Insulin and AMPK regulate FA translocase/CD36 plasma membrane recruitment in cardiomyocytes via Rab GAP AS160 and Rab8a Rab GTPase

Abstract

regulated by multiple factors, including insulin and contraction ( 1, 2 ). Several proteins have been proposed to facilitate FA uptake by the myocardium, and these include the scavenger receptor cluster of differentiation 36 (CD36), the FA transport proteins, caveolin1, and plasma membrane-associated FA binding protein (as reviewed in Ref. 1 ). In addition to these proteins, acyl-CoA ligases that activate FA by generating the FA acyl-CoA, couple FA entry to metabolism and help maintain the gradient for FA infl ux across the plasma membrane ( 1,3 ) CD36 is abundantly expressed in the heart and facilitates a signifi cant part of myocardial FA uptake measured in vivo in humans and rodents ( 4, 5 ). Unlike other proteins implicated in FA uptake, CD36 cycles between intracellular stores and the plasma membrane, similar to the glucose transporter GLUT4. CD36 traffi cking is regulated by a number of factors including insulin, muscle contraction ( 1, 2 ), purinergic agonists such as uridine-5 ′ -triphosphate (UTP) ( 6 ), and FAs ( 7-9 ). It is believed that the effect of muscle contraction on CD36 surface translocation is mediated via activation of AMP-dependent protein kinase (AMPK) ( 10 ), although this notion was recently challenged in skeletal muscle ( 11 ).Insulin and contraction increase CD36 surface expression on cardiomyocytes to enhance myocardial extraction of circulating FA. The internalized FA is either directly oxidized in mitochondria (AMPK and contraction) or partitioned fi rst into triglycerides (insulin) that can later be hydrolyzed to provide FA for oxidation (as reviewed in Ref. Press, February 6, 2012 DOI 10.1194 Abbreviations: AICAR, 5-aminoimidazole-4-carboxamide-1-beta-Dribofuranoside; AMPK, AMP-dependent protein kinase; AS160, Akt substrate 160; CA, constitutively active; CD36, fatty acid translocase cluster of differentiation 36; CHO, Chinese hamster ovary; DN, dominant-negative; GAP, GTPase-activating protein; GEF, guanine exchange factor; GFP, green fl uorescent protein; RNAi, RNA interference; siRNA, small interfering RNA; UTP, uridine-5 ′ -triphosphate; Wt, wild-type. Published, JLR Papers in

Calcium signaling recruits substrate transporters GLUT4 and CD36 to the sarcolemma without increasing cardiac substrate uptake

“…AMPK-mediated transporter translocation has been found to be dependent on phosphorylation-mediated inhibition of AS160 (18,39), and in agreement, oligomycin treatment resulted in AS160 phosphorylation (Fig. 5A).…”

“…In cardiomyocytes from LKB1-null mice, contraction-induced GLUT4 and CD36 translocation was abolished, disclosing LKB1 as the responsible upstream kinase of AMPK (21). Activation of AMPK results in a series of signaling events, such as Akt substrate of 160 kDa (AS160) phosphorylation causing GLUT4 and CD36 translocation (39,40) and a consequential increase in substrate uptake. Additionally, AMPK activation increases glucose and LCFA oxidation through phosphorylation of glycolytic enzymes and of acetylCoA carboxylase (ACC), respectively (27).…”

The Effects of AS160 Modulation on Fatty Acid Transporters Expression and Lipid Profile in L6 Myotubes

“…The data presented herein showed that moderate AS160 down regulation followed by the increment in pAS160 level has upregulated total expression of the fatty acid transporters, namely FABPpm and FAT/CD36 in L6 myotubes. To the best of our knowledge only one article on this specific topic exists where FAT/CD36 expression after knock-down of AS160 was measured [11]. The authors of these data have found that in HL-1 cardiomyocytes the trafficking of FAT/CD36, a major facilitator of myocardial FA uptake, is regulated by AS160 [11].…”

Prolonged daily light exposure increases body fat mass through attenuation of brown adipose tissue activity

“…Prolonged light exposure decreased phosphorylation of CREB and AMPK, two main targets of β3-adrenergic signaling in the brown adipocyte. AMPK not only modulates intracellular lipolysis by phosphorylation of HSL, but also regulates uptake of lipids and glucose by inducing translocation of CD36, LPL, and GLUT4 to the plasma membrane (22,23), which may explain the reduced nutrient uptake by BAT. Moreover, we showed that in the absence of sympathetic input, BAT activity is equal among the various light-exposure groups.…”