title: Cyclooxygenase-2 dependent metabolism of 20-HETE increases adiposity and adipocyte enlargement in mesenchymal stem cell-derived adipocytes.
abstract: 20-Hydroxy-5,8,11,14-eicosatetraenoic acid (20-HETE), a product of the cytochrome P450 (CYP)-catalyzed ω-hydroxylation of arachidonic acid, induces oxidative stress and, in clinical studies, is associated with increased body mass index (BMI) and the metabolic syndrome. This study was designed to examine the effects of exogenous 20-HETE on mesenchymal stem cell (MSC)-derived adipocytes. The expression levels of CYP4A11 and CYP4F2 (major 20-HETE synthases in humans) in MSCs decreased during adipocyte differentiation; however, exogenous administration of 20-HETE (0.1-1 μM) increased adipogenesis in a dose-dependent manner in these cells (P < 0.05). The inability of a 20-HETE analog to reproduce these effects suggested the involvement of a metabolic product of 20-HETE in mediating its pro-adipogenic effects. A cyclooxygenase (COX)-1 selective inhibitor enhanced, whereas a COX-2 selective or a dual COX-1/2 inhibitor attenuated adipogenesis induced by 20-HETE. The COX-derived metabolite of 20-HETE, 20-OH-PGE₂, enhanced adipogenesis and lipid accumulation in MSCs. The pro-adipogenic effects of 20-HETE and 20-OH-PGE₂ resulted in the increased expression of the adipogenic regulators PPARγ and β-catenin in MSC-derived adipocytes. Taken together we show for the first time that 20-HETE-derived COX-2-dependent 20-OH-PGE₂ enhances mature inflamed adipocyte hypertrophy in MSC undergoing adipogenic differentiation.
authors.affiliation: Joan C. Edwards School of Medicine, Marshall University, Huntington, WV.
authors.forename: Dong Hyun
authors.initials: DH
authors.lastname: Kim
authors.affiliation: Department of Physiology and Pharmacology, University of Toledo College of Medicine, Toledo, OH.
authors.forename: Nitin
authors.initials: N
authors.lastname: Puri
authors.affiliation: Joan C. Edwards School of Medicine, Marshall University, Huntington, WV.
authors.forename: Komal
authors.initials: K
authors.lastname: Sodhi
authors.affiliation: Department of Biochemistry and Pharmacology, University of Texas Southwestern Medical Center of Dallas, Dallas, TX.
authors.forename: John R
authors.initials: JR
authors.lastname: Falck
authors.affiliation: Joan C. Edwards School of Medicine, Marshall University, Huntington, WV.
authors.forename: Nader G
authors.initials: NG
authors.lastname: Abraham
authors.affiliation: Joan C. Edwards School of Medicine, Marshall University, Huntington, WV.
authors.forename: Joseph
authors.initials: J
authors.lastname: Shapiro
authors.affiliation: Department of Pharmacology, New York Medical College, Valhalla, NY.
authors.forename: Michal L
authors.initials: ML
authors.lastname: Schwartzman
mesh_terms: D017667:Adipocytes / Q000166:cytology*; D050154:Adiposity / Q000502:physiology; D015153:Blotting, Western; D002454:Cell Differentiation; D002478:Cells, Cultured; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D006801:Humans; D006893:Hydroxyeicosatetraenoic Acids / Q000378:metabolism*; D059630:Mesenchymal Stem Cells / Q000166:cytology*; D060888:Real-Time Polymerase Chain Reaction
chemical_list: D006893:Hydroxyeicosatetraenoic Acids; C055987:20-hydroxy-5,8,11,14-eicosatetraenoic acid; D051546:Cyclooxygenase 2