Endothelin-1 promotes cytoplasmic accumulation of RIP140 through a ET(A)-PLCβ-PKCε pathway.
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.
Department of Pharmacology, University of Minnesota Medical School, Minneapolis, MN 55455-0217, USA.
Ping-Chih
PC
Ho
Yao-Chen
YC
Tsui
Yi-Wei
YW
Lin
Shawna D
SD
Persaud
Li-Na
LN
Wei
D041721:3T3-L1 Cells; D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D017667:Adipocytes / Q000378:metabolism; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D002478:Cells, Cultured; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy / Q000378:metabolism; D059305:Diet, High-Fat; D065130:Endothelin A Receptor Antagonists; D019332:Endothelin-1 / Q000037:antagonists & inhibitors* / Q000378:metabolism* / Q000494:pharmacology; D005234:Fatty Liver; D007333:Insulin Resistance; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D009687:Nuclear Proteins / Q000378:metabolism*; D000078723:Nuclear Receptor Interacting Protein 1; D009765:Obesity; D010666:Phenylpropionates / Q000494:pharmacology*; D054801:Phosphoinositide Phospholipase C / Q000235:genetics / Q000378:metabolism; D054799:Phospholipase C beta / Q000037:antagonists & inhibitors / Q000378:metabolism; D011724:Pyridazines / Q000494:pharmacology*; D034622:RNA Interference; D020733:RNA, Small Cytoplasmic; D044022:Receptor, Endothelin A / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; D001786:Blood Glucose; D065130:Endothelin A Receptor Antagonists; D019332:Endothelin-1; D009687:Nuclear Proteins; D000078723:Nuclear Receptor Interacting Protein 1; D010666:Phenylpropionates; D011724:Pyridazines; D020733:RNA, Small Cytoplasmic; D044022:Receptor, Endothelin A; D054801:Phosphoinositide Phospholipase C; D054799:Phospholipase C beta; C423320:phospholipase C epsilon; C467894:ambrisentan