Hepatitis C virus genotype-3a (HCV-3a) is directly linked to the development of steatosis. We previously showed that, through sterol regulatory element binding protein-1 (SREBP-1), HCV-3a core protein upregulates the promoter activity of fatty acid synthase, a major enzyme involved in lipid synthesis. In this study, we investigated whether HCV-3a core can activate SREBP-1 and studied the role of phosphoinositide 3-kinase (PI3K)–Akt-2 pathway in modulating SREBP-1 activity by HCV-3a core. To determine whether HCV-3a core could activate SREBP-1, the level of mature SREBP-1 was analysed by Western blotting. Our results showed that the level of mature SREBP-1 was enhanced by HCV-3a core protein after transient expression and in the chimeric HCV-3a core/1b replicon cells in comparison to controls. To investigate the role of the PI3K–Akt-2 pathway in SREBP-1 activation by HCV-3a core, PI3K and Akt-2 activity was inhibited by using the chemical inhibitor LY294002, a dominant-negative Akt-2 plasmid, or knockdown of Akt-2 by small hairpin RNA. Our results showed that inhibition of PI3K and Akt-2 was associated with reduced SREBP-1 activation by HCV-3a core. These results indicate a role for PI3K and Akt-2 in increasing SREBP-1 activity by HCV-3a core protein and provide a mechanism of steatosis caused by HCV.


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