Peroxisome proliferator-activated receptor-α accelerates α-chlorofatty acid catabolism

alpha-Chlorofatty aldehydes are generated from myeloperoxidase-derived HOCl targeting plasmalogens, and are subsequently oxidized to -chlorofatty acids (-ClFAs). The catabolic pathway for -ClFA is initiated by -oxidation. Here, we examine PPAR- activation as a mechanism to increase -ClFA catabolism. Pretreating both HepG2 cells and primary mouse hepatocytes with the PPAR- agonist, pirinixic acid (Wy 14643), increased the production of -chlorodicarboxylic acids (-ClDCAs) in cells treated with exogenous -ClFA. Additionally, -ClDCA production in Wy 14643-pretreated wild-type mouse hepatocytes was accompanied by a reduction in cellular free -ClFA. The dependence of PPAR--accelerated -ClFA catabolism was further demonstrated by both impaired metabolism in mouse PPAR-(-/-) hepatocytes and decreased clearance of plasma -ClFA in PPAR-(-/-) mice. Furthermore, Wy 14643 treatments decreased plasma 2-chlorohexadecanoic acid levels in wild-type mice. Additional studies showed that -ClFA increases PPAR-, PPAR-, and PPAR- activities, as well as mRNA expression of the PPAR- target genes, CD36, CPT1a, Cyp4a10, and CIDEC. Collectively, these results indicate that PPAR- accelerates important pathways for the clearance of -ClFA, and -ClFA may, in part, accelerate its catabolism by serving as a ligand for PPAR-alpha.