The Biological Functions And Mechanism Of AIDA In Maintaining Whole-Body Energy Balance

AIDA was initially identified as an Axin-interacting protein through a yeast two-hybrid system by our laboratory.Our previous studies have shown that AIDA is critical for regulating fat absorption and storage and plays an important role in the development of obesity and related metabolic syndromes.Following these observations,we reveal that AIDA promotes the degradation of GPAT3,MOGAT2 and DGAT2,three of the rate-limiting enzymes in the TAG synthesis pathway by facilitating the interaction between HRD1,the major E3-ligase of ERAD,and these enzymes and enhancing the ubiquitination of these enzymes.Pretreatment of WT mice with ERAD inhibitor Eeyarestatin I(EerI)increased the fat absorption to the same levels as those in untreated Aida-/-mice,showing significantly increased protein levels of GPAT3,MOGAT2,and DGAT2.These results indicate that the increased fat absorption in Aida-global knockout GKO mice(Aid?-GKO)is controlled by AIDA-mediated ERAD.To verify the critical role of AIDA in small intestine,we generated intestine-specific A ida knockout mice(A ida-IKO)and found that Aida-IKO mice generally phenocopieu Aida-/-mice in increased fat absorption and body weight.We further characterized Aida-IKO and Aida-GKO mice,and found that Aida-IKO mice showed similar daily food intake but increased energy expenditure compared with Aida-GKO mice,which results in much reduced body weight increase in Aida-IKO mice.These results indicate that intestinal AIDA regulate whole-body energy metabolism through retarding intestinal fat absorption which could promote food intake and antagonize the excess fat absorbed by promoting fat oxidation in other energy consuming tissues.In addition,we also found that the intestinal flora did not contribute to the obese phenotype of Aida-/-mice,but was associated with hyperglycemia,liver steatosis and insulin resistance in these mice.These studies of the physiological functions and mechanisms of AIDA in maintaining whole-body energy homeostasis not only reveal the complexity of the regulation of whole-body energy homeostasis but could also provide new strategies for the prevention and treatment of obesity and its complications.