Abstract 12337: Peroxidsome Proliferator Activated Receptor-Alpha Regulates Trans-Endothelial Fatty Acid Transport in Capillary Endothelial Cells; Functional Similarity Between PPAR-Alpha and PPAR-Gamma
Peroxisome proliferator activated receptor (PPAR) is the primary transcriptional regulator of fat metabolism. PPAR-α mainly functions in tissues with high fatty acid (FA) oxidation rates, such as heart, skeletal muscle and liver whereas PPAR-γ primarily acts to store lipid in adipose tissue and others. We recently found that capillary-endothelial PPAR-γ regulates FA transport from circulation into FA-metabolizing organs such as heart and adipose tissue via induction of fatty acid binding protein 4 (FABP4) and fatty acid translocase (FAT). Although many studies on PPAR-α have been done regarding the parenchymal cells, little is known about its function in capillary endothelial cells (EC). We first re-examined tissue distribution of PPAR-α by immunohistochemistry. In addition to the parenchymal cells, PPAR-α was strongly expressed in capillary EC in heart and skeletal muscle, but not in liver, which was accompanied by expression of FABP4 and FAT. Consistent with this, expression of both mRNA and protein for FABP4 and FAT was induced by WY-14643 and bezafibrate, synthetic PPAR-α ligands, in human cardiac microvessel EC (HCMEC), but not in human umbilical vein EC (HUVEC) or 3T3L1 fibroblasts/adipocytes, suggesting capillary-EC-specific effects. Treatment of mice with bezafibrate (100 mg/kg/day) for two weeks enhanced expression of FABP4 in capillary EC of hearts. The luciferase reporter construct of FABP4 was markedly trans-activated by the PPAR-α ligands in HCMEC via two canonical PPAR-responsive elements. We next studied whether PPAR-α stimulation facilitates uptake of FA in HCMEC. Uptake of C14-palmitic acid was promoted by WY-14643 and the increase in the uptake was partially inhibited by treatment of siRNA for FABP4 and FAT. These findings suggest that PPAR-α and its target genes play a crucial role in trans-endothelial FA transport to supply adequate FA to FA-metabolizing organs. Our study also provides intriguing notions that functionally opposite PPARs on lipid metabolism utilize similar system in capillary EC to transport FA from circulation to myocardium and that FABP4, a representative marker for adipocyte differentiation and lipid storage, is the primary target gene of PPAR-α, a crucial transcriptional regulator for lipid consumption.
- © 2011 by American Heart Association, Inc.