A negative regulatory pathway of GLUT4 trafficking in adipocyte: new function of RIP140 in the cytoplasm via AS160.
Receptor-interacting protein 140 (RIP140), a nuclear receptor corepressor, is important for lipid and glucose metabolism. In adipocytes, RIP140 can be phosphorylated by protein kinase C epsilon (PKCvarepsilon), followed by arginine methylation, and exported to the cytoplasm. This study demonstrates for the first time a cytoplasmic function for RIP140: to counteract insulin-stimulated glucose transporter 4 (GLUT4) membrane partitioning and glucose uptake in adipocytes. Cytoplasmic RIP140 interacts with the Akt substrate AS160, thereby impeding AS160 phosphorylation by Akt; this in turn reduces GLUT4 trafficking. This signal transduction pathway can be recapitulated in the epididymal adipocytes of diet-induced obese mice: nuclear PKCvarepsilon is activated, cytoplasmic RIP140 increases, and GLUT4 trafficking and glucose uptake are reduced. The data reveal a new, cytoplasmic function for RIP140 as a negative regulator of GLUT4 trafficking and glucose uptake, and shed insight into the regulation of basal and insulin-stimulated glucose disposal by a nuclear-initiated counteracting mechanism.
Ho
Ping-Chih
PC
Department of Pharmacology, University of Minnesota Medical School, Minneapolis, MN 55455, USA.
Lin
Yi-Wei
YW
Tsui
Yao-Chen
YC
Gupta
Pawan
P
Wei
Li-Na
LN
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D017667:Adipocytes / Q000378:metabolism*; D000818:Animals; D002460:Cell Line; D003593:Cytoplasm / Q000378:metabolism; D015536:Down-Regulation; D020690:GTPase-Activating Proteins / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism; D051275:Glucose Transporter Type 4 / Q000378:metabolism*; D051379:Mice; D008820:Mice, Obese; D009687:Nuclear Proteins / Q000378:metabolism*; D000078723:Nuclear Receptor Interacting Protein 1; D051744:Protein Kinase C-epsilon / Q000378:metabolism; D021381:Protein Transport; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction; D050151:Subcutaneous Fat / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; D020690:GTPase-Activating Proteins; D051275:Glucose Transporter Type 4; D009687:Nuclear Proteins; D000078723:Nuclear Receptor Interacting Protein 1; C505647:Tbc1d4 protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D051744:Protein Kinase C-epsilon; D005947:Glucose