2. Academic Validation
  3. 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: [email protected].
  • 5 State Key Laboratory of Natural Medicines, Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing 210009, China. Electronic address: [email protected].
PMID: 30337250 DOI: 10.1016/j.ebiom.2018.10.028
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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