Glutathionylated lipid aldehydes are products of adipocyte oxidative stress and activators of macrophage inflammation.
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.
Department of Pediatrics, University of Minnesota, Minneapolis, MN.
Brigitte I
BI
Frohnert
Eric K
EK
Long
Wendy S
WS
Hahn
David A
DA
Bernlohr
D017667:Adipocytes / Q000187:drug effects / Q000378:metabolism*; D000449:Aldehyde Reductase / Q000378:metabolism; D000447:Aldehydes / Q000378:metabolism; D000818:Animals; D005947:Glucose / Q000494:pharmacology; D005978:Glutathione / Q000378:metabolism; D005982:Glutathione Transferase / Q000378:metabolism; D007249:Inflammation / Q000378:metabolism*; D007333:Insulin Resistance / Q000502:physiology*; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D000447:Aldehydes; D014409:Tumor Necrosis Factor-alpha; D000449:Aldehyde Reductase; D005982:Glutathione Transferase; D005978:Glutathione; D005947:Glucose