Gastroenterology

Gastroenterology

Volume 132, Issue 5, May 2007, Pages 1955-1967
Gastroenterology

Basic–liver, pancreas, and biliary tract
Hepatitis B Virus X Protein Induces Hepatic Steatosis Via Transcriptional Activation of SREBP1 and PPARγ

https://doi.org/10.1053/j.gastro.2007.03.039Get rights and content

Background & Aims: Hepatic steatosis occurs frequently in patients with chronic hepatitis B virus (HBV) or chronic hepatitis C virus (HCV) infection. Recently, several studies suggested that steatosis plays an important role as a cofactor in other liver diseases such as hepatic fibrosis, hepatitis, and liver cancer. In contrast to HCV, however, the molecular mechanism by which HBV mediates hepatic steatosis has not been clearly studied. Here, we show the molecular mechanism by which hepatitis B virus X protein (HBx) induces hepatic steatosis. Methods: Lipid accumulation and the expression of various lipid metabolic genes were investigated in HBx-transfected Chang liver cells, HepG2-HBx stable cells, and HBx-transgenic mice. Results: Overexpression of HBx induced hepatic lipid accumulation in HepG2-HBx stable cells and HBx-transgenic mice. It also up-regulated the messenger RNA and protein levels of sterol regulatory element binding protein 1, but not peroxisome proliferator-activated receptor alpha (PPARα). Moreover, we also determined that the expression of HBx increases PPARγ gene expression as well as its transcriptional activity in hepatic cells, mediated by CCAAT enhancer binding protein α activation. Finally, we showed that HBx expression is able to up-regulate the gene expressions of various lipogenic and adipogenic enzymes in hepatic cells. Conclusions: We showed that the increased HBx expression causes lipid accumulation in hepatic cells mediated by sterol regulatory element binding protein 1 and PPARγ, which could be a putative molecular mechanism mediating the pathophysiology of HBV infection.

Section snippets

Transgenic Animals

The production of HBx transgenic mice used in this study already has been reported.19 Briefly, we generated HBx homozygous (+/+) transgenic mice by mating HBx heterozygous transgenic mice to each other. To generate HBx homozygous transgenic mice on mixed-background of C57BL/6 and CBA strains, HBx homozygous mice on C57BL/6 mice were crossed with CBA wild-type mice. The heterozygous transgenic offspring with a mixed background of C57BL/6 and CBA strains were mated between them. Among their

Overexpression of HBx Induces Lipid Accumulation in HepG2 and HBx-Transgenic Mice

To investigate the effects of HBx protein on hepatic lipid accumulation, we examined the hepatic lipid content in the liver tissues of HBx-transgenic mice. The livers of 11-week-old HBx-transgenic mice were enlarged and light-colored (Figure 1A). The liver weight per body weight of HBx mice was increased 2-fold compared with the wild-type mice at the same age (Figure 1B). We examined histologic changes of the liver of HBx-transgenic mice. The H&E-stained liver sections of HBx-transgenic mice

Discussion

Increasing evidence indicates that hepatic lipid accumulation is related to hepatic fibrosis, inflammation, apoptosis, and cancer.3, 4 In particular, it is assumed that lipid accumulation is a prerequisite for subsequent events leading to liver injury in nonalcoholic fatty liver disease.31 In addition, it recently was shown that hepatic steatosis may be a more vulnerable factor in HCV-induced liver pathogenesis3 and may impair the response of interferon-based therapy.32, 33 Because of the

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    Supported by the Korean Ministry of Health and Welfare, Republic of Korea (A050404), and the 21st century Frontier Program in the Functional Human Genome Project of Korea (HGC0300526).

    1

    K.H.K. and H.-J.S. contributed equally to this work.

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