Expression of apolipoprotein C-IV is regulated by Ku antigen/peroxisome proliferator-activated receptor γ 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...

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Veröffentlicht in:Journal of hepatology 2008-11, Vol.49 (5), p.787-798
Hauptverfasser: Kim, Eun, Li, Ke, Lieu, Charmiane, Tong, Shuping, Kawai, Shigenobu, Fukutomi, Takayoshi, Zhou, Yonghong, Wands, Jack, Li, Jisu
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Sprache:eng
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Zusammenfassung: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 PPARγ/RXRα as key regulators of ApoC-IV gene expression. Both Ku70 overexpression and PPARγ agonist significantly increased ApoC-IV promoter activity; conversely, Ku70 silencing or mutation of PPARγ 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 PPARγ/RXRα complex.
ISSN:0168-8278
1600-0641
DOI:10.1016/j.jhep.2008.06.029