Endothelin-1 promotes cytoplasmic accumulation of RIP140 through a ET(A)-PLCß-PKCε pathway.
Mol Cell Endocrinol
; 351(2): 176-83, 2012 Apr 04.
Article
in En
| MEDLINE
| ID: mdl-22209746
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-PLCß-nuclear PKCε. Blocking this pathway in 3T3-L1 adipocyte cultures, by treating cells with an ET(A) antagonist, inhibiting PLCß, 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.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Phenylpropionates
/
Pyridazines
/
Nuclear Proteins
/
Endothelin-1
/
Adaptor Proteins, Signal Transducing
/
Endothelin A Receptor Antagonists
Limits:
Animals
Language:
En
Journal:
Mol Cell Endocrinol
Year:
2012
Document type:
Article
Affiliation country:
United States
Publication country:
IE
/
IRELAND
/
IRLANDA