Hepatitis B virus X protein induces lipogenic transcription factor SREBP1 and fatty acid synthase through the activation of nuclear receptor LXRα

Abstract

HBV (hepatitis B virus) is a primary cause of chronic liver disease, which frequently results in hepatitis, cirrhosis and ultimately HCC (hepatocellular carcinoma). Recently, we showed that HBx (HBV protein X) expression induces lipid accumulation in hepatic cells mediated by the induction of SREBP1 (sterol-regulatory-element-binding protein 1), a key regulator of lipogenic genes in the liver. However, the molecular mechanisms by which HBx increases SREBP1 expression and transactivation remain to be clearly elucidated. In the present study, we demonstrated that HBx interacts with LXRalpha (liver X receptor alpha) and enhances the binding of LXRalpha to LXRE (LXR-response element), thereby resulting in the up-regulation of SREBP1 and FAS (fatty acid synthase) in the presence or absence of the LXR agonist T0901317 in the hepatic cells and HBx-transgenic mice. Furthermore, HBx also augments the ability to recruit ASC2 (activating signal co-integrator 2), a transcriptional co-activator that controls liver lipid metabolic pathways, to the LXRE with LXRalpha. These studies place LXRalpha in a key position within the HBx-induced lipogenic pathways, and suggest a molecular mechanism through which HBV infection can stimulate the SREBP1-mediated control of hepatic lipid accumulation.

Liver X receptor mediates hepatitis B virus X protein–induced lipogenesis in hepatitis B virus–associated hepatocellular carcinoma #

“…1C). A similar observation was reported in a recent article 30 that was published during the processing of this article.…”

Impact of fatty liver on hepatitis B virus replication and virologic response to tenofovir and entecavir

“…Besides papers that claimed suppression of viral replication by NAFLD, there are also studies that reported an increase in the rate of NAFLD with HBV (21,(23)(24)(25)(26). HBV X protein (HBx) has been shown to increase the transcription of sterol regulatory element-binding protein-1c (SREBP-1c) and peroxisome proliferator-activated receptor (PPAR) (23)(24)(25)(26).…”

Liver X receptor α-mediated regulation of lipogenesis by core and NS5A proteins contributes to HCV-induced liver steatosis and HCV replication

“…It has been shown that hepatitis B virus X protein induces lipogenic genes through the activation of LXRa. 42 Thus, hepatitis B virus X protein physically interacts with LXRa in the nucleus and enhances the binding of LXRa to LXRE (LXR-response element). 43 In this study, core and NS5A are mainly detected in the cytoplasm of replicating cells, as previously described.…”