Insulin and AMPK regulate FA translocase/CD36 plasma membrane recruitment in cardiomyocytes via Rab GAP AS160 and Rab8a Rab GTPase.
The FA translocase cluster of differentiation 36 (CD36) facilitates FA uptake by the myocardium, and its surface recruitment in cardiomyocytes is induced by insulin, AMP-dependent protein kinase (AMPK), or contraction. Dysfunction of CD36 trafficking contributes to disordered cardiac FA utilization and promotes progression to disease. The Akt substrate 160 (AS160) Rab GTPase-activating protein (GAP) is a key regulator of vesicular trafficking, and its activity is modulated via phosphorylation. Our study documents that AS160 mediates insulin or AMPK-stimulated surface translocation of CD36 in cardiomyocytes. Knock-down of AS160 redistributes CD36 to the surface and abrogates its translocation by insulin or the AMPK agonist 5-aminoimidazole-4-carboxamide-1-beta-d-ribofuranoside (AICAR). Conversely, overexpression of a phosphorylation-deficient AS160 mutant (AS160 4P) suppresses the stimulated membrane recruitment of CD36. The AS160 substrate Rab8a GTPase is shown via overexpression and knock-down studies to be specifically involved in insulin/AICAR-induced CD36 membrane recruitment. Our findings directly demonstrate AS160 regulation of CD36 trafficking. In myocytes, the AS160 pathway also mediates the effect of insulin, AMPK, or contraction on surface recruitment of the glucose transporter GLUT4. Thus, AS160 constitutes a point of convergence for coordinating physiological regulation of CD36 and GLUT4 membrane recruitment.
Department of Cell Biology, Washington University School of Medicine, St. Louis, MO 63110, USA.
Dmitri
D
Samovski
Xiong
X
Su
Yingcheng
Y
Xu
Nada A
NA
Abumrad
Philip D
PD
Stahl
D000263:Adenylate Kinase / Q000378:metabolism; D000818:Animals; D018955:CD36 Antigens / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000201:enzymology / Q000378:metabolism; D004789:Enzyme Activation; D020690:GTPase-Activating Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007328:Insulin / Q000494:pharmacology*; D020935:MAP Kinase Signaling System; D051379:Mice; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism; D021381:Protein Transport; D034622:RNA Interference; D014162:Transfection; D020691:rab GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*
D018955:CD36 Antigens; D020690:GTPase-Activating Proteins; D007328:Insulin; C546061:Rab8a protein, mouse; C518767:TBC1D4 protein, human; C505647:Tbc1d4 protein, mouse; D000263:Adenylate Kinase; D020691:rab GTP-Binding Proteins