Explore The Role Of Catalytic Subunit Of PP2A In The Liver Metabolism

The increased prevalence of obesity and type 2 diabetes has become a worldwide threat to the human health of modern life.The liver is a major target site for insulin which regulates glucose and lipid metabolism.Protein Phosphatase 2A(PP2A)is a ubiquitously expressed family of serine/threonine phosphatases,which plays critical roles in the regulation of many cellular functions,including signal transduction,organismal metabolism,cell cycle,tumor suppress,protein synthesis,etc.There are two isoforms of the catalytic subunit of PP2A,Ppp2ca and Ppp2C?.Null mutation of the alpha isoform-catalytic subunit of Ppp2ca leads to early embryonic lethal at E6.5.It is impossible to dissect in vivo roles of PP2A beyond this stage.To explore the role of hepatic Ppp2c?,we generated liver-specific Ppp2ca knockout mice.The mice deleted Ppp2ca in the liver display enhanced systemic glucose tolerance and triglyceride and cholesterol levels.Ppp2ca deletion mice were resistant to high fat diet induced obesity and obesity-associated with pathologies,such as increased body weight and fat content,fatty liver.Moreover,we found serum cholesterolel,triglyceride,LDL and HDL was elevated.The phosphorylation of Akt,GSK3? and GS was improved in Ppp2ca knockout mice.The mRNA levels of G6P and PEPCK were decreased.These results suggest that PP2A is a negative regulator of insulin-induced signaling in the liver and PP2A may be a possible target for therapeutic intervention for disorders associated with insulin.In summary,we have established a new mouse for model obesity and type 2 diabetes.The phenotype and molecular analysis of Ppp2ca deletion mice indicates Ppp2ca enhance insulin signaling sensitivity,regulating body weight and glucose homeostasis.