HNF6 and Rev-erbα integrate hepatic lipid metabolism by overlapping and distinct transcriptional mechanisms

Genes Dev. 2016 Jul 15;30(14):1636-44. doi: 10.1101/gad.281972.116. Epub 2016 Jul 21.

Abstract

Hepatocyte nuclear factor 6 (HNF6) is required for liver development, but its role in adult liver metabolism is not known. Here we show that deletion of HNF6 in livers of adult C57Bl/6 mice leads to hepatic steatosis in mice fed normal laboratory chow. Although HNF6 is known mainly as a transcriptional activator, hepatic loss of HNF6 up-regulated many lipogenic genes bound directly by HNF6. Many of these genes are targets of the circadian nuclear receptor Rev-erbα, and binding of Rev-erbα at these sites was lost when HNF6 was ablated in the liver. While HNF6 and Rev-erbα coordinately regulate hepatic lipid metabolism, each factor also affects additional gene sets independently. These findings highlight a novel mechanism of transcriptional repression by HNF6 and demonstrate how overlapping and distinct mechanisms of transcription factor function contribute to the integrated physiology of the liver.

Keywords: HNF6; Onecut; Rev-erbα; integrative physiology; lipid metabolism; liver; steatosis.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Fatty Liver / genetics
  • Gene Deletion
  • Gene Expression Regulation / genetics*
  • Gene Knockout Techniques
  • Hepatocyte Nuclear Factor 6 / genetics*
  • Hepatocyte Nuclear Factor 6 / metabolism*
  • Lipid Metabolism / genetics*
  • Liver / metabolism*
  • Liver / physiopathology*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Nuclear Receptor Subfamily 1, Group D, Member 1 / genetics
  • Nuclear Receptor Subfamily 1, Group D, Member 1 / metabolism*
  • Protein Binding / genetics

Substances

  • Hepatocyte Nuclear Factor 6
  • Nr1d1 protein, mouse
  • Nuclear Receptor Subfamily 1, Group D, Member 1