A Negative Regulatory Pathway of GLUT4 Trafficking in Adipocyte: New Function of RIP140 in the Cytoplasm via AS160

Ping Chih Ho, Yi Wei Lin, Yao Chen Tsui, Pawan Gupta, Li Na Wei

Research output: Contribution to journalArticlepeer-review

44 Scopus citations

Abstract

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 (PKCε), 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 PKCε 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.

Original languageEnglish (US)
Pages (from-to)516-523
Number of pages8
JournalCell Metabolism
Volume10
Issue number6
DOIs
StatePublished - Dec 2 2009

Bibliographical note

Funding Information:
We thank J. Bogan for G7 cells; N.-P. Tsai for discussions on the manuscript; M. Parker for RIP140-null MEF; and S.G. Ha, S.C. Chan and Y.-S. Chuang for technical help. This study was supported in part by NIH grants DK54733, DK60521, DA11190, and K02-DA13926 to L.-N.W.

Keywords

  • HUMDISEASE
  • SIGNALING

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