Receptor mediated activation of ceramidase activity initiates the pleiotropic actions of adiponectin英文文献.pdfVIP

a r t i c l e s Receptor-­mediated activation of ceramidase activity initiates the pleiotropic actions of adiponectin 1 2 1 1 3 4 1 William L Holland , Russell A Miller , Zhao V Wang , Kai Sun , Brian M Barth , Hai H Bui , Kathryn E Davis , 5 1,6 1 4 1 4 Benjamin T Bikman , Nils Halberg , Joseph M Rutkowski , Mark R Wade , Vincent M Tenorio , Ming-Shang Kuo , 4 7 2 3,5,8 1,9 Joseph T Brozinick , Bei B Zhang , Morris J Birnbaum , Scott A Summers Philipp E Scherer The adipocyte-derived secretory factor adiponectin promotes insulin sensitivity, decreases inflammation and promotes cell . d survival. No unifying mechanism has yet explained how adiponectin can exert such a variety of beneficial systemic effects. Here, e v we show that adiponectin potently stimulates a ceramidase activity associated with its two receptors, AdipoR1 and AdipoR2, and r e s enhances ceramide catabolism and formation of its antiapoptotic metabolite—sphingosine-1-phosphate (S1P)—independently e r of AMP-dependent kinase (AMPK). Using models of inducible apoptosis in pancreatic beta cells and cardiomyocytes, we show s t that transgenic overproduction of adiponectin decreases caspase-8-mediated death, whereas genetic ablation of adiponectin h g enhances apoptosis in vivo through a sphingolipid-mediated pathway. Ceramidase activity is impaired in cells lacking both i r l adiponectin receptor isoforms, leading to elevated cera