Cyclooxygenase-2 dependent metabolism of 20-HETE increases adiposity
and adipocyte enlargement in mesenchymal stem cell-derived
adipocytes |
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Authors: | Dong Hyun Kim Nitin Puri Komal Sodhi John R Falck Nader G Abraham Joseph Shapiro Michal L Schwartzman |
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Institution: | *Joan C. Edwards School of Medicine, Marshall University, Huntington, WV;†Department of Physiology and Pharmacology, University of Toledo College of Medicine, Toledo, OH;§Department of Biochemistry and Pharmacology, University of Texas Southwestern Medical Center of
Dallas, Dallas, TX;**Department of Pharmacology, New York Medical College, Valhalla, NY |
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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. |
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Keywords: | adipogenesis arachidonic acid mesenchymal stem cells |
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