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环氧化酶-2 依赖性 20-HETE 代谢增加间充质干细胞来源脂肪细胞中的脂肪堆积和脂肪细胞增大。

Cyclooxygenase-2 dependent metabolism of 20-HETE increases adiposity and adipocyte enlargement in mesenchymal stem cell-derived adipocytes.

机构信息

Joan C. Edwards School of Medicine, Marshall University, Huntington, WV.

Department of Physiology and Pharmacology, University of Toledo College of Medicine, Toledo, OH.

出版信息

J Lipid Res. 2013 Mar;54(3):786-793. doi: 10.1194/jlr.M033894. Epub 2013 Jan 4.

DOI:10.1194/jlr.M033894
PMID:23293373
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC3617952/
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.

摘要

20-羟二十碳四烯酸（20-HETE）是花生四烯酸细胞色素 P450（CYP）催化ω-羟化的产物，可诱导氧化应激，在临床研究中与体重指数（BMI）增加和代谢综合征有关。本研究旨在研究外源性 20-HETE 对间充质干细胞（MSC）来源的脂肪细胞的影响。在脂肪细胞分化过程中，MSC 中 CYP4A11 和 CYP4F2（人类主要的 20-HETE 合酶）的表达水平降低；然而，外源性 20-HETE（0.1-1 μM）以剂量依赖性方式增加这些细胞中的脂肪生成（P < 0.05）。20-HETE 类似物无法复制这些作用表明 20-HETE 的代谢产物参与介导其促脂肪生成作用。环氧化酶（COX）-1 选择性抑制剂增强，而 COX-2 选择性或双重 COX-1/2 抑制剂减弱 20-HETE 诱导的脂肪生成。20-HETE 的 COX 衍生代谢物 20-OH-PGE₂增强了 MSC 中的脂肪生成和脂质积累。20-HETE 和 20-OH-PGE₂ 的促脂肪生成作用导致 MSC 来源的脂肪细胞中脂肪生成调节剂 PPARγ和β-catenin 的表达增加。总之，我们首次表明 20-HETE 衍生的 COX-2 依赖性 20-OH-PGE₂ 增强了 MSC 中正在进行脂肪生成分化的成熟炎症脂肪细胞的肥大。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7795/3617952/a647f86d4478/786fig7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7795/3617952/0d91a3f9e57a/786fig1.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7795/3617952/65044574be91/786fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7795/3617952/65c446d9d232/786fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7795/3617952/4aeddecebf76/786fig5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7795/3617952/2a7fc1b587a7/786fig6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7795/3617952/a647f86d4478/786fig7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7795/3617952/0d91a3f9e57a/786fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7795/3617952/8ec29fa66c24/786fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7795/3617952/65044574be91/786fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7795/3617952/65c446d9d232/786fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7795/3617952/4aeddecebf76/786fig5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7795/3617952/2a7fc1b587a7/786fig6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7795/3617952/a647f86d4478/786fig7.jpg

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