Hepatocyte nuclear factor 4alpha coordinates a transcription factor network regulating hepatic fatty acid metabolism.
Adaptation of liver to nutritional signals is regulated by several transcription factors that are modulated by intracellular metabolites. Here, we demonstrate a transcription factor network under the control of hepatocyte nuclear factor 4alpha (HNF4alpha) that coordinates the reciprocal expression of fatty acid transport and metabolizing enzymes during fasting and feeding conditions. Hes6 is identified as a novel HNF4alpha target, which in normally fed animals, together with HNF4alpha, maintains PPARgamma expression at low levels and represses several PPARalpha-regulated genes. During fasting, Hes6 expression is diminished, and peroxisome proliferator-activated receptor alpha (PPARalpha) replaces the HNF4alpha/Hes6 complex on regulatory regions of target genes to activate transcription. Gene expression and promoter occupancy analyses confirmed that HNF4alpha is a direct activator of the Pparalpha gene in vivo and that its expression is subject to feedback regulation by PPARalpha and Hes6 proteins. These results establish the fundamental role of dynamic regulatory interactions between HNF4alpha, Hes6, PPARalpha, and PPARgamma in the coordinated expression of genes involved in fatty acid transport and metabolism.
Martinez-Jimenez
Celia Pilar
CP
Biomedical Sciences Research Center Alexander Fleming, 16672 Vari, Greece.
Kyrmizi
Irene
I
Cardot
Philippe
P
Gonzalez
Frank J
FJ
Talianidis
Iannis
I
D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism*; D001692:Biological Transport / Q000502:physiology; D045744:Cell Line, Tumor; D005227:Fatty Acids / Q000378:metabolism*; D015971:Gene Expression Regulation, Enzymologic / Q000235:genetics / Q000502:physiology; D053263:Gene Regulatory Networks; D051557:Hepatocyte Nuclear Factor 4 / Q000378:metabolism*; D006801:Humans; D008099:Liver / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D008822:Mice, Transgenic; D047493:PPAR alpha / Q000378:metabolism; D047495:PPAR gamma / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000502:physiology; D012097:Repressor Proteins / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D014157:Transcription Factors / Q000378:metabolism*; D015533:Transcriptional Activation / Q000502:physiology
D051792:Basic Helix-Loop-Helix Proteins; D005227:Fatty Acids; D051557:Hepatocyte Nuclear Factor 4; D047493:PPAR alpha; D047495:PPAR gamma; D012097:Repressor Proteins; D014157:Transcription Factors; C486570:Hes6 protein, mouse