Expression of apolipoprotein C-IV is regulated by Ku antigen/peroxisome proliferator-activated receptor gamma complex and correlates with liver steatosis.

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.Transcriptional regulators were identified by DNA affinity purification and steatosis was ...
detected by oil red O staining and triglyceride assay.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.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.
Mesh Terms:
Apolipoproteins C, Base Sequence, Cell Line, DNA Helicases, DNA Primers, Fatty Liver, Hepacivirus, Hepatitis C, Humans, Lipid Metabolism, Models, Biological, Molecular Sequence Data, Multiprotein Complexes, PPAR gamma, Promoter Regions, Genetic, Recombinant Proteins, Retinoid X Receptor alpha, Transcriptional Activation, Viral Core Proteins
J. Hepatol.
Date: Nov. 01, 2008
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