Glutathionylated Lipid Aldehydes Are Products of Adipocyte Oxidative Stress and Activators of Macrophage Inflammation
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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.
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Oxidative modification of cellular components such as glutathionylated 4-hydroxy-2-nonenal can directly stimulate a macrophage-mediated proinflammatory response.
“In addition, oxidative modification of cellular components such as glutathionylated 4-hydroxy-2-nonenal can directly stimulate a macrophage-mediated proinflammatory response (81).”
From The ominous triad of adipose tissue dysfunction: inflammation, fibrosis, and impaired angiogenesis. (2017) · cites this paper as [81]
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- Authors
- Frohnert, B. I., Long, E. K., Hahn, W. S., & Bernlohr, D. A.
- Affiliations
- University of Minnesota (US)
- Corresponding author
- Bernlohr, David A.
- Venue
- Diabetes
- Publisher
- American Diabetes Association
- Published
- 2013-12-13
- Volume
- 63
- Issue
- 1
- Pages
- 89-100
- ISSN
- 0012-1797 (ISSN-L)
- 1939-327X
- PMC
- PMC3868039
- OpenAlex
- W2165264002
- Cited by
- 60
- References
- 50
- Citations by year
- 2026: 4 · 2025: 1 · 2024: 2 · 2023: 2 · 2022: 5 · 2021: 6 · 2020: 5 · 2019: 3 · 2018: 8 · 2017: 3 · 2016: 4 · 2015: 7 · 2014: 8 · 2013: 1
- FWCI
- 5.10
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Diabetes (publishedVersion, cc-by-nc-nd)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Funders
- University of Minnesota
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK084669, P30DK050456, DK053189, F32DK091004, DK-084669, R56DK084669, K12DK094712, R56DK053189, R01DK053189)
- Topics
- Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Glutathione Transferases and Polymorphisms
- Keywords
- 4-hydroxynonenal, macrophage inflammation, insulin resistance, obesity, visceral adipose tissue, TNF-α, adipose tissue inflammation, glucose tolerance, protein carbonylation
- MeSH terms
- Aldehydes, Aldehyde Reductase, Animals, Glucose, Glutathione, Glutathione Transferase, Inflammation, Insulin Resistance, Macrophages, Tumor Necrosis Factor-alpha, Adipocytes, Oxidative Stress, Mice
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