X-ray repair cross-complementing protein 6
transcription cis-regulatory region binding
Expression of apolipoprotein C-IV is regulated by Ku antigen/peroxisome proliferator-activated receptor gamma complex and correlates with liver steatosis.
<h4>Background/aims</h4>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.<h4>Methods</h4>Transcriptional regulators were identified by DNA affinity purification and steatosis was detected by oil red O staining and triglyceride assay.<h4>Results</h4>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.<h4>Conclusions</h4>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.