Hepatocyte nuclear factor 4alpha coordinates a transcription factor network regulating hepatic fatty acid metabolism

Mol Cell Biol. 2010 Feb;30(3):565-77. doi: 10.1128/MCB.00927-09. Epub 2009 Nov 23.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Basic Helix-Loop-Helix Transcription Factors / metabolism*
  • Biological Transport / physiology
  • Cell Line, Tumor
  • Fatty Acids / metabolism*
  • Gene Expression Regulation, Enzymologic / genetics
  • Gene Expression Regulation, Enzymologic / physiology
  • Gene Regulatory Networks*
  • Hepatocyte Nuclear Factor 4 / metabolism*
  • Humans
  • Liver / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Inbred CBA
  • Mice, Transgenic
  • PPAR alpha / metabolism
  • PPAR gamma / metabolism
  • Promoter Regions, Genetic / physiology
  • Repressor Proteins / metabolism*
  • Signal Transduction / genetics
  • Signal Transduction / physiology
  • Transcription Factors / metabolism*
  • Transcriptional Activation / physiology


  • Basic Helix-Loop-Helix Transcription Factors
  • Fatty Acids
  • Hepatocyte Nuclear Factor 4
  • Hes6 protein, mouse
  • PPAR alpha
  • PPAR gamma
  • Repressor Proteins
  • Transcription Factors