Glutathionylated Lipid Aldehydes Are Products of Adipocyte Oxidative Stress and Activators of Macrophage Inflammation

被引:40
作者
Frohnert, Brigitte I. [1 ]
Long, Eric K. [2 ]
Hahn, Wendy S. [2 ]
Bernlohr, David A. [2 ]
机构
[1] Univ Minnesota, Dept Pediat, Minneapolis, MN 55455 USA
[2] Univ Minnesota, Dept Biochem Mol Biol & Biophys, Minneapolis, MN 55455 USA
基金
美国国家卫生研究院;
关键词
FATTY-ACID-BINDING; ALDOSE REDUCTASE; INSULIN-RESISTANCE; TNF-ALPHA; 4-HYDROXY-TRANS-2-NONENAL HNE; PROTEIN CARBONYLATION; EXPRESSION; RLIP76; IDENTIFICATION; ADDUCTS;
D O I
10.2337/db13-0777
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
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- 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.
引用
收藏
页码:89 / 100
页数:12
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[1]   Systems biology of antioxidants [J].
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