Role of bile acids in autophagy and alcohol‐induced liver injury

Abstract

Autophagy is a lysosomal degradation process and cellular protective mechanism. Bile acids display hepatotoxicity by inducing cell death and has been shown to modulate alcohol‐induced liver injury but the mechanism is not clear. We found that Farnesoid X Receptor deficient (FXR‐/−) mice which have increased hepatic bile acid levels had impaired autophagy. This is supported by the finding that the levels of LC3‐II and p62, two proteins which are normally degraded by autophagy, are significantly higher in FXR−/− mouse livers compare to that of wild type. Because inhibition of autophagy exacerbates alcohol‐induced liver injury, we hypothesized that FXR−/− mice may have exacerbated liver injury after alcohol treatment. Indeed, alcohol treated‐FXR−/− mice had increased serum alanine aminotransferase (ALT) and hepatic triglyceride levels compared to wild type mice. Alcohol‐treatment increased the expression of autophagy genes in wild type mice, but not in FXR−/− mice, suggesting the expression of autophagy genes might require FXR. In conclusion, the impaired autophagy in FXR−/− mice may contribute to the increased alcohol‐induced liver injury.This work was supported by NIH R01 AA020518–01 (WXD) and P20 RR021940 (COBRE).