Dietary advanced glycation end-products aggravate non-alcoholic fatty liver disease.
OBJECTIVE
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.


CONCLUSIONS
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.
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
C
Leung
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.
Chandana B
CB
Herath
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.
Zhiyuan
Z
Jia
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.
Sof
S
Andrikopoulos
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.
Bronwyn E
BE
Brown
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.
Michael J
MJ
Davies
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.
Leni R
LR
Rivera
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.
John B
JB
Furness
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.
Josephine M
JM
Forbes
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.
Peter W
PW
Angus
D019342:Acetic Acid; D000818:Animals; D002784:Cholesterol / Q000008:administration & dosage; D059305:Diet, High-Fat; D018450:Disease Progression; D005234:Fatty Liver / Q000378:metabolism; D005632:Fructose / Q000008:administration & dosage; D017127:Glycation End Products, Advanced / Q000008:administration & dosage*; D007249:Inflammation / Q000378:metabolism; D007728:Kupffer Cells / Q000166:cytology; D008099:Liver / Q000378:metabolism; D008103:Liver Cirrhosis / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D065626:Non-alcoholic Fatty Liver Disease / Q000378:metabolism*; D018384:Oxidative Stress; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction
D017127:Glycation End Products, Advanced; D005632:Fructose; D002784:Cholesterol; D019342:Acetic Acid
Advanced glycation end-products; Fructose; Hepatic fibrosis; Non-alcoholic fatty liver disease; Oxidative stress; Steatohepatitis
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