Therapeutic intervention of AGE/RAGE pathway in NAFLD

Project Details

Non-alcoholic fatty liver disease (NAFLD) affects up to 30% of the adult population and is now a major cause of liver disease related premature illness and death in Australia. Currently there is no established drug therapy and treatment is largely based on lifestyle modification, which is difficult to achieve in most patients. As a result, there remains a major need to identify potentially modifiable factors that exacerbate liver injury and fibrosis in NAFLD and to develop therapies that can prevent or slow liver scarring.

Advanced glycation end products (AGEs) are a complex and diverse group of biologically active compounds that are formed via a process beginning with the Maillard reaction, in which reducing sugars, such as glucose, react non-enzymatically with proteins and nucleic acids. The production of AGEs is a normal phenomenon in aging and occurs at an increased rate in diabetes owing to the excess of reducing sugars available as a consequence of hyperglycemia. In Australia, as in other developed countries, industrialized methods of food processing have dramatically changed diets. Meals now contain many highly processed foods, often with excess fat and sugar. Although the estimated bioavailability of orally ingested AGEs is relatively low, diets high in AGEs have been shown to significantly increase tissue inflammation and oxidative stress. Receptor for advanced glycation end products (RAGE) is the best characterised of known AGE receptors. We conduct studies to examine RAGE expression, AGE production and the effects of exogenous AGEs on disease progression in animal models of NAFLD, the most common liver disease seen in primary care, with studies showing 30% prevalence in the general population. We also study the effect of RAGE deletion in mice with liver disease and interventional studies using inhibitors of the AGE/RAGE pathway. To gain insight into pathogenesis of AGE/RAGE pathway in NAFLD, we use cultured hepatic stellate cells, Kupffer cells or hepatocytes alone or in a co-culture setting.

Both obesity and NAFLD are strongly associated with multiple changes in the gut which include disturbance of the intestinal microbiome or dysbiosis and increased permeability and translocation of bacterial products into the portal circulation, reaching the liver and then, the sytemic circulation. It has also been shown that AGEs alter the microbiome and thus, they may encourage the growth of harmful gut bacteria. Therefore we study the relationships between AGEs, microbiome and NAFLD to better understand the progression of NAFLD to NASH and to formulate therapies.

Researchers

  • Dr Chandana Herath, Senior Research Fellow
  • Professor Peter Angus, Medical Director of Victorian Liver Transplant Unit
  • Dr Kai Yen Mak, Research Officer
  • Dr Christopher Leung, Gastroenterologist, Department of Gastroenterology, Austin Health, Clinical Lead, Melbourne Clinical School
  • Ms Ping Huang, Research Assistant
  • Ms Dinali Fernando, PhD student

Collaborators

  • Prof Josephine Forbes, Glycation & Diabetes Complications, Mater Research, University of Queensland
  • Prof John Furness, Department of Anatomy & Neuroscience, The University of Melbourne
  • A/Prof Sof Andrikopoulos, Department of Medicine, Austin Health, The University of Melbourne

Funding

  • NHMRC project grant: Novel therapies targeting the alternate renin angiotensin system in chronic liver disease (2017-2021).

Research Publications

  • Leung C, Herath CB, Forbes J and Angus PW. Dietary advanced glycation end-products aggravate non-alcoholic fatty liver disease. World Journal of Gastroenterology 2016; 22(35): 8026-40.
  • Rivera LR, Leung C, Pustovit RV, Hunne BL, Andrikopoulos S, Herath CB, Testro A, Angus PW, Furness JB. Damage to enteric neurons occurs in mice that develop fatty liver disease but not diabetes in response to a high-fat diet. Neurogastroenterology and Motility 2014; 26(8):1188-99.
  • Leung C, Herath CB, Jia Z, Goodwin M, Mak KY, Watt MJ, Forbes JM, Angus PW. Dietary glycotoxins exacerbate progression of experimental fatty liver disease. Journal of Hepatology. 2014; 60(4):832-38.
  • Goodwin M, Herath CB, Jia Z, Leung C, Coughlan MT, Forbes J, Angus P. Advanced glycation end products augment experimental hepatic fibrosis. Journal of Gastroenterology and Hepatology 2013; 28(2):369-76.
  • Herath CB, Lubel JS, Jia Z, Velkoska E, Casley D, Brown L, Tikellis C, Burrell LM and Angus PW. Portal pressure responses and angiotensin peptide production in rat liver are determined by relative activity of ACE and ACE2. American Journal of Physiology – Gastrointestinal and Liver Physiology 2009; 297:G98-G106.

Research Group

Hepatology and Gastroenterology Research Group




Key Contact

For further information about this research, please contact the research group leader.

Department / Centre

Medicine and Radiology

Node

Austin Health

Unit / Centre

Hepatology and Gastroenterology Research Group