Hepatology and Gastroenterology Research Group

Research Overview

Liver fibrosis and its end-stage sequelae of cirrhosis and liver cancer are major causes of morbidity and mortality in Australia and throughout the world and their prevalence is rising, largely due to the increasing impact of chronic liver diseases including non-alcoholic fatty liver disease (NAFLD) and biliary diseases. It is hoped better disease prevention and more effective therapies will help reduce this disease burden. However, there remains a major need to identify potentially modifiable factors which exacerbate liver injury and fibrosis and to develop therapies that can prevent or slow liver scarring. This is particularly true for NAFLD, a disease which affects up to 30% of the adult population and is now a major cause of the premature illness and death, but for which there is still no established drug therapy.

Our group conducts translational research investigating the pathophysiology of liver fibrosis/cirrhosis and hepatocellular cancer using a number of animal models of liver disease. These animal models include dietary models such as short-term methionine and choline deficient (MCD) and long-term high fat high cholesterol (HFHC) models which produce pathological lesions similar to those that can be seen in patients with NAFLD/NASH. Our biliary fibrosis models include short-term bile duct ligation (BDL) and long-term model of Mdr2-KO mice. In addition, we have also developed a number of perfusion models such as liver perfusion model and mesenteric vascular perfusion model to study hyperdynamic splanchnic circulation that develops from hemodynamic changes associated with activated systemic as well as local renin angiotensin system (RAS) in cirrhosis. We are also using a number of mouse liver-cancer models to study the potential of therapies we developed. The translational studies in humanized mouse models have been designed to test various therapies before we commence our human studies in patients with liver disease.

Our studies will significantly improve understanding of the role of the RAS and advanced glycation end products (AGEs) in liver disease and the potential impact of modulation of these pathways on hepatic fibrogenesis, mesenteric hemodynamics and portal hypertension. Importantly, these studies are largely translational. They include therapies that have been successfully applied in other human diseases, including selective tissue upregulation of a specific gene, and are therefore likely to have a major impact on the treatment of human liver disease.

Current projects:

  1. Translational studies aimed at developing drugs for RAS (the renin angiotensin system) intervention in liver fibrosis/cirrhosis and portal hypertension.
  2. Translational studies aimed at developing drugs for intervention in AGEs/receptor for AGE (RAGE) signaling pathways in NAFLD/NASH (Non-alcoholic fatty liver disease/non-alcoholic steatohepatitis).
  3. Translational studies aimed at developing drugs for hepatocellular carcinoma (HCC

Staff

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

Collaborators

  • Prof Ian Alexander, Childrens Hospital Westmead, University of Sydney
  • 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
  • A/Prof Alexandra Sharland, Department of Surgery, Central Clinical School, University of Sydney
  • Prof Jonel Trebicka, Department of Internal Medicine, University of Bonn, Germany
  • Prof Missaka Wijayagunawardane, Department of Animal Science, University of Peradeniya, Sri Lanka
  • A/Prof Keerthi Siri Guruge, National Institute of Animal Health, Tsukuba, Japan
  • Dr Anthony Zulli, College of Health and Biomedicine, Victoria University
  • Dr Harinda Rajapaksha, LaTrobe University

Funding

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

Research Publications

  • Mak KY, Rajapaksha IG, Angus PW, Herath CB. The adeno-associated virus - A safe and effective vehicle for liver-specific gene therapy of inherited and non-inherited diseases. Current Gene Therapy. Mar 14, 2017 [Epub ahead of print].
  • 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.
  • Klein S, Herath CB, Schierwagen R, Grace JA, Haltenhoj T, Uschner FE, Strassburg CP, Sauerbruch T, Walther T, Angus PW, , Trebicka J. Hemodynamic effects of the non-peptidic angiotensin-(1-7) agonist AVE0991 in liver cirrhosis. PLOS ONE. 2015 Sep 25;10(9):e0138732.
  • Mak KY, Chin R, Cunningham S, Habib MR, Toressi J, Sharland AF, Alexander IE, Angus PW, Herath CB. ACE2 gene therapy using adeno-associated viral vector inhibits liver fibrosis in mice. Molecular Therapy 2015; 23(9): 1434-43.
  • Wijayagunawardane MPB, Wijerathne CUB, Herath CB. Indigenous herbal recipes for treatment of liver cirrhosis. Procedia Chemistry 2015; 14:270-76.
  • Herath CB, Mak K, Angus PW. Role of the alternate RAS in liver disease and the GI tract. In 'The protective arm of the renin angiotensin system' (Eds, Unger T, Santos R), ELSEVIER Publishers Inc. Chapter 34, 2015.
  • Alsaadon H, Kruzliak P, Smardencas A, Hayes A, Bader M, Angus P, Herath CB, Zulli A. Increased aortic intimal proliferation due to Mas R deletion in vitro. International Journal of Experimental Pathology 2015; 96(3):183-87.
  • 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.
  • Yeung LW, Guruge KS, Taniyasu S, Yamashita N, Angus PW, Herath CB. Profiles of perfluoroalkyl substances in the liver and serum of patients with liver cancer and cirrhosis in Australia. Ecotoxicology and Environment Safety. 2013; 96:139-46.
  • Herath CB, Grace JA and Angus PW. Targeting the renin angiotensin system in portal hypertension. Invited Editorial Review. World Journal of Gastrointestinal Pathophysiology 2013; 4(1): 1-11.
  • Herath CB, Mak KY, Burrell LM and Angus PW. Angiotensin-(1-7) reduces the portal pressure response to angiotensin II and methoxamine via an endothelial nitric oxide mediated pathway in cirrhotic rat liver. American Journal of Physiology – Gastrointestinal and Liver Physiology 2013; 304(1):G99-108.
  • Grace JA, Klein S, Herath CB, Granzow M, Schierwagen R, Masing N, Walther T, Sauerbruch T, Burrell LM, Angus PW, Trebicka J. Activation of the MAS receptor by angiotensin-(1-7) in the renin-angiotensin system mediates mesenteric vasodilatation in cirrhosis. Gastroenterology 2013; 145(4):874-84.
  • 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.
  • Garg M, Angus PW, Burrell LM, Herath CB, Gibson PR and Lubel JS. The pathophysiological roles of the renin–angiotensin system in the gastrointestinal tract. Review. Alimentary Pharmacology and Therapeutics 2012; 35(4):414-28.
  • Grace JA, Herath CB, Mak KY, Burrell LM and Angus PW. Update on new aspects of the renin-angiotensin system in liver disease: clinical implications and new therapeutic options. Review. Clinical Science (London) 2012; 123(4):225-39.
  • Neo JH, Ager EI, Angus PW, Zhu J, Herath CB, Christophi C. Changes in the renin angiotensin system during the development of colorectal cancer liver metastases. BMC Cancer 2010; Apr 10 [Epub ahead of print].
  • Kemp W, Kompa A, Phrommintikul A, Herath CB, Zhiyuan J, Angus P, McLean C, Roberts S, Krum H. Urotensin II modulates hepatic fibrosis and portal haemodynamic alterations in rats. American Journal of Physiology – Gastrointestinal and Liver Physiology 2009; 297(4): G762-767.
  • 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.
  • Herath CB, Warner FJ, Lubel JS, Dean RG, Jia Z, Lew RA, Smith AI, Burrell LM, Angus PW. Upregulation of hepatic angiotensin-converting enzyme 2 (ACE2) and angiotensin-(1-7) levels in experimental biliary fibrosis. Journal of Hepatology 2007; 47:387-95.
  • Paizis G, Tikellis C, Cooper ME, Schembri JM, Lew RA, Smith AI, Shaw T, Warner FJ, Zuilli A, Burrell LM, Angus PW. Chronic liver injury in rats and humans upregulates the novel enzyme angiotensin converting enzyme 2. Gut 2005 54:1790-6.