Abstract 5045: Muscle-Type Capillary Endothelial Cells Actively Transport Fatty Acids via Intracellular Fatty Acid Binding Protein-4 and -5

Endothelial cells (EC) of muscle-type continuous capillary act as functional interface between the blood plasma and the tissue fluid. They have been considered to perform transendothelial exchange for many substances to transport them into interstitial compartment. Fatty acids are major source of energy metabolism in various organs including heart, skeletal muscle and adipose tissue, but it is uncertain how they can reach interstitial space through endothelial layer of capillary. Fatty acid binding proteins (FABP) are cytosolic fatty acid chaperones whose biological role is not fully understood. FABP4, also known as aP2, is believed to be exclusively expressed in adipocytes and macrophages while FABP5, also called mal1, is detected more widely. Thus far, we have reported that disrupted function of FABP4 and FABP5 in mice (double KO mice) exhibited a striking phenotype with strong protection from diet-induced obesity, insulin resistance and type 2 diabetes. Here we report an unexpected function of the FABPs in capillary EC. We first re-examined tissue distribution of the FABPs by immunohistochemistry. We found that in addition to highly expressing organs already reported, both FABP4/5 were strongly expressed in capillary EC, but not in any arteries, in heart, skeletal muscle, and adipose tissue. In mice deficient for either FABP4 or FABP5, or both, their expression was absent in capillary EC of the organs. Of interest, FABP5 expression was markedly enhanced in capillary EC in mice lacking FABP4, suggesting compensatory induction of FABP5. The tissue distribution of FABPs, along with the phenotype of the double KO mice, raised an intriguing possibility that capillary EC actively transport fatty acids from capillary lumen to interstitial compartment via intracellular FABP4 and FABP5. Consistent with this hypothesis, fatty acid metabolism was markedly reduced while glucose consumption was reciprocally and dramatically elevated in the heart (16.9 folds) and the skeletal muscle (3.7 folds) in the double KO mice, as estimated in vivo by uptake of fatty acid analog, 125 I-BMIPP, and glucose analog, 18 F-FDG. Considering the highest impacts of the FABPs in preventing the metabolic syndrome, this novel pathway may lend a new approach to treat the type 2 diabetes.