期刊
LABORATORY INVESTIGATION
卷 92, 期 8, 页码 1191-1202出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/labinvest.2012.88
关键词
HCV proteins; HCV replication; lipogenic genes; LXR; PI3K/AKT pathway; steatosis
资金
- Ministerio de Educacion y Ciencia [BFU2007-62977, BFU2010-15784, SAF2007-60667]
- Junta de Castilla y Leon [GRS 482/A/10]
- Ministerio de Ciencia e Innovacion, Instituto de Salud Carlos III, FEDER [PI10/00101]
- CIBERehd contract
- Instituto de Salud Carlos III, Spain
Molecular mechanisms contributing to hepatitis C virus (HCV)-associated steatosis are not well established, although HCV gene expression has been shown to alter host cell cholesterol/lipid metabolism. As liver X receptors (LXRs) play a role as key modulators of metabolism signaling in the development of steatosis, we aimed to investigate in an HCV in vitro model the effect of HCV NS5A protein, core protein, and viral replication on the intracellular lipid accumulation and the LXR alpha-regulated expression of lipogenic genes. The effects of LXR alpha siRNA or agonist GW3965 treatment on lipogenesis and HCV replication capacity in our HCV replicon system were also examined. NS5A- and core-expressing cells and replicon-containing cells exhibited an increase of lipid accumulation by inducing the gene expression and the transcriptional activity of LXR alpha, and leading to an increased expression of its lipogenic target genes sterol regulatory element binding protein-1c, peroxisome proliferator-activated receptor-gamma, and fatty acid synthase. Transcriptional induction by NS5A protein, core protein, and viral replication occurred via LXR response element activation in the lipogenic gene promoter. No physical association between HCV proteins and LXR alpha was observed, whereas NS5A and core proteins indirectly upregulated LXR alpha through the phosphatidylinositol 3-kinase pathway. Finally, it was found that LXR alpha knockdown or agonist-mediated LXR alpha induction directly regulated HCV-induced lipogenesis and HCV replication efficiency in replicon-containing cells. Combined, our data suggest that LXR alpha-mediated regulation of lipogenesis by core and NS5A proteins may contribute to HCV-induced liver steatosis and to the efficient replication of HCV. Laboratory Investigation (2012) 92, 1191-1202; doi:10.1038/labinvest.2012.88; published online 28 May 2012
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据