title: Sarcolemmal fatty acid uptake vs. mitochondrial beta-oxidation as target to regress cardiac insulin resistance.
abstract: Cardiomyopathy and heart failure are frequent comorbid conditions in type-2 diabetic patients. However, it has become increasingly evident that insulin resistance, type-2 diabetes, and cardiomyopathy are not independent variables, and are linked through changes in metabolism. Specifically, elevated intracellular levels of long-chain fatty acid (LCFA) metabolites are a central feature in the development of cardiac insulin resistance, and their prolonged accumulation is an important cause of heart failure. In the insulin-resistant heart, the abundance of the LCFA transporters CD36 and FABPpm at the sarcolemma of cardiac myocytes appears to be markedly increased. Because circulating LCFA levels are increased in insulin resistance, the cardiac LCFA metabolizing machinery is confronted with drastic increases in substrate supply. Indeed, LCFA esterification into triacylglycerol and other lipid intermediates is increased, as is beta-oxidation and reactive oxygen species production. Therapeutic strategies to normalize the cardiac LCFA flux would be most successful when the target is the rate-limiting step in cardiac LCFA utilization. Carnitine palmitoyltransferase (CPT)-I has long been considered to be this rate-limiting site and, accordingly, pharmacological inhibition of CPT-I, or beta-oxidation enzymes, has been proposed as an insulin-resistance-antagonizing strategy. However, recent evidence indicates that, instead, sarcolemmal LCFA transport mediated by CD36 in concert with FABPpm provides a major site of flux control. In this review, it is proposed that a pharmacologically imposed net internalization of CD36 and FABPpm is the preferable strategy to limit LCFA entry and accumulation of LCFA metabolites, to regress cardiac insulin resistance and, eventually, prevent diabetic heart failure.
authors.affiliation: Department of Molecular Genetics, Cardiovascular Research Institute Maastricht, Maastricht University, P.O. Box 616, NL-6200 MD Maastricht, the Netherlands. j.luiken@gen.unimaas.nl
authors.forename: Joost J F P
authors.initials: JJ
authors.lastname: Luiken
mesh_terms: D005227:Fatty Acids / Q000378:metabolism*; D006801:Humans; D007333:Insulin Resistance / Q000502:physiology*; D008928:Mitochondria / Q000378:metabolism*; D009206:Myocardium / Q000378:metabolism*; D010084:Oxidation-Reduction; D012508:Sarcolemma / Q000378:metabolism*
chemical_list: D005227:Fatty Acids