Peroxisome Proliferator-Activated Receptor-γ in Capillary Endothelia Promotes Fatty Acid Uptake by Heart During Long-Term Fasting

Background-Endothelium is a crucial blood-tissue interface controlling energy supply according to organ needs. We investigated whether peroxisome proliferator-activated receptor-gamma (PPAR gamma) induces expression of fatty acid-binding protein 4 (FABP4) and fatty acid translocase (FAT)/CD36 in capillary endothelial cells (ECs) to promote FA transport into the heart. Methods and Results-Expression of FABP4 and CD36 was induced by the PPAR gamma agonist pioglitazone in human cardiac microvessel ECs (HCMECs), but not in human umbilical vein ECs. Real-time PCR and immunohistochemistry of the heart tissue of control (Pparg(fl/null)) mice showed an increase in expression of FABP4 and CD36 in capillary ECs by either pioglitazone treatment or 48 hours of fasting, and these effects were not found in mice deficient in endothelial PPAR gamma (Pparg(Delta EC/null)). Luciferase reporter constructs of the Fabp4 and CD36 promoters were markedly activated by pioglitazone in HCMECs through canonical PPAR-responsive elements. Activation of PPAR gamma facilitated FA uptake by HCMECs, which was partially inhibited by knockdown of either FABP4 or CD36. Uptake of an FA analogue, I-125-BMIPP, was significantly reduced in heart, red skeletal muscle, and adipose tissue in Pparg(Delta EC/null) mice as compared with Pparg(fl/null) mice after olive oil loading, whereas those values were comparable between Pparg(fl/null) and Pparg(Delta EC/null) null mice on standard chow and a high-fat diet. Furthermore, Pparg(Delta EC/null) mice displayed slower triglyceride clearance after olive oil loading. Conclusions-These findings identified a novel role for capillary endothelial PPAR gamma as a regulator of FA handing in FA-metabolizing organs including the heart in the postprandial state after long-term fasting.