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Endogenous formation of Nε-(carboxymethyl)lysine is increased in fatty livers and induces inflammatory markers in an in vitro model of hepatic steatosis
Open accessAbstract
Background & aims Increased lipid peroxidation and inflammation are major factors in the pathogenesis of nonalcoholic fatty liver disease (NAFLD). A lipoxidation product that could play a role in the induction of hepatic inflammation is N(ε)-(carboxymethyl)lysine (CML). The aim of the present study was to investigate the relationship between steatosis and CML and to study the role of CML in hepatic inflammation.Methods We included 74 obese individuals, which were categorized into 3 groups according to the grade of hepatic steatosis. CML accumulation in liver biopsies was assessed by immunohistochemistry and plasma CML levels were measured by mass spectrometry. Plasma CML levels were also determined in the hepatic artery, portal, and hepatic vein of 22 individuals, and CML fluxes across the liver were calculated. Hepatocyte cell lines were used to study CML formation during intracellular lipid accumulation and the effect of CML on pro-inflammatory cytokine expression. Gene expression levels of the inflammatory markers were determined in liver biopsies of the obese individuals.Results CML accumulation was significantly associated with the grade of hepatic steatosis, the grade of hepatic inflammation, and gene expression levels of inflammatory markers PAI-1, IL-8, and CRP. Analysis of CML fluxes showed no release/uptake of CML by the liver. Lipid accumulation in hepatocytes, induced by incubation with fatty acids, was associated with increased CML formation and expression of the receptor for advanced glycation endproducts (RAGE), PAI-1, IL-8, IL-6, and CRP. Pyridoxamine and aminoguanidine inhibited the endogenous CML formation and the increased RAGE, PAI-1, IL-8, IL-6, and CRP expression. Incubation of hepatocytes with CML-albumin increased the expression of RAGE, PAI-1, and IL-6, which was inhibited by an antibody against RAGE.Conclusions Accumulation of CML and a CML-upregulated RAGE-dependent inflammatory response in steatotic livers may play an important role in hepatic steatosis and in the pathogenesis of NAFLD.
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“Intracellular AGE accumulation is observed in animal models of hepatic steatosis and other advanced liver diseases, such as hepatic inflammation (steatohepatitis) and fibrosis/cirrhosis.”
From Advanced glycation end products (AGEs) and other adducts in aging-related diseases and alcohol-mediated tissue injury (2021) · cites this paper as [123]
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“Accumulated AGEs in hepatocytes can stimulate apoptosis and inflammation, leading to cellular dysfunction, steatosis, and ultimately nonalcoholic fatty liver disease (NAFLD)121–123.”
From Advanced glycation end products (AGEs) and other adducts in aging-related diseases and alcohol-mediated tissue injury (2021) · cites this paper as [123]
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Short chain fatty acids exchange across the gut and liver in humans measured at surgery
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Obesity-associated low-grade inflammation in type 2 diabetes mellitus: causes and consequences.
van Greevenbroek, M. M. J., Schalkwijk, C., & Stehouwer, C. D. A. (2013) · PubMed · Cited by 233
Self-citationPolimeni, L. (2015) · World Journal of Hepatology · doi:10.4254/wjh.v7.i10.1325 · Cited by 213
Gaens, K. H. J., Goossens, G. H., Niessen, P., van Greevenbroek, M. M. J., Kallen, C., Niessen, H. W. M., Rensen, S. S., Buurman, W. A., Greve, J. W. M., Blaak, E. E., et al. (2014) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/atvbaha.113.302281 · Cited by 196
Self-citationFernando, D. H., Forbes, J. M., Angus, P. W., & Herath, C. B. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20205037 · Cited by 184
Metadata
- Authors
- Gaens, K. H. J., Niessen, P. M. G., Rensen, S. S., Buurman, W. A., Greve, J. W. M., Driessen, A., Wolfs, M. G. M., Hofker, M. H., Bloemen, J. G., Dejong, C. H., Stehouwer, C. D. A., & Schalkwijk, C. G.
- Affiliations
- Maastricht University Medical Centre (NL)
- University Medical Center Groningen (NL)
- Corresponding author
- Schalkwijk, Casper G.
- ORCID
- Venue
- Journal of Hepatology
- Publisher
- Elsevier BV
- Published
- 2012-03
- Volume
- 56
- Issue
- 3
- Pages
- 647-655
- ISSN
- 0168-8278 (ISSN-L)
- OpenAlex
- W1964714465
- Cited by
- 109
- References
- 36
- Citations by year
- 2026: 4 · 2025: 3 · 2024: 6 · 2023: 7 · 2022: 8 · 2021: 9 · 2020: 6 · 2019: 14 · 2018: 10 · 2017: 15 · 2016: 7 · 2015: 8 · 2014: 2 · 2013: 6 · 2012: 3
- FWCI
- 2.89
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Hepatology (publishedVersion)
- PubMed (publishedVersion)
- Research Publications (Maastricht University) (submittedVersion, other-oa)
- Funders
- Universiteit Maastricht
- Nierstichting (01C-104)
- Diabetes Fonds (01C-104)
- Maastricht Universitair Medisch Centrum
- Center for Translational Molecular Medicine (01 C-104)
- Transnationale Universiteit Limburg
- SenterNovem
- Topics
- Health Sciences › Medicine › Hepatology › Liver Disease Diagnosis and Treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Advanced Glycation End Products research
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Keywords
- carboxymethyllysine, advanced glycation end products, non-alcoholic fatty liver disease, hepatic steatosis, liver inflammation, receptor for advanced glycation end products, lipid peroxidation, inflammatory cytokines, plasminogen activator inhibitor-1, interleukin-8, C-reactive protein, pyridoxamine, aminoguanidine, hepatocyte lipid accumulation, obesity
- MeSH terms
- Aged, Biopsy, Enzyme Inhibitors, Fatty Liver, Female, Guanidines, Humans, Liver, Lysine, Male, Middle Aged, Obesity, Pyridoxamine, Vitamin B Complex, Biomarkers, Gene Expression, Cytokines, Hepatocytes, Hep G2 Cells, Non-alcoholic Fatty Liver Disease, In Vitro Techniques
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