Noncanonical farnesoid X receptor signaling inhibits apoptosis and impedes liver fibrosis

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 antiapoptotic molecular events and it lacks effective approach to combat hepatocyte apoptosis. We investigated the anti-apoptotic effect and mechanism of famesoid 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 antifibrotic 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. Adenoviius-FXR transfection impedes liver fibrosis in CCI4-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. (C) 2018 Published by Elsevier B.V.