Endothelin-1 promotes cytoplasmic accumulation of RIP140 through a ET A-PLCβ-PKCε pathway

Ping Chih Ho, Yao Chen Tsui, Yi Wei Lin, Shawna D. Persaud, Li Na Wei

Research output: Contribution to journalArticlepeer-review

6 Scopus citations

Abstract

The physiological signal activating cytoplasmic accumulation of nuclear receptor interacting protein 140 (RIP140) in adipocytes was unclear. We uncover that endothelin-1 (ET-1) promotes cytoplasmic accumulation of RIP140 in 3T3-L1 adipocytes. We determine ET-1's signal transduction pathway in adipocytes, which is by activating ET A receptor-PLCβ-nuclear PKCε. Blocking this pathway in 3T3-L1 adipocyte cultures, by treating cells with an ET A antagonist, inhibiting PLCβ, or silencing PKCε, reduces ET-1-stimulated cytoplasmic accumulation of RIP140. In a HFD-fed obese mouse model, administration of a selective ET A antagonist, ambrisentan, effectively dampens cytoplasmic accumulation of RIP140 in the epididymal adipose tissue and reduces HFD-caused adipocyte dysfunctions. Importantly, ambrisentan improves blood glucose control and reduces the severity of hepatic steatosis in HFD-fed mice. This study reports a physiological signal that stimulates nuclear export of RIP140 in adipocytes and provides evidence for a strategy using selective ET A antagonist to treat obesity-induced insulin resistance and, possibly, other metabolic disorders.

Original languageEnglish (US)
Pages (from-to)176-183
Number of pages8
JournalMolecular and Cellular Endocrinology
Volume351
Issue number2
DOIs
StatePublished - Apr 4 2012

Bibliographical note

Funding Information:
This work is supported by NIH Grants DK54733, DK054733-09S1, DK60521, DK060521-07S1, DA11190, K02-DA13926 and the Distinguished McKnight University Professorship to LNW. P.-C. H. is also supported by American Heart Association predoctoral fellowship. We thank A. Smith, C.-H. Hung, Y.-S. Chuang, F.A. Beyan and S.-C. Luo for technical help, and M Parker for RIP140-null MEF.

Copyright:
Copyright 2012 Elsevier B.V., All rights reserved.

Keywords

  • Ambrisentan
  • Cytoplasm
  • ET receptor
  • Endothelin-1
  • Insulin sensitivity
  • RIP140

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