Abstract 15250: Peroxisome Proliferator Activated Receptor-Gamma Regulates Trans-endothelial Fatty Acid Transport via Induction of Fatty Acid Binding Protein 4 and Fatty Acid Translocase in Capillary Endothelial Cells in Heart and Adipose Tissue
Continuous capillary endothelial cells (EC) act as functional interface between blood plasma and tissue fluid. Fatty acids (FA) are major source of energy metabolism in various organs including heart and adipose tissue, but little is known about how FA reach the interstitial space through the endothelial layer of capillary. Fatty acid binding proteins 4 and 5 (FABP4/5) are expressed in capillary EC in the heart and facilitate FA transport from circulation into cardiac muscle. The current study shows that peroxisome proliferator activated receptor-γ (PPAR-γ) plays a role in trans-endothelial FA transport. Expression of FABP4 and fatty acid translocase (FAT) mRNA and protein were induced by pioglitazone (Pio), a synthetic PPAR-γ ligand, in human cardiac microvessel EC (HCMEC). Luciferase reporter constructs of FABP4 was markedly trans-activated by Pio only in HCMEC, but not at all in human umbilical vein EC. Reporter constructs with non-functional PPAR-responsive elements did not respond to Pio. Activation of PPAR-γ was found to facilitate uptake of FA into HCMEC; C14-palmitic acid uptake was stimulated by Pio and the increase in the uptake was partially inhibited by pre-treatment of cells with FAT siRNA. In vivo studies using PPAR-γ endothelial-specific knockout (PG-E null) mice provided genetic evidence for a role for capillary-endothelial PPAR-γ in FA uptake. Pio induced expression of FABP4 and FAT mRNAs in the heart of the wild-type (WT), but not in PG-E null mice. Immunohistochemistry also showed that capillary-specific expression of FABP4 was markedly enhanced by Pio in the WT, but not in the PG-E null mice. Although basal uptake of 125I-BMIPP, a FA analogue, was comparable in the heart and the adipose tissue after 24 hours fasting, the uptake was significantly reduced in these organs in the PG-E null mice after olive oil loading. Further, triglyceride clearance was markedly slower in the PG-E null than in the WT mice at 2, 4 and 8 hours after olive oil loading. These findings strongly suggest that capillary-endothelial PPAR-γ promotes trans-endothelial FA transport via induction of FABP4 and FAT in FA-metabolizing organs such as heart and adipose tissue.
- © 2010 by American Heart Association, Inc.