Mechanism Of CIDEB Controls Liver Lipid Metabolism By Promoting SREBP Processing

Non-alcoholic fatty liver disease(NAFLD)is one of the most prevalent and challenging liver diseases in the worldwide.Associated with other metabolic diseases such as obesity,diabetes and cardiovascular diseases,NAFLD can develop from simple triglycerides accumulation in hepatocytes to hepatic steatosis with inflammation and further more severe liver fibrosis and cirrhosis.A series of factors can contribute to the fat accumulation in hepatocytes,among which the de novo lipogenesis play a key role in the development of NAFLD.Loading of specific cargoes to the COPII complex at the endoplasmic reticulum(ER)is essential for their targeting to the secretory pathway.Regulatory factor(s)orchestrating cargo loading enables precise regulation by physiological demands.Sterol-dependent incorporation of Sterol regulatory element-binding protein(SREBP)into COPII-coated vesicles,mediated by its escort protein SREBP cleavage activating protein(SCAP),is central to the cleavage and maturation of the master transcriptional regulator of de novo lipogenesis at the Golgi.Here,we show that the ER/lipid droplet-associated protein Cideb controls the transport of SREBP/SCAP complex from ER to Golgi by promoting their incorporation into COPII vesicles.Loss of Cideb leads to reduced hepatic SREBP activation and the lower expression of genes involved in lipogenesis and cholesterol metabolism.Mechanistically,under sterol deprivation,SCAP dissociates from Insulin-induced Gene 1 protein(Insig),and Cideb binds to SCAP,which leads to Golgi enrichment of SREBP/SCAP and processing and maturation of SREBP.Cideb also enhances COPII-SREBP complex assembly by binding to the guanine nucleotide exchange factor Sec12 of the GTPase Sar1.Consistently,Cideb deficiency results in greatly diminished SREBP activation,and protects mice from lipogenic diet-induced hepatic steatosis,dyslipidemia,liver injury and systemic inflammation.Our data point to a linchpin role of Cideb in bridging the SREBP/SCAP cargo to its assembly with the COPII machinery for SREBP activation and controlling hepatic lipid homeostasis.