title: The Inactivation of RabGAP Function of AS160 Promotes Lysosomal Degradation of GLUT4 and Causes Postprandial Hyperglycemia and Hyperinsulinemia.
abstract: The AS160 (Akt substrate of 160 kDa) is a Rab-GTPase activating protein (RabGAP) with several other functional domains, and its deficiency in mice or human patients lowers GLUT4 protein levels and causes severe insulin resistance. How its deficiency causes diminished GLUT4 proteins remains unknown. We found that the deletion of AS160 decreased GLUT4 levels in a cell/tissue-autonomous manner. Consequently, skeletal muscle-specific deletion of AS160 caused postprandial hyperglycemia and hyperinsulinemia. The pathogenic effects of AS160 deletion are mainly, if not exclusively, due to the loss of its RabGAP function since the RabGAP-inactive AS160R917Kmutant mice phenocopied the AS160 knockout mice. The inactivation of RabGAP of AS160 promotes lysosomal degradation of GLUT4, and the inhibition of lysosome function could restore GLUT4 protein levels. Collectively, these findings demonstrate that the RabGAP activity of AS160 maintains GLUT4 protein levels in a cell/tissue-autonomous manner and its inactivation causes lysosomal degradation of GLUT4 and postprandial hyperglycemia and hyperinsulinemia.
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology and MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Nanjing University, Pukou District, Nanjing, China.
authors.forename: Bingxian
authors.initials: B
authors.lastname: Xie
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology and MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Nanjing University, Pukou District, Nanjing, China.
authors.forename: Qiaoli
authors.initials: Q
authors.lastname: Chen
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology and MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Nanjing University, Pukou District, Nanjing, China.
authors.forename: Liang
authors.initials: L
authors.lastname: Chen
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology and MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Nanjing University, Pukou District, Nanjing, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Sheng
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology and MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Nanjing University, Pukou District, Nanjing, China wanghy@nicemice.cn schen6@163.com.|Collaborative Innovation Center of Genetics and Development, Shanghai, China.
authors.forename: Hong Yu
authors.initials: HY
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology and MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Nanjing University, Pukou District, Nanjing, China wanghy@nicemice.cn schen6@163.com.|Collaborative Innovation Center of Genetics and Development, Shanghai, China.
authors.forename: Shuai
authors.initials: S
authors.lastname: Chen
mesh_terms: D017667:Adipocytes / Q000378:metabolism; D000818:Animals; D001823:Body Composition / Q000502:physiology; D002454:Cell Differentiation / Q000502:physiology; D002460:Cell Line; D020690:GTPase-Activating Proteins / Q000378:metabolism*; D005838:Genotype; D005947:Glucose / Q000378:metabolism; D051275:Glucose Transporter Type 4 / Q000378:metabolism*; D006801:Humans; D006943:Hyperglycemia / Q000209:etiology / Q000378:metabolism*; D006946:Hyperinsulinism / Q000209:etiology / Q000378:metabolism*; D007328:Insulin / Q000378:metabolism; D008247:Lysosomes / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D018482:Muscle, Skeletal / Q000378:metabolism
chemical_list: D020690:GTPase-Activating Proteins; D051275:Glucose Transporter Type 4; D007328:Insulin; C505647:Tbc1d4 protein, mouse; D005947:Glucose