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Regulation of cardiac long-chain fatty acid and glucose uptake by translocation of substrate transporters

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Abstract

Cardiac uptake of long-chain fatty acids (FA) is mediated predominantly by two membrane-associated proteins, the 43-kDa plasma membrane fatty acid-binding protein (FABPpm) and the 88-kDa fatty acid translocase/CD36 (FAT/CD36). While FABPpm is present constitutively in the sarcolemma, FAT/CD36 is recycled between an intracellular membrane compartment and the sarcolemma. Since the amount of sarcolemmal FAT/CD36 is a major determinant of cellular FA uptake, understanding of the regulation of its recycling is likely to provide new insights into altering substrate preference of the heart. FAT/CD36 recycling displays a remarkable similarity with that of the two glucose transporters (GLUT) in the heart, GLUT1 and GLUT4. Translocation of all three transporters is induced by insulin and by contraction, which stimuli activate distinct signalling cascades. The insulin pathway involves phosphatidylinositol-3 kinase (PI3K) whilst the contraction pathway is dependent on AMP-activated protein kinase (AMPK). For the identification of additional protein components involved in the regulation of FAT/CD36 recycling, valuable lessons can be learned from GLUT1 and GLUT4 recycling. Especially GLUT4 recycling is an intensively studied process in which a number of signalling proteins, both upstream and downstream from PI3 K and AMPK, have been identified, as well as proteins that are part of the translocation machinery involving Rab GTPases and soluble N-ethylmaleimide attachment protein receptors (SNAREs). Comparison of the magnitude of the effects of insulin and contraction on substrate uptake and on transporter appearance in the sarcolemma have revealed that FAT/CD36 recycling resembles GLUT1 recycling more closely than that of GLUT4. This pinpoints the recycling compartment and excludes a pre-endosomal storage compartment as the intracellular storage site for FAT/CD36. Further research will probably establish whether FAT/CD36 translocation is (partly) coupled to that of one or both GLUTs or, alternatively, whether it is a distinct process that also can be induced independently of GLUT1 or GLUT4 movement. In the latter case, a unique set of proteins would be dedicated to FAT/CD36 recycling, which would then provide an attractive target for manipulating cardiac substrate preference.

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Abbreviations

AICAR :

5-aminoimidazole-4-carboxyamide-1-β-d-ribofuranoside, cell-permeable activator of AMPK

AMPK :

AMP-activated protein kinase

amrinone :

specific inhibitor of phosphodiesterase III

CPT-I :

carnitine palmitoyl transferase I

dibutyryl cyclic AMP :

cell-permeable analogue of cyclic AMP, mimics cyclic AMP-activated signalling

DNP :

2,4-dinitrophenol, mitochondrial uncoupling agent

ERK :

extracellular signal-regulated kinase

etomoxir :

specific inhibitor of CPT-I

FA :

long-chain fatty acid(s)

FABPpm :

plasma membrane fatty acid-binding protein

FAT/CD36 :

fatty acid translocase/CD36

GTPγS :

guanosine 5′-O-(3-thiotriphosphate), non-hydrolysable GTP analogue, locks Rab proteins in a persistently active state

IGF-II :

insulin-like growth factor II

5-iodotubercidin :

specific inhibitor of adenosine kinase, prevents conversion of AICAR into ZMP

IRAP :

insulin-responsive aminopeptidase

IRS :

insulin receptor substrate

isoproterenol :

potent β-agonist

myristoylated PKCζ pseudosubstrate :

cell-permeable, specific inhibitor of atypical PKCs

oligomycin :

potent inhibitor of mitochondrial F1F0-ATPase

PD98059 :

specific inhibitor of mitogen-activated protein kinase signalling

PI3K :

phosphatidylinositol-3 kinase

PKB (PKB/Akt):

protein kinase B

PKC :

protein kinase C

rotenone :

inhibitor of electron transfer in mitochondria

SCAMP :

secretory carrier membrane protein

SNAP23 :

synaptosomal-associated protein (23 kDa)

SNARE :

soluble N-ethylmaleimide attachment protein receptor

SSO :

sulpho-N-succinimidyloleate, specific inhibitor of transport function of FAT/CD36

VAMP2 (-3):

vesicle-associated membrane protein-2 (-3)

VAP33 :

vesicle-associated protein 33

wortmannin :

inhibitor of PI3K

ZMP :

5′-monophosphate of AICAR

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Acknowledgements

Work in the authors’ laboratories is supported by the Netherlands Heart Foundation, grant 2000.156, and by the Heart and Stroke Foundation of Ontario. Joost Luiken is the recipient of a VIDI-Innovational Research grant from the Netherlands Organisation for Scientific Research (NWO-ZonMw grant No. 016.036.305). Arend Bonen is a Canada Research Chair in Metabolism and Health. Jan Glatz is Netherlands Heart Foundation Professor of Cardiac Metabolism.

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Authors and Affiliations

  1. Department of Molecular Genetics, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, P.O. Box 616, 6200 MD, Maastricht, The Netherlands

    Joost J. F. P. Luiken, Susan L. M. Coort, Debby P. Y. Koonen & Jan F. C. Glatz

  2. Department of Biochemical Physiology and Institute of Biomembranes, Utrecht University, 3584 CH, Utrecht, TheNetherlands

    Dick J. van der Horst

  3. Department of Human Biology and Nutritional Sciences, University of Guelph, Guelph, N1WG 2W1, Canada

    Arend Bonen

  4. Departament de Bioquímica i Biologia Molecular, Facultat de Biologia, Universitat de Barcelona and Parc Científic de Barcelona, Barcelona, Spain

    Antonio Zorzano

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  1. Joost J. F. P. Luiken
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Correspondence to Joost J. F. P. Luiken.

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Luiken, J.J.F.P., Coort, S.L.M., Koonen, D.P.Y. et al. Regulation of cardiac long-chain fatty acid and glucose uptake by translocation of substrate transporters. Pflugers Arch - Eur J Physiol 448, 1–15 (2004). https://doi.org/10.1007/s00424-003-1199-4

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