Copyright
©The Author(s) 2016. Published by Baishideng Publishing Group Inc. All rights reserved.
Dietary advanced glycation end-products aggravate non-alcoholic fatty liver disease
Christopher Leung, Chandana B Herath, Zhiyuan Jia, Sof Andrikopoulos, Bronwyn E Brown, Michael J Davies, Leni R Rivera, John B Furness, Josephine M Forbes, Peter W Angus
Christopher Leung, Chandana B Herath, Zhiyuan Jia, Sof Andrikopoulos, Peter W Angus, Department of Medicine, the University of Melbourne, Austin Health, Heidelberg, Melbourne, Victoria 3084, Australia
Christopher Leung, Peter W Angus, Department of Gastroenterology and Hepatology, Austin Health, Austin Hospital, Heidelberg, Melbourne, Victoria 3084, Australia
Bronwyn E Brown, Michael J Davies, Heart Research Institute, Newtown, New South Wales 2042, Australia
Leni R Rivera, John B Furness, University of Melbourne, Victoria 3052, Australia
Leni R Rivera, Metabolic Research Unit, School of Medicine, Deakin University, Victoria 3216, Australia
Josephine M Forbes, Glycation and Diabetes Complications Group, Mater Medical Research Institute, South Brisbane, Queensland 4101, Australia
Author contributions: Leung C, Herath CB, Forbes JM and Angus PW substantially contributed to the conception, design, analysis, interpretation of data; Leung C, Herath CB and Jia Z performed the majority of experiments; Andrikopoulos S, Brown BE, Davies MJ and Rivera LR provided vital analytical tools and experiments; all authors were involved in editing and approving the final manuscript.
Supported by National Health and Medical Research Council of Australia; NHMRC early career fellowship.
Institutional review board statement: The study was reviewed and approved by the Austin Health Animal Ethics Committee (Project number A2011/04342).
Institutional animal care and use committee statement: All procedures involving animals were reviewed and approved by the Institutional Animal Care and Use Committee of the Austin Health Animal Ethics Committee (Project number A2011/04342).
Conflict-of-interest statement: To the best of our knowledge, no conflict of interest exists.
Data sharing statement: Data set available from the corresponding author at chris.leung@y7mail.com.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Christopher Leung, MBBS, FRACP, Department of Gastroenterology and Hepatology, Austin Health, Austin Hospital, 145 Studley Rd, Heidelberg, Victoria 3084, Australia.
chris.leung@y7mail.com
Telephone: + 61-3-94965000 Fax: +61-3-94963487
Received: May 5, 2016
Peer-review started: May 6, 2016
First decision: June 20, 2016
Revised: June 27, 2016
Accepted: August 10, 2016
Article in press: August 10, 2016
Published online: September 21, 2016
Processing time: 131 Days and 22.6 Hours
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.
Core tip: A novel high fructose, high cholesterol diet produces hepatic non-alcoholic steatohepatitis (NASH) with fibrosis in 33 wk and increasing the Advanced glycation end products (AGEs), content of this diet via baking increases hepatic fibrosis whilst vinegar marination decreases dietary AGE levels, abrogating the harmful effects of AGEs. RAGE-/- animals appeared to be protected from the additional harmful effects of a high AGE containing diet suggesting the central role of RAGE in progression of NASH. Increased cell proliferation and oxidative stress in isolated primary Kupffer cells with the addition of AGEs suggests they are an important mechanism in which AGEs contribute to liver injury.
