The Mechanism Of CRTC2 In Regulating Hepatic Lipid Metabolism

Insulin resistance is a complicated metabolic disorder induced by many etiological pathways.Ectopic accumulation of triglycerides in liver,partially caused by de novo lipogenesis,leads to fatty liver disease and insulin resistance.Hepatic lipogenesis is regulated in a combinatorial manner by many transcription factors,including SREBP1.SREBP1,which activates the expression of many genes involved in lipogenesis,is synthesized as an inactive precursor bound to endoplasmic reticulum(ER).In response to insulin signaling,SCAP transports SREBP1 from the ER to the Golgi apparatus in a COPII-dependent manner.COPII vesicles form on the ER through sequential binding of Sar1,Sec23/24 and Sec13/31.Release of SREBP1 from the membrane is mediated by two Golgi-located proteases,S1 P and S2 P.Then,the cleaved SREBP1 shuttles to the nucleus to induce the expression of lipogenic genes.However,the mechanisms underlying the enhanced SREBP1 activity in insulin resistant obesity and diabetes remain to be resolved.In this study,we demonstrate that the CREB coactivator CRTC2 functions as a mediator of mTOR to regulate the COPII-dependent SREBP1 processing.CRTC2 competed with Sec23 to interact with Sec31,disrupting the transport of SREBP1.During feeding,mTOR phosphorylated CRTC2 and attenuated its inhibitory effect on COPII-dependent SREBP1 processing.As hepatic overexpression of an mTOR-defective CRTC2 mutant in obese mice improved the lipogenic program and insulin sensitivity,these results demonstrate how CRTC2 regulates mTOR-mediated lipid homeostasis in the fed state and in obesity.In conclusion,this investigation demonstrated,for the first time,that cytosolic CRTC2 functions as a mediator of mTOR to regulate COPII activity,SREBP1 maturation and de novo lipogenesis,further modulating hepatic lipid levels and insulin sensitivity.Our results expand the role of the transcription coactivator CRTC2 to include lipid metabolism and provide insight into how SREBP1 activity is enhanced in obesity and diabetes.Our findings provide us a better understanding of insulin resistance.