Expression of apolipoprotein C-IV is regulated by Ku antigen/peroxisome proliferator-activated receptor gamma complex and correlates with liver steatosis.
BACKGROUND/AIMS: We previously reported that hepatitis C virus (HCV) core protein up regulated transcription of apolipoprotein C-IV (ApoC-IV, 10.7-fold increase), a member of the apolipoprotein family implicated in liver steatosis. Here, we identified host transcription factors regulating the ApoC-IV gene expression. METHODS: Transcriptional regulators were identified by DNA affinity purification and steatosis was detected by oil red O staining and triglyceride assay. RESULTS: We defined a 163-bp ApoC-IV promoter as a core protein responsive element, and identified Ku antigen complex (Ku70 and Ku80) as well as nuclear receptors PPARgamma/RXRalpha as key regulators of ApoC-IV gene expression. Both Ku70 overexpression and PPARgamma agonist significantly increased ApoC-IV promoter activity; conversely, Ku70 silencing or mutation of PPARgamma binding site diminished the ApoC-IV promoter activity. Interestingly, transient transfection of ApoC-IV cDNA into a human hepatoma cell line was able to trigger moderate lipid accumulation. In agreement with this in vitro study, ApoC-IV transcript level was increased in HCV infected livers which correlated with triglyceride accumulation. CONCLUSIONS: ApoC-IV overexpression may perturb lipid metabolism leading to lipid accumulation. HCV core protein may modulate ApoC-IV expression through Ku antigen and PPARgamma/RXRalpha complex.[1]References
- Expression of apolipoprotein C-IV is regulated by Ku antigen/peroxisome proliferator-activated receptor gamma complex and correlates with liver steatosis. Kim, E., Li, K., Lieu, C., Tong, S., Kawai, S., Fukutomi, T., Zhou, Y., Wands, J., Li, J. J. Hepatol. (2008) [Pubmed]
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