The CREB coactivator CRTC2 controls hepatic lipid metabolism by regulating SREBP1

Nature. 2015 Aug 13;524(7564):243-6. doi: 10.1038/nature14557. Epub 2015 Jul 6.


Abnormal accumulation of triglycerides in the liver, caused in part by increased de novo lipogenesis, results in non-alcoholic fatty liver disease and insulin resistance. Sterol regulatory element-binding protein 1 (SREBP1), an important transcriptional regulator of lipogenesis, is synthesized as an inactive precursor that binds to the endoplasmic reticulum (ER). In response to insulin signalling, SREBP1 is transported from the ER to the Golgi in a COPII-dependent manner, processed by proteases in the Golgi, and then shuttled to the nucleus to induce lipogenic gene expression; however, the mechanisms underlying enhanced SREBP1 activity in insulin-resistant obesity and diabetes remain unclear. Here we show in mice that CREB regulated transcription coactivator 2 (CRTC2) functions as a mediator of mTOR signalling to modulate COPII-dependent SREBP1 processing. CRTC2 competes with Sec23A, a subunit of the COPII complex, to interact with Sec31A, another COPII subunit, thus disrupting SREBP1 transport. During feeding, mTOR phosphorylates CRTC2 and attenuates its inhibitory effect on COPII-dependent SREBP1 maturation. As hepatic overexpression of an mTOR-defective CRTC2 mutant in obese mice improved the lipogenic program and insulin sensitivity, these results demonstrate how the transcriptional coactivator CRTC2 regulates mTOR-mediated lipid homeostasis in the fed state and in obesity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Binding, Competitive
  • COP-Coated Vesicles / chemistry
  • COP-Coated Vesicles / metabolism
  • Homeostasis
  • Insulin Resistance
  • Lipid Metabolism*
  • Lipogenesis
  • Liver / metabolism*
  • Male
  • Mice
  • Mice, Obese
  • Obesity / metabolism
  • Phosphorylation
  • Protein Processing, Post-Translational
  • Protein Transport
  • Signal Transduction
  • Sterol Regulatory Element Binding Protein 1 / metabolism*
  • TOR Serine-Threonine Kinases / metabolism
  • Transcription Factors / deficiency
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*
  • Vesicular Transport Proteins / metabolism


  • Crtc2 protein, mouse
  • SEC31A protein, human
  • Sec23a protein, mouse
  • Srebf1 protein, mouse
  • Sterol Regulatory Element Binding Protein 1
  • Transcription Factors
  • Vesicular Transport Proteins
  • TOR Serine-Threonine Kinases
  • mTOR protein, mouse