Insulin Stimulates Long-Chain Fatty Acid Utilization by Rat Cardiac Myocytes Through Cellular Redistribution of FAT/CD36
The existence of an intracellular pool of fatty acid translocase (FAT/CD36), an 88-kDa membrane transporter for long-chain fatty acids (FAs), and the ability of insulin to induce translocation events prompted us to investigate the direct effects of insulin on cellular uptake of FA by the heart. Insulin (0.1 nmol/l and higher) increased FA uptake by isolated rat cardiac myocytes by 1.5-fold. This insulin-induced increase in FA uptake was completely blocked by phloretin, sulfo-N-succinimidylpalmitate (SSP), and wortmannin, indicating the involvement of FAT/CD36 and the dependence on phosphatidylinositol-3 (PI-3) kinase activation. Subcellular fractionation of insulin-stimulated cardiac myocytes demonstrated a 1.5-fold increase in sarcolemmal FAT/CD36 and a 62% decrease in intracellular FAT/CD36 with parallel changes in subcellular distribution of GLUT4. Induction of cellular contractions upon electrostimulation at 4 Hz enhanced cellular FA uptake 1.6-fold, independent of PI-3 kinase. The addition of insulin to 4 Hz-stimulated cells further stimulated FA uptake to 2.3-fold, indicating that there are at least two functionally independent intracellular FAT/CD36 pools, one recruited by insulin and the other mobilized by contractions. In conclusion, we have demonstrated a novel role of insulin in cardiac FA utilization. Malfunctioning of insulin-induced FAT/CD36 translocation may be involved in the development of type 2 diabetic cardiomyopathies.
Address correspondence and reprint requests to Joost J.F.P. Luiken, Department of Physiology, CARIM, Maastricht University, P.O. Box 616, NL-6200 MD Maastricht. E-mail:.
Received for publication 19 June 2001 and accepted in revised form 31 May 2002.
Y.F. is currently affiliated with Solvay Pharmaceuticals, Hannover, Germany.
BCA, bicinchoninic acid; FA, fatty acid; FAT/CD36, fatty acid translocase; LDM, low density microsomes; PI-3, phosphatidylinositol-3; PM, plasma membrane; SSP, sulfo-N-succinimidylpalmitate.