Natural Medicines, Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing 210009, China.
  • 2 State 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, China.
  • 3 Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
  • 4 State Key Laboratory of Natural Medicines, Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing 210009, China. Electronic address: gjwang@cpu.edu.cn.
  • 5 State Key Laboratory of Natural Medicines, Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing 210009, China. Electronic address: haipinghao@cpu.edu.cn.
Abstract

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; Caspase 8; FXR; Liver fibrosis; Transactivation independent.

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