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Liver X receptor mediates hepatitis B virus X protein–induced lipogenesis in hepatitis B virus–associated hepatocellular carcinoma
Author(s) -
Na TaeYoung,
Shin Young Kee,
Roh Kyung Jin,
Kang ShinAe,
Hong Il,
Oh Sae Jin,
Seong Je Kyung,
Park Cheol Keun,
Choi Yoon La,
Lee MiOck
Publication year - 2009
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.22740
Subject(s) - hbx , lipogenesis , liver x receptor , steatosis , transactivation , fatty acid synthase , sterol regulatory element binding protein , biology , hepatitis b virus , hepatocellular carcinoma , cancer research , fatty liver , lipid metabolism , endocrinology , medicine , chemistry , gene expression , nuclear receptor , transcription factor , cholesterol , virus , virology , gene , sterol , biochemistry , disease
Although hepatitis B virus X protein (HBx) has been implicated in abnormal lipid metabolism in hepatitis B virus (HBV)–associated hepatic steatosis, its underlying molecular mechanism remains unclear. Liver X receptor (LXR) plays an important role in regulating the expression of genes involved in hepatic lipogenesis. Here we demonstrate that LXRα and LXRβ mediate HBV‐associated hepatic steatosis. We have found that HBx induces the expression of LXR and its lipogenic target genes, such as sterol regulatory element binding protein‐1c (SREBP‐1c), fatty acid synthase (FAS), and peroxisome proliferator‐activated receptor, and this is accompanied by the accumulation of lipid droplets. RNA interference with LXR expression decreases the amount of lipid droplets as well as the expression of the lipogenic genes, and this indicates that HBx‐induced lipogenesis is LXR‐dependent. LXRα and HBx colocalize in the nucleus and are physically associated. HBx induces the transactivation function of LXRα by recruiting CREB binding protein to the promoter of the target gene. Furthermore, we have observed that expression of LXR is increased in the livers of HBx‐transgenic mice. Finally, there is a significant increase in the expression of LXRβ ( P = 0.036), SREBP‐1c ( P = 0.008), FAS, and stearoyl–coenyzme A desaturase‐1 ( P = 0.001) in hepatocellular carcinoma (HCC) in comparison with adjacent nontumorous nodules in human HBV‐associated HCC specimens. Conclusion: Our results suggest a novel association between HBx and LXR that may represent an important mechanism explaining HBx‐induced hepatic lipogenesis during HBV‐associated hepatic carcinogenesis. (H EPATOLOGY 2009.)