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谷胱甘肽化脂质醛是脂肪细胞氧化应激的产物，也是巨噬细胞炎症的激活剂。

Glutathionylated lipid aldehydes are products of adipocyte oxidative stress and activators of macrophage inflammation.

机构信息

Department of Pediatrics, University of Minnesota, Minneapolis, MN.

出版信息

Diabetes. 2014 Jan;63(1):89-100. doi: 10.2337/db13-0777. Epub 2013 Sep 23.

DOI:10.2337/db13-0777
PMID:24062247
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC3868039/
Abstract

Obesity-induced insulin resistance has been linked to adipose tissue lipid aldehyde production and protein carbonylation. Trans-4-hydroxy-2-nonenal (4-HNE) is the most abundant lipid aldehyde in murine adipose tissue and is metabolized by glutathione S-transferase A4 (GSTA4), producing glutathionyl-HNE (GS-HNE) and its metabolite glutathionyl-1,4-dihydroxynonene (GS-DHN). The objective of this study was to evaluate adipocyte production of GS-HNE and GS-DHN and their effect on macrophage inflammation. Compared with lean controls, GS-HNE and GS-DHN were more abundant in visceral adipose tissue of ob/ob mice and diet-induced obese, insulin-resistant mice. High glucose and oxidative stress induced production of GS-HNE and GS-DHN by 3T3-L1 adipocytes in a GSTA4-dependent manner, and both glutathionylated metabolites induced secretion of tumor necrosis factor-α from RAW 264.7 and primary peritoneal macrophages. Targeted microarray analysis revealed GS-HNE and GS-DHN induced expression of inflammatory genes, including C3, C4b, c-Fos, igtb2, Nfkb1, and Nos2. Transgenic overexpression of GSTA4 in mouse adipose tissue led to increased production of GS-HNE associated with higher fasting glucose levels and moderately impaired glucose tolerance. These results indicated adipocyte oxidative stress results in GSTA4-dependent production of proinflammatory glutathione metabolites, GS-HNE and GS-DHN, which may represent a novel mechanism by which adipocyte dysfunction results in tissue inflammation and insulin resistance.

摘要

肥胖引起的胰岛素抵抗与脂肪组织脂质醛的产生和蛋白质碳化有关。反式-4-羟基-2-壬烯醛（4-HNE）是鼠类脂肪组织中含量最丰富的脂质醛，由谷胱甘肽 S-转移酶 A4（GSTA4）代谢，生成谷胱甘肽-HNE（GS-HNE）及其代谢产物谷胱甘肽-1,4-二羟壬烯（GS-DHN）。本研究的目的是评估脂肪细胞中 GS-HNE 和 GS-DHN 的产生及其对巨噬细胞炎症的影响。与瘦对照组相比，ob/ob 小鼠和饮食诱导的肥胖、胰岛素抵抗小鼠的内脏脂肪组织中 GS-HNE 和 GS-DHN 更为丰富。高葡萄糖和氧化应激以 GSTA4 依赖的方式诱导 3T3-L1 脂肪细胞产生 GS-HNE 和 GS-DHN，这两种谷胱甘肽化代谢物均可诱导 RAW 264.7 和原代腹腔巨噬细胞分泌肿瘤坏死因子-α。靶向微阵列分析显示，GS-HNE 和 GS-DHN 诱导了炎症基因的表达，包括 C3、C4b、c-Fos、igtb2、Nfkb1 和 Nos2。GSTA4 在小鼠脂肪组织中的过表达导致 GS-HNE 的产生增加，与空腹血糖水平升高和糖耐量中度受损有关。这些结果表明，脂肪细胞氧化应激导致 GSTA4 依赖性产生促炎的谷胱甘肽代谢物 GS-HNE 和 GS-DHN，这可能代表了脂肪细胞功能障碍导致组织炎症和胰岛素抵抗的一种新机制。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6dc6/3868039/d4d69efbbdaa/89fig8.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6dc6/3868039/89dc369a99d8/89fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6dc6/3868039/979fb39af589/89fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6dc6/3868039/eb089d647b0f/89fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6dc6/3868039/07e9a9f09ae8/89fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6dc6/3868039/d85d14192c37/89fig5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6dc6/3868039/9cf0ed0d3067/89fig6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6dc6/3868039/c4fd59b7315f/89fig7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6dc6/3868039/d4d69efbbdaa/89fig8.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6dc6/3868039/89dc369a99d8/89fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6dc6/3868039/979fb39af589/89fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6dc6/3868039/eb089d647b0f/89fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6dc6/3868039/07e9a9f09ae8/89fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6dc6/3868039/d85d14192c37/89fig5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6dc6/3868039/9cf0ed0d3067/89fig6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6dc6/3868039/c4fd59b7315f/89fig7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6dc6/3868039/d4d69efbbdaa/89fig8.jpg

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