title: Dietary glycotoxins exacerbate progression of experimental fatty liver disease.
abstract: OBJECTIVE
  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.
authors: 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.
authors: Christopher
authors: C
authors: Leung
authors: Department of Medicine, The University of Melbourne, Austin Health, Heidelberg, Victoria, Australia.
authors: Chandana B
authors: CB
authors: Herath
authors: Department of Medicine, The University of Melbourne, Austin Health, Heidelberg, Victoria, Australia.
authors: Zhiyuan
authors: Z
authors: Jia
authors: 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.
authors: Michelle
authors: M
authors: Goodwin
authors: Department of Medicine, The University of Melbourne, Austin Health, Heidelberg, Victoria, Australia.
authors: Kai Yan
authors: KY
authors: Mak
authors: Department of Physiology, Monash University, Clayton, Victoria, Australia.
authors: Matthew J
authors: MJ
authors: Watt
authors: Glycation and Diabetes Group, Baker IDI Diabetes Institute, Melbourne, Victoria, Australia; Glycation and Diabetes Complications Group, Mater Medical Research Institute, South Brisbane, Queensland, Australia.
authors: Josephine M
authors: JM
authors: Forbes
authors: 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.
authors: Peter W
authors: PW
authors: Angus
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D002796:Choline Deficiency / Q000150:complications; D004032:Diet / Q000009:adverse effects*; D018450:Disease Progression; D015870:Gene Expression; D017127:Glycation End Products, Advanced / Q000008:administration & dosage* / Q000378:metabolism / Q000633:toxicity*; D055166:Hepatic Stellate Cells / Q000378:metabolism / Q000473:pathology; D007333:Insulin Resistance; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008297:Male; D008715:Methionine / Q000172:deficiency; D065626:Non-alcoholic Fatty Liver Disease / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D018384:Oxidative Stress; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D017127:Glycation End Products, Advanced; D008715:Methionine
keywords: Advanced glycation end-products; Hepatic stellate cell; Non-alcoholic fatty liver disease; Oxidative stress; Steatohepatitis