Lysine Acetylation of CREBH Regulates Fasting-Induced Hepatic Lipid Metabolism

Mol Cell Biol. 2015 Dec;35(24):4121-34. doi: 10.1128/MCB.00665-15. Epub 2015 Oct 5.

Abstract

Cyclic AMP-responsive element-binding protein 3-like 3, hepatocyte specific (CREBH), is a hepatic transcription factor that functions as a key regulator of energy homeostasis. Here, we defined a regulatory CREBH posttranslational modification process, namely, lysine-specific acetylation, and its functional involvement in fasting-induced hepatic lipid metabolism. Fasting induces CREBH acetylation in mouse livers in a time-dependent manner, and this event is critical for CREBH transcriptional activity in regulating hepatic lipid homeostasis. The histone acetyltransferase PCAF-mediated acetylation and the deacetylase sirtuin-1-mediated deacetylation coexist to maintain CREBH acetylation states under fasting conditions. Site-directed mutagenesis and functional analyses revealed that the lysine (K) residue at position 294 (K294) within the bZIP domain of the CREBH protein is the site where fasting-induced acetylation/deacetylation occurs. Introduction of the acetylation-deficient (K294R) or acetylation-mimicking (K294Q) mutation inhibited or enhanced CREBH transcriptional activity, respectively. Importantly, CREBH acetylation at lysine 294 was required for the interaction and synergy between CREBH and peroxisome proliferator-activated receptor α (PPARα) in activating their target genes upon fasting or glucagon stimulation. Introduction of the CREBH lysine 294 mutation in the liver leads to hepatic steatosis and hyperlipidemia in animals under prolonged fasting. In summary, our study reveals a molecular mechanism by which fasting or glucagon stimulation modulates lipid homeostasis through acetylation of CREBH.

Publication types

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

MeSH terms

  • Acetylation
  • Animals
  • Cell Line
  • Cyclic AMP Response Element-Binding Protein / genetics*
  • Cyclic AMP Response Element-Binding Protein / metabolism
  • Energy Metabolism / genetics
  • Energy Metabolism / physiology
  • Fasting / metabolism*
  • Fatty Liver / genetics*
  • Fatty Liver / pathology
  • Glucagon / metabolism
  • Hepatocytes / metabolism
  • Histone Acetyltransferases / metabolism
  • Hyperlipidemias / genetics*
  • Hyperlipidemias / pathology
  • Lipid Metabolism / genetics*
  • Lipid Metabolism / physiology
  • Liver / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mutagenesis, Site-Directed
  • PPAR gamma / metabolism
  • Protein Structure, Tertiary
  • Sirtuin 1 / metabolism
  • Transcriptional Activation
  • p300-CBP Transcription Factors / metabolism

Substances

  • Creb3l3 protein, mouse
  • Cyclic AMP Response Element-Binding Protein
  • PPAR gamma
  • Glucagon
  • Histone Acetyltransferases
  • p300-CBP Transcription Factors
  • p300-CBP-associated factor
  • Sirt1 protein, mouse
  • Sirtuin 1