Regulation of sarcolemmal glucose and fatty acid transporters in cardiac disease.
Circulating long-chain fatty acids (LCFA) and glucose are the main sources for energy production in the heart. In the healthy heart the ratio of glucose and LCFA oxidation is sensitively balanced and chronic alterations in this substrate mix are closely associated with cardiac dysfunction. While it has been accepted for several years that cardiac glucose uptake is mediated by facilitated transport, i.e. by means of the glucose transport proteins GLUT1 and GLUT4, only in the last few years it has become clear that proteins with high-affinity binding sites to LCFA, referred to as LCFA transporters, are responsible for bulk LCFA uptake. Similar to the GLUTs, the LCFA transporters CD36 and FABP(pm) can be recruited from an intracellular storage compartment to the sarcolemma to increase the rate of substrate uptake. Permanent relocation of LCFA transporters, mainly CD36, from intracellular stores to the sarcolemma is accompanied by accumulation of lipids and lipid metabolites in the heart. As a consequence, insulin signalling and glucose utilization are impaired, leading to decreased contractile activity of the heart. These observations underline the particular role and interplay of substrate carriers for glucose and LCFA in modulating cardiac metabolism, and the development of heart failure. The signalling and trafficking pathways and subcellular machinery regulating translocation of glucose and LCFA transporters are beginning to be unravelled. More knowledge on substrate transporter recycling, especially the similarities and differences between glucose and LCFA transporters, is expected to enable novel therapies aimed at changing the subcellular distribution of glucose and LCFA transporters, thereby manipulating the substrate preference of the diseased heart to help restore cardiac function.
Schwenk
Robert W
RW
Department of Molecular Genetics, Cardiovascular Research Institute Maastricht , Maastricht University, PO Box 616, 6200 MD Maastricht, The Netherlands.
Luiken
Joost J F P
JJ
Bonen
Arend
A
Glatz
Jan F C
JF
D000818:Animals; D001692:Biological Transport / Q000502:physiology; D004195:Disease Models, Animal; D050612:Fatty Acid Transport Proteins / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism*; D006331:Heart Diseases / Q000378:metabolism*; D006801:Humans; D012508:Sarcolemma / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology
D050612:Fatty Acid Transport Proteins; D005947:Glucose