Hepatitis C virus genotype-3a core protein enhances sterol regulatory element-binding protein-1 activity through the phosphoinositide 3-kinase-Akt-2 pathway.
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 de novo 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.
Jackel-Cram
Candice
C
Vaccine and Infectious Disease Organization, University of Saskatchewan, Saskatoon, Saskatchewan, Canada.
Qiao
Ling
L
Xiang
Zhongua
Z
Brownlie
Robert
R
Zhou
Yan
Y
Babiuk
Lorne
L
Liu
Qiang
Q
D015153:Blotting, Western; D002460:Cell Line; D002867:Chromones / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D055785:Gene Knockdown Techniques; D005838:Genotype; D016174:Hepacivirus / Q000145:classification / Q000235:genetics / Q000472:pathogenicity*; D022781:Hepatocytes / Q000821:virology; D006801:Humans; D009025:Morpholines / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051780:Sterol Regulatory Element Binding Protein 1 / Q000096:biosynthesis*; D014758:Viral Core Proteins / Q000502:physiology*
D002867:Chromones; D004791:Enzyme Inhibitors; D009025:Morpholines; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D051780:Sterol Regulatory Element Binding Protein 1; D014758:Viral Core Proteins; C069130:nucleocapsid protein, Hepatitis C virus; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C494921:AKT2 protein, human