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J Hepatol. 2014 Apr;60(4):832-8. doi: 10.1016/j.jhep.2013.11.033. Epub 2013 Dec 6.

Dietary glycotoxins exacerbate progression of experimental fatty liver disease.

Author information

1
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: chris.leung@y7mail.com.
2
Department of Medicine, The University of Melbourne, Austin Health, Heidelberg, Victoria, Australia.
3
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.
4
Department of Physiology, Monash University, Clayton, Victoria, Australia.
5
Glycation and Diabetes Group, Baker IDI Diabetes Institute, Melbourne, Victoria, Australia; Glycation and Diabetes Complications Group, Mater Medical Research Institute, South Brisbane, Queensland, Australia.

Abstract

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.

KEYWORDS:

Advanced glycation end-products; Hepatic stellate cell; Non-alcoholic fatty liver disease; Oxidative stress; Steatohepatitis

PMID:
24316518
DOI:
10.1016/j.jhep.2013.11.033
[Indexed for MEDLINE]

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