title: Peroxisome proliferator-activated receptor-α accelerates α-chlorofatty acid catabolism.
abstract: α-Chlorofatty aldehydes are generated from myeloperoxidase-derived HOCl targeting plasmalogens, and are subsequently oxidized to α-chlorofatty acids (α-ClFAs). The catabolic pathway for α-ClFA is initiated by ω-oxidation. Here, we examine PPAR-α activation as a mechanism to increase α-ClFA catabolism. Pretreating both HepG2 cells and primary mouse hepatocytes with the PPAR-α agonist, pirinixic acid (Wy 14643), increased the production of α-chlorodicarboxylic acids (α-ClDCAs) in cells treated with exogenous α-ClFA. Additionally, α-ClDCA production in Wy 14643-pretreated wild-type mouse hepatocytes was accompanied by a reduction in cellular free α-ClFA. The dependence of PPAR-α-accelerated α-ClFA catabolism was further demonstrated by both impaired metabolism in mouse PPAR-α-/-hepatocytes and decreased clearance of plasma α-ClFA in PPAR-α-/-mice. Furthermore, Wy 14643 treatments decreased plasma 2-chlorohexadecanoic acid levels in wild-type mice. Additional studies showed that α-ClFA increases PPAR-α, PPAR-δ, and PPAR-γ activities, as well as mRNA expression of the PPAR-α target genes, CD36, CPT1a, Cyp4a10, and CIDEC. Collectively, these results indicate that PPAR-α accelerates important pathways for the clearance of α-ClFA, and α-ClFA may, in part, accelerate its catabolism by serving as a ligand for PPAR-α.
authors.affiliation: Edward A. Doisy Department of Biochemistry and Molecular Biology and Center for Cardiovascular Research, Saint Louis University School of Medicine, St. Louis, MO 63104.
authors.forename: Elisa N D
authors.initials: EN
authors.lastname: Palladino
authors.affiliation: Edward A. Doisy Department of Biochemistry and Molecular Biology and Center for Cardiovascular Research, Saint Louis University School of Medicine, St. Louis, MO 63104.
authors.forename: Wen-Yi
authors.initials: WY
authors.lastname: Wang
authors.affiliation: Edward A. Doisy Department of Biochemistry and Molecular Biology and Center for Cardiovascular Research, Saint Louis University School of Medicine, St. Louis, MO 63104.
authors.forename: Carolyn J
authors.initials: CJ
authors.lastname: Albert
authors.affiliation: Edward A. Doisy Department of Biochemistry and Molecular Biology and Center for Cardiovascular Research, Saint Louis University School of Medicine, St. Louis, MO 63104.
authors.forename: Cédric
authors.initials: C
authors.lastname: Langhi
authors.affiliation: Edward A. Doisy Department of Biochemistry and Molecular Biology and Center for Cardiovascular Research, Saint Louis University School of Medicine, St. Louis, MO 63104.
authors.forename: Ángel
authors.initials: Á
authors.lastname: Baldán
authors.affiliation: Edward A. Doisy Department of Biochemistry and Molecular Biology and Center for Cardiovascular Research, Saint Louis University School of Medicine, St. Louis, MO 63104 fordda@slu.edu.
authors.forename: David A
authors.initials: DA
authors.lastname: Ford
mesh_terms: D000818:Animals; D005227:Fatty Acids / Q000378:metabolism; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D008660:Metabolism / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D010084:Oxidation-Reduction; D047493:PPAR alpha / Q000235:genetics* / Q000378:metabolism; D047494:PPAR delta / Q000096:biosynthesis; D010169:Palmitic Acids / Q000378:metabolism*; D012333:RNA, Messenger / Q000096:biosynthesis
chemical_list: C532464:2-chlorohexadecanoic acid; D005227:Fatty Acids; D047493:PPAR alpha; D047494:PPAR delta; D010169:Palmitic Acids; D012333:RNA, Messenger
keywords: fatty acid; fatty acid/oxidation; lipid biochemistry; liver metabolism; myeloperoxidase; nuclear receptors/peroxisome proliferator-activated receptor