Dietary advanced glycation end-products aggravate non-alcoholic fatty liver disease
Open accessAbstract
AIM: To determine if manipulation of dietary advanced glycation end product (AGE), intake affects non-alcoholic fatty liver disease (NAFLD) progression and whether these effects are mediated via RAGE. METHODS: Male C57Bl6 mice were fed a high fat, high fructose, high cholesterol (HFHC) diet for 33 wk and compared with animals on normal chow. A third group were given a HFHC diet that was high in AGEs. Another group was given a HFHC diet that was marinated in vinegar to prevent the formation of AGEs. In a second experiment, RAGE KO animals were fed a HFHC diet or a high AGE HFHC diet and compared with wildtype controls. Hepatic biochemistry, histology, picrosirius red morphometry and hepatic mRNA were determined. RESULTS: Long-term consumption of the HFHC diet generated significant steatohepatitis and fibrosis after 33 wk. In this model, hepatic 4-hydroxynonenal content (a marker of chronic oxidative stress), hepatocyte ballooning, picrosirius red staining, α-smooth muscle actin and collagen type 1A gene expression were all significantly increased. Increasing the AGE content of the HFHC diet by baking further increased these markers of liver damage, but this was abrogated by pre-marination in acetic acid. In response to the HFHC diet, RAGE(-/-) animals developed NASH of similar severity to RAGE(+/+) animals but were protected from the additional harmful effects of the high AGE containing diet. Studies in isolated Kupffer cells showed that AGEs increase cell proliferation and oxidative stress, providing a likely mechanism through which these compounds contribute to liver injury. CONCLUSION: In the HFHC model of NAFLD, manipulation of dietary AGEs modulates liver injury, inflammation, and liver fibrosis via a RAGE dependent pathway. This suggests that pharmacological and dietary strategies targeting the AGE/RAGE pathway could slow the progression of NAFLD.
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Accumulated AGEs and AGE-RAGE interactions in liver cells augment ROS generation and MAPK/NF-κB activation, leading to inflammatory cell death in the parenchyma and tissue remodeling during fibrosis.
“Accumulated AGEs and AGE-RAGE interactions in these cells augment the generation of ROS and the activation of MAPK and NF-κB pathways, leading to inflammatory cell death in the parenchyma and tissue remodeling processes during fibrosis127,128.”
From Advanced glycation end products (AGEs) and other adducts in aging-related diseases and alcohol-mediated tissue injury (2021) · cites this paper as [128]
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- Authors
- Leung, C., Herath, C. B., Jia, Z., Andrikopoulos, S., Brown, B. E., Davies, M. J., Rivera, L. R., Furness, J. B., Forbes, J. M., & Angus, P. W.
- Affiliations
- Deakin University (AU)
- Corresponding author
- Leung, Christopher
- ORCID
- Venue
- World Journal of Gastroenterology
- Publisher
- Baishideng Publishing Group Inc.
- Published
- 2016
- Volume
- 22
- Issue
- 35
- Pages
- 8026
- ISSN
- 1007-9327 (ISSN-L)
- PMC
- PMC5028816
- OpenAlex
- W2520817907
- Cited by
- 80
- References
- 49
- Citations by year
- 2026: 2 · 2025: 8 · 2024: 7 · 2023: 7 · 2022: 14 · 2021: 12 · 2020: 5 · 2019: 10 · 2018: 6 · 2017: 9
- FWCI
- 7.80
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- cc-by-nc
- Locations
- World Journal of Gastroenterology (publishedVersion, cc-by-nc)
- PubMed Central (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- Minerva Access (University of Melbourne) (submittedVersion, cc-by-nc)
- Figshare (submittedVersion, cc-by-nc)
- Funders
- Medical Research Council
- National Health and Medical Research Council
- Topics
- Health Sciences › Medicine › Epidemiology › Liver Disease Diagnosis and Treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Advanced Glycation End Products research
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diet, Metabolism, and Disease
- Keywords
- advanced glycation end products, non-alcoholic fatty liver disease, receptor for advanced glycation end products, RAGE, steatohepatitis, liver fibrosis, oxidative stress, 4-hydroxynonenal, Kupffer cells, vinegar, acetic acid, hepatocyte ballooning, alpha-smooth muscle actin, type I collagen
- MeSH terms
- Animals, Cholesterol, Fatty Liver, Fructose, Inflammation, Kupffer Cells, Liver, Liver Cirrhosis, Male, Mice, Inbred C57BL, Signal Transduction, Glycation End Products, Advanced, Mice, Knockout, Oxidative Stress, Disease Progression, Acetic Acid, Mice, Diet, High-Fat, Real-Time Polymerase Chain Reaction, Non-alcoholic Fatty Liver Disease
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