The CREB coactivator CRTC2 controls hepatic lipid metabolism by regulating SREBP1

• Published in: Nature (London) 2015-08, Vol.524 (7564), p.243-246
• Main Authors: Han, Jinbo, Li, Erwei, Chen, Liqun, Zhang, Yuanyuan, Wei, Fangchao, Liu, Jieyuan, Deng, Haiteng, Wang, Yiguo
• Format: Article
• Language: English
• Subjects: 13/1; 13/106; 13/109; 13/89; 13/95; 631/80/304; Analysis; Animals; Binding, Competitive; Cholesterol; COP-Coated Vesicles - chemistry; COP-Coated Vesicles - metabolism; Fatty acids; Gene expression; Genetic aspects; Glucose; Homeostasis; Humanities and Social Sciences; Insulin; Insulin Resistance; letter; Lipid Metabolism; Lipids; Lipogenesis; Liver; Liver - metabolism; Liver diseases; Male; Metabolism; Mice; Mice, Obese; multidisciplinary; Obesity; Obesity - metabolism; Phosphorylation; Protein Processing, Post-Translational; Protein Transport; Proteins; Rodents; Science; Signal Transduction; Sterol Regulatory Element Binding Protein 1 - metabolism; Sterols; TOR Serine-Threonine Kinases - metabolism; Transcription factors; Transcription Factors - deficiency; Transcription Factors - genetics; Transcription Factors - metabolism; Vesicular Transport Proteins - metabolism
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/nature14557

Studies in mice reveal that CREB regulated transcription coactivator 2 (CRTC2) acts as a mediator of mTOR signalling in the liver to regulate SREBP1-controlled lipid homeostasis during feeding and diabetes; overexpression of a CRTC2 mutant defective for mTOR regulation improves the lipogenic program and insulin sensitivity in obese mice. Hepatic control of lipid metabolism SREBP1 is an important transcriptional regulator of lipogenesis. Upon insulin stimulation, it is transported from the endoplasmic reticulum to the Golgi where it is processed, then shuttled to the nucleus to induce genes involved in cholesterol and fatty acid synthesis. From studies in mice, Yiguo Wang and colleagues show that the CREB regulated transcription coactivator 2 (CRTC2) acts as a mediator of mTOR signalling in the liver to regulate SREBP1-controlled lipid homeostasis during feeding and diabetes. CRTC2 can disrupt SREBP1 processing and transport by competing with binding to a subunit of COPII. During feeding, mTOR signalling inhibits the action of CRTC2 on SREBP1 processing. Overexpression of a CRTC2 mutant defective for mTOR regulation improves the lipogenic program and insulin sensitivity in obese mice. 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 1 , 2 . 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 3 , 4 , 5 ; 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) 6 functions as a mediator of mTOR 7 signalling to modulate COPII-dependent SREBP1 processing. CRTC2 competes with Sec23A, a subunit of the COPII complex 8 , 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