Molecular Mechanism Of High-BCAAs Diet Enhancing Liver Gluconeogenesis In Mice

BCAAs(Branched-chain amino acids)refer to Leu,Ile and Val,of which Val and Ile catabolism produce propionyl-Co A,while Leu and Ile catabolism generate acetylCo A.Propionyl-Co A and acetyl-Co A are donors for protein lysine propionylation and acetylation in vivo,respectively.Accumulating studies have shown that the plasma BCAAs are significantly increased in patients and mouse models with type 2 diabetes.In addition,dysregulated gluconeogenesis metabolism is one of the major causes for type 2 diabetes.In this thesis,I investigated the molecular mechanism by which high concentration of BCAAs affects gluconeogenesis.Our results showed that diet with high fat and high BCAAs could significantly increase fasting blood glucose level,gluconeogenesis,fat mass and lipid droplets accumulation in mice and promote the development of type 2 diabetes.However,combined high fat and high BCAA diet affected neither the transcription of gluconeogenesis-related genes nor the protein levels of key gluconeogenic enzymes PCK1 and PC.Importantly,co-feeding with high fat and high BCAAs dramatically elevated the global levels of propionylation in liver tissues,suggesting that excessive BCAAs in the diet may promote propionylation in livers by supplying propionyl-Co A through BCAA catabolism.I further showed that high BCAAs can promote propionylation modification of PCK1,a key enzyme for gluconeogenesis.Previous studies in our laboratory demonstrated that GCN5 is a key propionyltransferase in cells.I went on to demonstrate through immunoprecipitation experiment that GCN5 interacted with PCK1 and that GCN5 could catalyze PCK1 propionylation and that propionylation enhanced PCK1 gluconeogenic activity.In summary,this study demonstrates that high levels of BCAAs can promote gluconeogenesis through increased propionylation modification of PCK1.GCN5 is the major enzyme catalyzing PCK1 propionylation,which in turn promotes its gluconeogenic activity.These findings provide novel insights into the link between BCAA catabolism,protein propionylation,and type 2 diabetes.