LAUSR

Chronic hepatitis B virus infection is a major risk factor for hepatocellular carcinoma (HCC). Hepatitis B virus X protein (HBx) is a hepatitis B virus protein that has multiple cellular functions, but its role in HCC pathogenesis has been controversial. Farnesoid X receptor (FXR) is a nuclear receptor with activities in anti‐inflammation and inhibition of hepatocarcinogenesis. However, whether or how FXR can impact hepatitis B virus/HBx‐induced hepatocarcinogenesis remains unclear. In this study, we showed that HBx can interact with FXR and function as a coactivator of FXR. Expression of HBx in vivo enhanced FXR‐responsive gene regulation. HBx also increased the transcriptional activity of FXR in a luciferase reporter gene assay. The HBx–FXR interaction was confirmed by coimmunoprecipitation and glutathione S‐transferase pull‐down assays, and the FXR activation function 1 domain was mapped to bind to the third α helix in the C terminus of HBx. We also found that the C‐terminally truncated variants of HBx, which were found in clinical HCC, were not effective at transactivating FXR. Interestingly, recruitment of the full‐length HBx, but not the C‐terminally truncated HBx, enhanced the binding of FXR to its response element. In vivo, FXR ablation markedly sensitized mice to HBx‐induced hepatocarcinogenesis. Conclusions: We propose that transactivation of FXR by full‐length HBx may represent a protective mechanism to inhibit HCC and that this inhibition may be compromised upon the appearance of C‐terminally truncated HBx or when the expression and/or activity of FXR is decreased. (Hepatology 2017;65:893‐906)