Dietary glycotoxins exacerbate progression of experimental fatty liver disease
Open accessAbstract
Background & aims Advanced glycation end-products (AGEs) levels are high in western diets and contribute to tissue injury via activation of RAGE (receptor for AGEs) and generation of reactive oxygen species (ROS). Here, we determined if high dietary AGE intake worsens progression of non-alcoholic fatty liver disease (NAFLD).Methods Male Sprague Dawley rats were fed a methionine choline deficient (MCD) diet for 6 weeks before 6 weeks of a high AGE MCD diet through baking. They were compared with animals on MCD diet or a methionine choline replete (MCR) diet alone for 12 weeks. Hepatic ROS, triglycerides, biochemistry, picro-sirius morphometry, hepatic mRNA expression and immunohistochemistry were determined. Primary hepatic stellate cells (HSCs) from both MCR and MCD animals were exposed to AGEs. ROS, proliferation and mRNA expression were determined.Results The high AGE MCD diet increased hepatic AGE content and elevated triglycerides, NADPH dependent superoxide production, HNE adducts, steatosis, steatohepatitis (CD43, IL-6, TNF-α) and fibrosis (α-SMA, CTGF, COL1A, picrosirius) compared to MCD alone. In HSCs, AGEs significantly increased ROS production, bromodeoxyuridine proliferation and MCP-1, IL-6, α-SMA, and RAGE expression in HSCs from MCD but not MCR animals. These effects were abrogated by RAGE or NADPH oxidase blockade.Conclusions In the MCD model of NAFLD, high dietary AGEs increases hepatic AGE content and exacerbates liver injury, inflammation, and liver fibrosis via oxidative stress and RAGE dependent profibrotic effects of AGEs on activated HSCs. This suggests that pharmacological and dietary strategies targeting the AGE/RAGE pathway could slow the progression of NAFLD.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
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 [124]
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 [124]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Origins and evolution of the Western diet: health implications for the 21st century1,2
Cordain, L., Eaton, S. B., Sebastian, A., Mann, N., Lindeberg, S., Watkins, B. A., O’Keefe, J. H., & Brand-Miller, J. (2005) · The American Journal of Clinical Nutrition · doi:10.1093/ajcn.81.2.341 · Cited by 2,397 · see citing works
Advanced Glycation End Products: Sparking the Development of Diabetic Vascular Injury
Goldin, A., Beckman, J. A., Schmidt, A. M., & Creager, M. A. (2006) · Circulation · doi:10.1161/circulationaha.106.621854 · Cited by 2,261 · see citing works
Williams, C. D., Stengel, J. Z., Asike, M., Torres, D. M., Shaw, J. C., Contreras, M., Landt, C. L., & Harrison, S. A. (2010) · Gastroenterology · doi:10.1053/j.gastro.2010.09.038 · Cited by 2,146 · see citing works
Advanced glycation endproducts—role in pathology of diabetic complications
Ahmed, N. (2004) · Diabetes Research and Clinical Practice · doi:10.1016/j.diabres.2004.09.004 · Cited by 1,457 · see citing works
Understanding RAGE, the receptor for advanced glycation end products
Bierhaus, A., Humpert, P. M., Morcos, M., Wendt, T., Chavakis, T., Arnold, B., Stern, D. M., & Nawroth, P. P. (2005) · Journal of Molecular Medicine · doi:10.1007/s00109-005-0688-7 · Cited by 1,297 · see citing works
Advanced glycation end products in foods and a practical guide to their reduction in the diet
Uribarri, J., Woodruff, S., Goodman, S., Cai, W., Chen, X., Pyzik, R., Yong, A., Striker, G. E., & Vlassara, H. (2010) · Journal of the American Dietetic Association · doi:10.1016/j.jada.2010.03.018 · Cited by 1,289 · see citing works
CYP2E1 and CYP4A as microsomal catalysts of lipid peroxides in murine nonalcoholic steatohepatitis
Leclercq, I. A., Farrell, G. C., Field, J., Bell, D., Gonzalez, F. J., & Robertson, G. R. (2000) · Journal of Clinical Investigation · doi:10.1172/jci8814 · Cited by 763 · see citing works
Advanced glycoxidation end products in commonly consumed foods
Goldberg, T., Cai, W., Peppa, M., Dardaine, V., Baliga, B. S., Uribarri, J., & Vlassara, H. (2004) · Journal of the American Dietetic Association · doi:10.1016/j.jada.2004.05.214 · Cited by 744 · see citing works
Increased Hepatic and Circulating Interleukin-6 Levels in Human Nonalcoholic Steatohepatitis
Wieckowska, A., Papouchado, B. G., Li, Z., Lopez, R., Zein, N. N., & Feldstein, A. E. (2008) · The American Journal of Gastroenterology · doi:10.1111/j.1572-0241.2007.01774.x · Cited by 597 · see citing works
Uribarri, J., Cai, W., Peppa, M., Goodman, S., Ferrucci, L., Striker, G., & Vlassara, H. (2007) · The Journals of Gerontology Series A: Biological Sciences and Medical Sciences · doi:10.1093/gerona/62.4.427 · Cited by 570 · see citing works
Cytokines and Nash: A Pilot Study of the Effects of Lifestyle Modification and Vitamin E
Kugelmas, M., Hill, D. B., Vivian, B., Marsano, L. S., & McClain, C. J. (2003) · Hepatology · doi:10.1053/jhep.2003.50316 · Cited by 503 · see citing works
Rinella, M. E., & Green, R. M. (2003) · Journal of Hepatology · doi:10.1016/j.jhep.2003.09.020 · Cited by 462 · see citing works
Activation of hepatic stellate cells - a key issue in liver fibrosis
Reeves, H. L. (2002) · Frontiers in bioscience · doi:10.2741/reeves · Cited by 420 · see citing works
Coordinate Contribution of Lipid Oxidation and Maillard Reaction to the Nonenzymatic Food Browning
Zamora, R., & Hidalgo, F. J. (2005) · Critical Reviews in Food Science and Nutrition · doi:10.1080/10408690590900117 · Cited by 419 · see citing works
Thallas‐Bonke, V., Thorpe, S. R., Coughlan, M. T., Fukami, K., Yap, F. Y. T., Sourris, K. C., Penfold, S. A., Bach, L. A., Cooper, M. E., & Forbes, J. M. (2007) · Diabetes · doi:10.2337/db07-1119 · Cited by 345 · see citing works
Self-citationMiyata, T., Hori, O., Zhang, J., Yan, S. S., Ferran, L., Iida, Y., & Schmidt, A. M. (1996) · Journal of Clinical Investigation · doi:10.1172/jci118889 · Cited by 278 · see citing works
Protein-bound advanced glycation endproducts (AGEs) as bioactive amino acid derivatives in foods
Henle, T. (2005) · Amino Acids · doi:10.1007/s00726-005-0200-2 · Cited by 253 · see citing works
Guimarães, E. L. M., Empsen, C., Geerts, A. E., & van Grunsven, L. A. (2009) · Journal of Hepatology · doi:10.1016/j.jhep.2009.12.007 · Cited by 226 · see citing works
Hyogo, H., Yamagishi, S., Iwamoto, K., Arihiro, K., Takeuchi, M., Sato, T., Ochi, H., Nonaka, M., Nabeshima, Y., Inoue, M., et al. (2007) · Journal of Gastroenterology and Hepatology · doi:10.1111/j.1440-1746.2007.04943.x · Cited by 188 · see citing works
Zeng, S., Feirt, N. M., Goldstein, M., Guarrera, J. V., Ippagunta, N., Ekong, U. D., Dun, H., Lu, Y., Qu, W., Schmidt, A. M., et al. (2004) · Hepatology · doi:10.1002/hep.20045 · Cited by 179 · see citing works
Aso, Y., Inukai, T., Tayama, K., & Takemura, Y. (2000) · Acta Diabetologica · doi:10.1007/s005920070025 · Cited by 157 · see citing works
4-Hydroxynonenal–protein adducts: A reliable biomarker of lipid oxidation in liver diseases
Poli, G., Biasi, F., & Leonarduzzi, G. (2007) · Molecular Aspects of Medicine · doi:10.1016/j.mam.2007.09.016 · Cited by 157 · see citing works
Fibrogenic impact of high serum glucose in chro nic hepatitis C
Ratziu, V., Munteanu, M., Charlotte, F., Bonyhay, L., & Poynard, T. (2003) · Journal of Hepatology · doi:10.1016/s0168-8278(03)00456-2 · Cited by 151 · see citing works
Cardiac inflammation associated with a Western diet is mediated via activation of RAGE by AGEs
Tikellis, C., Thomas, M. C., Harcourt, B. E., Coughlan, M. T., Pete, J., Bialkowski, K., Tan, A. L. Y., Bierhaus, A., Cooper, M. E., & Forbes, J. M. (2008) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00024.2008 · Cited by 129 · see citing works
Self-citationAdvanced Glycation End Products (AGEs) and their Involvement in Liver Disease
Hyogo, H., & Yamagishi, S. (2008) · Current Pharmaceutical Design · doi:10.2174/138161208784139701 · Cited by 127 · see citing works
Tan, A. L. Y., Sourris, K. C., Harcourt, B. E., Thallas‐Bonke, V., Penfold, S. A., Andrikopoulos, S., Thomas, M. C., O’Brien, R. C., Bierhaus, A., Cooper, M. E., et al. (2009) · American Journal of Physiology-Renal Physiology · doi:10.1152/ajprenal.00591.2009 · Cited by 125 · see citing works
Self-citationCoughlan, M. T., Thallas-Bonke, V., Pete, J., Long, D. M., Gasser, A., Tong, D. C. K., Arnstein, M., Thorpe, S. R., Cooper, M. E., & Forbes, J. M. (2007) · Endocrinology · doi:10.1210/en.2006-1300 · Cited by 124 · see citing works
Self-citationAdvanced glycation end products enhance the proliferation and activation of hepatic stellate cells
Iwamoto, K., Kanno, K., Hyogo, H., Yamagishi, S., Takeuchi, M., Tazuma, S., & Chayama, K. (2008) · Journal of Gastroenterology · doi:10.1007/s00535-007-2152-7 · Cited by 110 · see citing works
Patella, S., Phillips, D. J., Tchongue, J., de Kretser, D. M., & Sievert, W. (2005) · American Journal of Physiology-Gastrointestinal and Liver Physiology · doi:10.1152/ajpgi.00080.2005 · Cited by 110 · see citing works
Effect of Dietary Advanced Glycation End Products on Mouse Liver
Patel, R. A., Baker, S. S., Liu, W., Desai, S. S., Alkhouri, R. H., Kozielski, R., Mastrandrea, L. D., Sarfraz, A., Cai, W., Vlassara, H., et al. (2012) · PLoS ONE · doi:10.1371/journal.pone.0035143 · Cited by 102 · see citing works
Ekong, U. D., Zeng, S., Dun, H., Feirt, N. M., Guo, J., Ippagunta, N., Guarrera, J. V., Lu, Y., Weinberg, A. D., Qu, W., et al. (2006) · Journal of Gastroenterology and Hepatology · doi:10.1111/j.1440-1746.2006.04225.x · Cited by 65 · see citing works
Advanced glycation end products augment experimental hepatic fibrosis
Goodwin, M., Herath, C. B., Jia, Z., Leung, C., Coughlan, M. T., Forbes, J. M., & Angus, P. (2012) · Journal of Gastroenterology and Hepatology · doi:10.1111/jgh.12042 · Cited by 65 · see citing works
Self-citationFrancque, S., Wamutu, S., Chatterjee, S., Marck, E. V., Herman, A. G., Ramon, A., Jung, A., Vermeulen, W., Winter, B. Y. D., Pelckmans, P. A., et al. (2009) · Liver International · doi:10.1111/j.1478-3231.2009.02136.x · Cited by 52 · see citing works
Role of the receptor for advanced glycation end products inhepatic fbrosis
Lohwasser, C., Neureiter, D., Popov, Y. V., Bauer, M. W., & Schuppan, D. (2009) · World Journal of Gastroenterology · doi:10.3748/wjg.15.5789 · Cited by 49 · see citing works
Opposing roles of RAGE and Myd88 signaling in extensive liver resection
Zeng, S., Zhang, Q., Huang, J., Vedantham, S., Rosario, R., Ananthakrishnan, R., Yan, S. F., Ramasamy, R., DeMatteo, R. P., Emond, J. C., et al. (2011) · The FASEB Journal · doi:10.1096/fj.11-192997 · Cited by 32 · see citing works
Sourris, K. C., Harcourt, B. E., Penfold, S. A., Yap, F. Y. T., Morley, A. L., Morgan, P. E., Davies, M. J., Baker, S. T., Jerums, G., & Forbes, J. M. (2010) · Experimental Diabetes Research · doi:10.1155/2010/974681 · Cited by 23 · see citing works
Self-citationBeyond reasonable doubt: Who is the culprit in lipotoxicity in NAFLD/NASH?
Rooyen, D. M. V., Larter, C. Z., Haigh, W. G., et al. (2012) · Hepatology · doi:10.1002/hep.25721 · Cited by 20 · see citing works
Flagged first, then by citations
Research works printed but not linked: 6
- Sourris KC, Harcourt BE, Penfold SA, Yap FYT, Morley AL, Morgan PE, et al. Modulation of the Cellular Expression of Circulating Advanced Glycation End-Product Receptors in Type 2 Diabetic Nephropathy. AGE 2010;4:11.
- Goodwin M, Herath C, Jia Z, Leung C, Coughlan M, Forbes J, et al. Advanced glycation endproducts augment experimental hepatic fibrosis. Journal of gastroenterology and hepatology 2012.
- Goldin A, Beckman JA, Schmidt AM, Creager MA. Advanced Glycation End Products. Circulation 2006;114:597-605.
- Iwamoto K, Kanno K, Hyogo H, Yamagishi S, Takeuchi M, Tazuma S, et al. Advanced glycation end products enhance the proliferation and activation of hepatic stellate cells. J Gastroenterol 2008;43:298-304.
- Goldberg T, Cai W, Peppa M, Dardaine V, Baliga BS, Uribarri J, et al. Advanced glycoxidation end products in commonly consumed foods. J Am Diet Assoc 2004;104:1287-1291.
- Leung, C., Herath, C. B., Jia, Z., Goodwin, M., Mak, K. Y., Watt, M. J., Forbes, J. M. & Angus, P. W. (2014). Dietary glycotoxins exacerbate progression of experimental fatty liver disease. JOURNAL OF HEPATOLOGY, 60 (4), pp.832-838. https://doi.org/10.1016/j.jhep.2013.11.033. Persistent Link: http://hdl.handle.net/11343/43831
Cited by
Sorted by citations
Treatment of NAFLD with diet, physical activity and exercise
Romero-Gómez, M., Zelber-Sagi, S., & Trenell, M. (2017) · Journal of Hepatology · doi:10.1016/j.jhep.2017.05.016 · Cited by 1,347 · see citing works
The role of the gut microbiota in NAFLD
Leung, C., Rivera, L., Furness, J. B., & Angus, P. W. (2016) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/nrgastro.2016.85 · Cited by 1,020 · see citing works
Self-citationRungratanawanich, W., Qu, Y., Wang, X., Essa, M. M., & Song, B.-J. (2021) · Experimental & Molecular Medicine · doi:10.1038/s12276-021-00561-7 · Cited by 411 · see citing works
Snelson, M., & Coughlan, M. (2019) · Nutrients · doi:10.3390/nu11020215 · Cited by 230 · see citing works
Meli, R., Mattace Raso, G., & Calignano, A. (2014) · Frontiers in Immunology · doi:10.3389/fimmu.2014.00177 · Cited by 137 · see citing works
Is Alzheimer’s Disease a Liver Disease of the Brain?
Bassendine, M. F., Taylor-Robinson, S. D., Fertleman, M., Khan, M., & Neely, D. (2020) · Journal of Alzheimer's Disease · doi:10.3233/jad-190848 · Cited by 124 · see citing works
Dietary advanced glycation end-products aggravate non-alcoholic fatty liver disease
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. (2016) · World Journal of Gastroenterology · doi:10.3748/wjg.v22.i35.8026 · Cited by 80 · see citing works
Self-citationInteraction mechanisms between major depressive disorder and non-alcoholic fatty liver disease
Shao, Q., Wu, Y., Ji, J., Xu, T., Yu, Q., Ma, C., Liao, X., Cheng, F., & Wang, X. (2021) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2021.711835 · Cited by 32 · see citing works
- Authors
- Leung, C., Herath, C. B., Jia, Z., Goodwin, M., Mak, K. Y., Watt, M. J., Forbes, J. M., & Angus, P. W.
- Affiliations
- Baker Heart and Diabetes Institute (AU)
- The University of Melbourne (AU)
- Monash University (AU)
- Corresponding author
- Leung, Christopher
- Venue
- Journal of Hepatology
- Publisher
- Elsevier BV
- Published
- 2014-04
- Volume
- 60
- Issue
- 4
- Pages
- 832-838
- ISSN
- 0168-8278 (ISSN-L)
- OpenAlex
- W2167403850
- Cited by
- 88
- References
- 37
- Citations by year
- 2025: 6 · 2024: 7 · 2023: 7 · 2022: 8 · 2021: 8 · 2020: 7 · 2019: 7 · 2018: 5 · 2017: 9 · 2016: 5 · 2015: 11 · 2014: 8
- FWCI
- 5.81
- Type
- journal article
- Language
- en
- Open access
- green
- hdl.handle.net
- Locations
- Journal of Hepatology (publishedVersion)
- PubMed (publishedVersion)
- Minerva Access (University of Melbourne) (submittedVersion)
- 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 › Hepatology › Liver physiology and pathology
- Keywords
- advanced glycation end products, non-alcoholic fatty liver disease, RAGE, hepatic stellate cells, liver fibrosis, oxidative stress, reactive oxygen species, methionine-choline-deficient diet, steatohepatitis, inflammation, NADPH oxidase, dietary AGE intake
- MeSH terms
- Animals, Choline Deficiency, Diet, Insulin Resistance, Liver, Male, Methionine, Gene Expression, Glycation End Products, Advanced, Rats, Sprague-Dawley, Oxidative Stress, Disease Progression, Cell Proliferation, Rats, Hepatic Stellate Cells, Non-alcoholic Fatty Liver Disease
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
