Expression of apolipoprotein C-IV is regulated by Ku antigen/peroxisome proliferator-activated receptor gamma complex and correlates with liver steatosis.
OBJECTIVE
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.
Kim
Eun
E
Liver Research Center, Rhode Island Hospital and Warren Alpert Medical School of Brown University, Providence, RI 02903, USA.
Li
Ke
K
Lieu
Charmiane
C
Tong
Shuping
S
Kawai
Shigenobu
S
Fukutomi
Takayoshi
T
Zhou
Yonghong
Y
Wands
Jack
J
Li
Jisu
J
D001056:Apolipoproteins C / Q000235:genetics* / Q000378:metabolism; D001483:Base Sequence; D002460:Cell Line; D004265:DNA Helicases / Q000378:metabolism*; D017931:DNA Primers / Q000235:genetics; D005234:Fatty Liver / Q000235:genetics* / Q000378:metabolism*; D016174:Hepacivirus / Q000235:genetics; D006526:Hepatitis C / Q000235:genetics / Q000378:metabolism / Q000821:virology; D006801:Humans; D000072200:Ku Autoantigen; D050356:Lipid Metabolism; D008954:Models, Biological; D008969:Molecular Sequence Data; D046912:Multiprotein Complexes; D047495:PPAR gamma / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D047490:Retinoid X Receptor alpha / Q000378:metabolism; D015533:Transcriptional Activation; D014758:Viral Core Proteins / Q000235:genetics
C097349:APOC4 protein, human; D001056:Apolipoproteins C; D017931:DNA Primers; D046912:Multiprotein Complexes; D047495:PPAR gamma; D011994:Recombinant Proteins; D047490:Retinoid X Receptor alpha; D014758:Viral Core Proteins; D004265:DNA Helicases; C106893:XRCC5 protein, human; D000072200:Ku Autoantigen