Regulation Of Lipid Storage By Aida

Triacylglycerol(TAG)is the primary form of energy storage in eukaryotic cells.TAG comprises more than 90%of the content of white adipocytes,and TAG synthesis is essential in hepatocytes for the synthesis and transport of VLDL,in mammary epithelial cells for the production of milk,and in enterocytes for the absorption of dietary lipids.Deregulated TAG accumulation leads to metabolic syndrome,which results in significant mortality by increasing the risk of diabetes,cardiovascular disease and so on.TAG is synthesized through two pathways,the glycerol phosphate pathway and the monoacylglycerol pathway.A series of enzymes participate in this process.However,how these enzymes are regulated remains unclear.Here we show that after refed or olive oil gavage,the Gpat3 protein level in the jejunum of Aida-/-mice is significant higher than WT controls.Since Gpat3 is one of the rate-limiting enzymes in the glycerol phosphate pathway,Gpat3 upregulation leads to accelerated fat storage in Aida-/-mice.Specifically,higher efficiency in the absorption of dietary fat,TAG resynthesis,and chylomicron emulsion secretion are observed in these mice,which promotes high fat diet induced obesity,steatosis and insulin resistance.Mechanistically,our data shows that Gpat3 is a substrate of ER-associated degradation(ERAD)pathway and Aida promotes Gpat3 degradation through enhancing the interaction between Gpat3 and its E3 ubiqutin ligase Hrdl.Overall,our results imply an important role for Aida in regulating the absorption and storage of dietary fats,as well as in the development of obesity and its associated complications.Understanding of these regulatory processes may offer us new avenues for therapeutic intervention to the prevention and treatment of human metabolic syndrome.