Effects of hepatocyte nuclear factor-4alpha on the regulation of the hepatic acute phase response.
Following injury, a large number of hepatic acute phase genes are rapidly modulated at the transcriptional level to restore metabolic homeostasis and limit tissue damage. Hepatocyte nuclear factor 4alpha (HNF-4alpha) is a liver-enriched transcription factor that controls embryonic liver development and regulates tissue-specific gene expression in adult liver cells. Many genes encoding acute phase proteins contain HNF-4alpha-binding sites in their promoter regions and are transcriptionally regulated by HNF-4alpha. Utilizing a cytokine induced acute phase response in HepG2 cells, we investigated the role of HNF-4alpha in regulating the transcription of three HNF-4alpha sensitive genes, alpha1-antitrypsin (alpha1-AT), transthyretin (TTR), and apolipoprotein B (ApoB) after injury. The transcriptional behavior of all three genes depends, in part, on the intracellular concentrations of HNF-4alpha. However, the unique mRNA expression patterns of alpha1-AT, TTR, and ApoB in response to cytokine treatment were abrogated in HepG2 cells with dramatically reduced HNF-4alpha protein concentrations. The mechanism by which HNF-4alpha mediates this injury response is through site-specific alterations in HNF-4alpha-binding abilities and transactivation potentials. Cytokine treatment phosphorylates HNF-4alpha, which directly affects HNF-4alpha activity. Our results demonstrate that HNF-4alpha is a crucial mediator in the regulation of alpha1-AT, TTR, and ApoB gene expression before and after injury, providing evidence of a novel role for HNF-4alpha in the control of the liver's acute phase response.
Wang
Zhongyan
Z
Department of Surgery, Boston University School of Medicine, Boston, MA 02118, USA.
Burke
Peter A
PA
D002457:Cell Extracts; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D016207:Cytokines / Q000494:pharmacology; D004247:DNA / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D051557:Hepatocyte Nuclear Factor 4 / Q000235:genetics / Q000378:metabolism*; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D010084:Oxidation-Reduction; D010766:Phosphorylation; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D012333:RNA, Messenger / Q000235:genetics; D012680:Sensitivity and Specificity; D013997:Time Factors
D002457:Cell Extracts; D016207:Cytokines; D051557:Hepatocyte Nuclear Factor 4; D012333:RNA, Messenger; D004247:DNA