NYMC Faculty Publications

Cyclooxygenase-2 Dependent Metabolism of 20-HETE Increases Adiposity and Adipocyte Enlargement in Mesenchymal Stem Cell-Derived Adipocytes

Author Type(s)

Faculty

DOI

10.1194/jlr.M033894

Journal Title

Journal of Lipid Research

First Page

786

Last Page

793

Document Type

Article

Publication Date

3-1-2013

Department

Medicine

Keywords

Adipocytes, Adiposity, Blotting, Western, Cell Differentiation, Cells, Cultured, Cyclooxygenase 2, Humans, Hydroxyeicosatetraenoic Acids, Mesenchymal Stem Cells, Real-Time Polymerase Chain Reaction

Disciplines

Medicine and Health Sciences

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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