Advanced glycation endproducts induce fibrogenic activity in nonalcoholic steatohepatitis by modulating TNF-α-converting enzyme activity in mice
Open accessAbstract
Advanced glycation endproducts (AGEs) accumulate in patients with diabetes, yet the link between AGEs and inflammatory and fibrogenic activity in nonalcoholic steatohepatitis (NASH) has not been explored. Tumor necrosis factor alpha (TNF-α)-converting enzyme (TACE) is at the center of inflammatory processes. Because the main natural regulator of TACE activity is the tissue inhibitor of metalloproteinase 3 (Timp3), we hypothesized that AGEs induce TACE through nicotinamide adenine dinucleotide phosphate reduced oxidase 2 (NOX2); and the down-regulation of Sirtuin 1 (Sirt1)/Timp3 pathways mediate fibrogenic activity in NASH. The role of NOX2, Sirt1, Timp3, and TACE was evaluated in choline-deficient L-amino acid defined (CDAA) or Western diet (WD)-fed wild-type (WT) and NOX2−/− mice. To restore Timp3, mice were injected with adenovirus (Ad)-Timp3. Sirt1 and Timp3 expressions were studied in livers from NASH patients, and we found that their levels were significantly lower than in healthy controls. In WT mice on the CDAA or WD, Sirt1 and Timp3 expressions were lower, whereas production of reactive oxidative species and TACE activity significantly increased with an increase in active TNF-α production as well as induction of fibrogenic transcripts. Ad-Timp3 injection resulted in a significant decline in TACE activity, procollagen α1 (I), alpha smooth muscle actin (α-SMA) and transforming growth factor beta (TGF-β) expression. NOX2−/− mice on the CDAA or WD had no significant change in Sirt1, Timp3, and TACE activity or the fibrosis markers assessed. In vitro , AGE exposure decreased Sirt1 and Timp3 in hepatic stellate cells by a NOX2-dependent pathway, and TACE was induced after exposure to AGEs. Conclusion : TACE activation is central to the pathogenesis of NASH and is mediated by AGEs through NOX2 induction and down-regulation of Sirt1/Timp3 pathways. (Hepatology 2013;58:1339–1348)
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Endogenous and exogenous AGEs provoke the initiation and progression of NAFLD, and dietary AGEs from fructose- or sucrose-enriched diets and/or soft drinks can worsen liver fibrosis faster than endogenous AGEs.
“Endogenous and exogenous AGEs provoke the initiation and progression of NAFLD.”
From Advanced glycation end products (AGEs) and other adducts in aging-related diseases and alcohol-mediated tissue injury (2021) · cites this paper as [126]
Aggregation of AGEs decreases GSH, SIRT1, and TIMP3 and increases oxidative stress and inflammation, promoting inflammatory liver injury and fibrosis in experimental animal models and NAFLD patients.
“The aggregation of AGEs decreases the levels of the most important cellular antioxidant peptides, glutathione (GSH), SIRT1, and tissue inhibitor of metalloproteinase 3 (TIMP3), accompanied by increased oxidative stress and inflammation, promoting inflammatory liver injury and fibrosis in experimental animal models and NAFLD patients55–57,124–126.”
From Advanced glycation end products (AGEs) and other adducts in aging-related diseases and alcohol-mediated tissue injury (2021) · cites this paper as [126]
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- Authors
- Jiang, J. X., Chen, X., Fukada, H., Serizawa, N., Devaraj, S., & Török, N. J.
- Affiliations
- University of California Davis Medical Center (US)
- Texas Children's Hospital (US)
- Venue
- Hepatology
- Published
- 2013-10
- Volume
- 58
- Issue
- 4
- Pages
- 1339-1348
- ISSN
- 0270-9139 (ISSN-L)
- PMC
- PMC3897213
- OpenAlex
- W1587796776
- Cited by
- 49
- References
- 35
- Citations by year
- 2026: 1 · 2025: 1 · 2024: 1 · 2023: 5 · 2022: 1 · 2021: 6 · 2020: 4 · 2019: 4 · 2018: 5 · 2017: 6 · 2016: 4 · 2015: 6 · 2014: 5
- FWCI
- 3.64
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Hepatology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute of Diabetes and Digestive and Kidney Diseases (R56DK083283, DK-083283, R01DK083283)
- Topics
- Health Sciences › Medicine › Epidemiology › Liver Disease Diagnosis and Treatment
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Advanced Glycation End Products research
- Keywords
- advanced glycation end products, nonalcoholic steatohepatitis, liver fibrosis, TNF-alpha converting enzyme, TIMP-3, SIRT1, NOX2, hepatic stellate cells, TNF-α, oxidative stress, choline-deficient L-amino acid-defined diet, Western diet, type I procollagen, alpha-smooth muscle actin, TGF-beta
- MeSH terms
- ADAM17 Protein, NADPH Oxidase 2, Actins, Animals, Cells, Cultured, Disease Models, Animal, Fatty Liver, Humans, Liver, Liver Cirrhosis, Membrane Glycoproteins, Mice, Inbred C57BL, Tumor Necrosis Factor-alpha, Signal Transduction, Case-Control Studies, Glycation End Products, Advanced, Rats, Sprague-Dawley, Mice, Knockout, NADPH Oxidases, Tissue Inhibitor of Metalloproteinase-3, Mice, ADAM Proteins, Sirtuin 1, Non-alcoholic Fatty Liver Disease, In Vitro Techniques
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