Farnesoid X receptor (FXR) is a promising target for nonalcoholic steatohepatitis (NASH) and fibrosis. Although various FXR agonists have shown anti-fibrotic effects in diverse preclinical animal models, the response rate and efficacies in clinical trials were not optimum. Here we report that prophylactic but not therapeutic administration of obeticholic acid (OCA) prevents hepatic stellate cell (HSC) activation and fibrogenesis. Activated HSCs show limited response to OCA and other FXR agonists due to enhanced FXR SUMOylation. SUMOylation inhibitors rescue FXR signaling and thereby increasing the efficacy of OCA against HSC activation and fibrosis. FXR upregulates Perilipin-1, a direct target gene of FXR, to stabilize lipid droplets and thereby prevent HSC activation. Therapeutic coadministration of OCA and SUMOylation inhibitors drastically impedes liver fibrosis induced by CCl 4 , bile duct ligation, and more importantly NASH. In conclusion, we propose a promising therapeutic approach by combining SUMOylation inhibitors and FXR agonists for liver fibrosis.

BackgroundHepatocyte 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.MethodsSensitivity 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.FindingsFXR 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.InterpretationFXR 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.FundNational Natural Science Foundation of China.

Obeticholic acid (OCA), the first FXR-targeting drug, has been claimed effective in the therapy of liver fibrosis. However, recent clinical trials indicated that OCA might not be effective against liver fibrosis, possibly due to the lower dosage to reduce the incidence of the side-effect of pruritus. Here we propose a combinatory therapeutic strategy of OCA and apoptosis inhibitor for combating against liver fibrosis. CCl 4 -injured mice, d-galactosamine/LPS (GalN/LPS)-treated mice and cycloheximide/TNF α (CHX/TNF α )-treated HepG2 cells were employed to assess the effects of OCA, or together with IDN-6556, an apoptosis inhibitor. OCA treatment significantly inhibited hepatic stellate cell (HSC) activation/proliferation and prevented fibrosis. Elevated bile acid (BA) levels and hepatocyte apoptosis triggered the activation and proliferation of HSCs. OCA treatment reduced BA levels but could not inhibit hepatocellular apoptosis. An enhanced anti-fibrotic effect was observed when OCA was co-administrated with IDN-6556. Our study demonstrated that OCA inhibits HSCs activation/proliferation partially by regulating BA homeostasis and thereby inhibiting activation of HSCs. The findings in this study suggest that combined use of apoptosis inhibitor and OCA at lower dosage represents a novel therapeutic strategy for liver fibrosis.

Capsaicin (CAP) is an active ingredient in chili pepper that is frequently consumed. It exerts various pharmacological activities, and also has potential effects on mental illness. However, its mechanism of antidepressant effects is still unclear. Based on the emerging perspective of the gut-brain axis, we investigated the effects of dietary CAP on gut microbes in mice with depression-like behaviors induced by lipopolysaccharide (LPS). C57BL/6J male mice (four weeks old) were given specific feed (standard laboratory chow or laboratory chow plus 0.005% CAP) for 4 months. During the last five days, LPS (0.052/0.104/0.208/0.415/0.83 mg/kg, 5-day) was injected intraperitoneally to induce depression. Behavioral indicators and serum parameters were measured, and gut microbiota were identified by sequencing analysis of the 16S gene. This study showed that dietary CAP improved depressive-like behavior (sucrose preference test, forced swimming test, tail suspension test) and levels of 5-HT and TNF-α in serum of LPS-induced mice with depression-like behaviors. In addition, CAP could recover abnormal changes in depression-related microbiota. Especially at the genus level, CAP enhanced the variations in relative abundance of certain pivotal microorganisms like Ruminococcus, Prevotella, Allobaculum, Sutterella, and Oscillospira. Correlation analysis revealed changes in microbiota composition that was closely related to depressive behavior, 5-HT and TNF-α levels. These results suggested that dietary CAP can regulate the structure and number of gut microbiota and play a major role in the prevention of depression.

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