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Title: Dietary advanced glycation end-products aggravate non-alcoholic fatty liver disease
Austin Authors: Leung, Christopher ;Herath, Chandana B;Jia, Zhiyuan;Andrikopoulos, Sofianos;Brown, Bronwyn E;Davies, Michael J;Rivera, Leni R;Furness, John B;Forbes, Josephine M;Angus, Peter W 
Affiliation: Austin Health, Heidelberg, Victoria, Australia
Department of Medicine, the University of Melbourne, Austin Health, Heidelberg, Victoria, Australia
Department of Gastroenterology and Hepatology, Austin Health, Heidelberg, Victoria, Australia
Heart Research Institute, Newtown, NSW, Australia
The University of Melbourne, Parkville, Victoria, Australia
Metabolic Research Unit, School of Medicine, Deakin University, Geelong, Victoria, Australia
Glycation and Diabetes Complications Group, Mater Medical Research Institute, South Brisbane, Queensland, Australia
Issue Date: 21-Sep-2016 2016-09-21
Publication information: World Journal of Gastroenterology 2016; 22(35): 8026-8040
Abstract: 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.
DOI: 10.3748/wjg.v22.i35.8026
PubMed URL:
Type: Journal Article
Subjects: Advanced glycation end-products
Hepatic fibrosis
Non-alcoholic fatty liver disease
Oxidative stress
Appears in Collections:Journal articles

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