Modulation of hepatocyte nuclear factor-4alpha function by the peroxisome-proliferator-activated receptor-gamma co-activator-1alpha in the acute-phase response.
HNF-4alpha (hepatocyte nuclear factor-4alpha) is a key regulator of liver-specific gene expression. To understand the mechanisms governing the regulation of HNF-4alpha function during the APR (acute-phase response), the effects of transcription co-activators, including p300, PGC-1alpha (peroxisome-proliferator-activated receptor-gamma co-activator-1alpha) and SRC (steroid receptor co-activator)-1alpha were investigated in an injury cell model. We have shown previously that the HNF-4alpha-sensitive APR genes ApoB (apolipoprotein B), TTR (transthyretin) and alpha1-AT (alpha1-antitrypsin) were regulated at the DNA binding and transcriptional levels after cytokine stimulation. We now show that co-activators have a differential impact on the transactivation of HNF-4alpha-sensitive genes via HNF-4alpha-binding sites in ApoB, TTR or alpha1-AT promoters. PGC-1alpha strongly enhances the transactivation of ApoB and alpha1-AT and, to a lesser extent, of TTR, whereas SRC-1alpha and p300 only have a weak or no effect on these three genes. More importantly, it was found that PGC-1alpha has a novel role in the modulation of the binding ability of HNF-4alpha in response to cytokine treatment. Using in vitro and in vivo approaches, electrophoretic mobility-shift and chromatin immunoprecipitation assays, we demonstrate that the reduced HNF-4alpha-DNA binding ability induced by cytokines is eliminated by overexpression of PGC-1alpha. Cytokine treatment does not significantly alter the protein levels of HNF-4alpha and PGC-1alpha, but it does reduce the recruitment of PGC-1alpha to HNF-4alpha-binding sites and thereby decreases transcriptional activity. These results establish the importance of PGC-1alpha for HNF-4alpha function and describe a new HNF-4alpha-dependent regulatory mechanism that is involved in the response to injury.
Department of Surgery, Boston University School of Medicine, 850 Harrison Avenue, Dowling 2 South, Boston, MA 02118, USA.
Zhongyan
Z
Wang
Peter A
PA
Burke
D000210:Acute-Phase Reaction / Q000235:genetics / Q000378:metabolism*; D001055:Apolipoproteins B / Q000235:genetics; D001665:Binding Sites; D002460:Cell Line; D045744:Cell Line, Tumor; D047369:Chromatin Immunoprecipitation; D016207:Cytokines / Q000494:pharmacology; D024202:Electrophoretic Mobility Shift Assay; D005786:Gene Expression Regulation / Q000187:drug effects; D006360:Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D051557:Hepatocyte Nuclear Factor 4 / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D051548:Histone Acetyltransferases / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D006801:Humans; D015151:Immunoblotting; D056920:Nuclear Receptor Coactivator 1; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D011228:Prealbumin / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000187:drug effects; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D014162:Transfection; D000515:alpha 1-Antitrypsin / Q000235:genetics; D050880:p300-CBP Transcription Factors / Q000235:genetics / Q000378:metabolism / Q000502:physiology
D001055:Apolipoproteins B; D016207:Cytokines; C496592:HNF4A protein, human; D006360:Heat-Shock Proteins; D051557:Hepatocyte Nuclear Factor 4; C486497:PPARGC1A protein, human; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D011228:Prealbumin; D014157:Transcription Factors; D000515:alpha 1-Antitrypsin; D051548:Histone Acetyltransferases; C538859:NCOA1 protein, human; D056920:Nuclear Receptor Coactivator 1; D050880:p300-CBP Transcription Factors