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Dietary glycotoxins exacerbate progression of experimental fatty liver disease.
MedLine Citation:
PMID:  24316518     Owner:  NLM     Status:  Publisher    
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.
Christopher Leung; Chandana B Herath; Zhiyuan Jia; Michelle Goodwin; Kai Yan Mak; Matthew J Watt; Josephine M Forbes; Peter W Angus
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2013-12-5
Journal Detail:
Title:  Journal of hepatology     Volume:  -     ISSN:  1600-0641     ISO Abbreviation:  J. Hepatol.     Publication Date:  2013 Dec 
Date Detail:
Created Date:  2013-12-9     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  8503886     Medline TA:  J Hepatol     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Copyright Information:
Copyright © 2013. Published by Elsevier B.V.
Department of Medicine, The University of Melbourne, Austin Health, Heidelberg, Victoria, Australia; Department of Gastroenterology and Hepatology, Austin Health, Austin Hospital, Heidelberg, Melbourne, Victoria, Australia; Glycation and Diabetes Group, Baker IDI Diabetes Institute, Melbourne, Victoria, Australia. Electronic address:
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