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Liver Enzymes in Metabolism and Inflammation Program

The ongoing increase in all forms of liver disease is a large burden for our healthcare system. Especially the 350% increase in liver cancer in the last 30 years. Much of this increase is attributed to metabolic disease, often in conjunction with diabetes. Our focus in liver disease research is understanding the roles of a key enzyme family in progressive liver damage and cancer.

Our discoveries indicate that the four enzymes of this family are drivers of liver disease towards liver failure and cancer. Fortunately, enzymes make excellent drug targets and one of the enzymes, named DPP4, is the target of a successful diabetes drug class that our research helped create. Our liver disease research has indicated that this type of drug can also combat fatty liver disease and liver scarring that can lead to cirrhosis and cancer.

We are working towards understanding what makes chronic liver diseases wax and wane, and are learning about the components of tumours that support the cancer cells, called the tumour microenvironment. This work is directed towards discovering new treatment options.

Understanding liver disease research at Centenary.

Current Projects:

  1. DPP4 enzyme activity in blood associates with fatty liver severity in type 2 diabetes and obesity.
  2. A drug that inhibits the DPP4 enzyme can increase the numbers of anti-tumour T cells getting into a tumour.
  3. The enzyme fibroblast activation protein in humans: Blood serum levels rise with liver fibrosis (scarring) and cirrhosis.
  4. How the enzyme fibroblast activation protein works to exacerbate fatty liver.
  5. DPP9 functions: What the DPP9 enzyme activity does in liver cancer.

Professor Mark Gorrell heads the Liver Enzymes in Metabolism and Inflammation Program. He trained in cell biology, virology, immunology and protein biochemistry at the Australian National University and University of Melbourne in Australia, and at Johns Hopkins University in the USA.

His research is focussed upon liver scarring and cancer prevention and treatment, chronic liver disease pathogenesis, diabetes, protein and enzyme biochemistry and cell biology related to the proteases DPP4, DPP9 and fibroblast activation protein (FAP).

He has authored over 160 publications attracting H index 49, i10 index 100 and > 8,000 citations. His research was important in the development of DPP4-targeted therapies for type 2 diabetes, which are now used to treat millions of patients. His research experience also includes small RNA viruses, transcriptomics, proteomics and cell biology.

Professor Gorrell has supervised more than 18 PhD and M Phil students, was the 2018 Supervisor of the Year of Sydney Research and received the 2019 SUPRA Award for a postgraduate coordinator. He is active in the International Proteolysis Society, the Gastroenterological Society of Australia, NHMRC grant reviews, and is an editorial board member for Cancers and for Scientific Reports.
Research:

With colleagues, Professor Gorrell discovered that DPP4 and DPP8 modify the activities of several chemokines (1997 J Exp Med; 2008 FEBS Letters), and discovered DPP8, DPP9 and DPP10 (2000 FEBS J; 2004 BBA; 2006 BBA) allowing the development of DPP4 selective inhibitors. His work on DPP4 function in human T cells and on DPP9 provided insights into the safety of DPP4 inhibitors in clinical use (2011 SJI; 2013 PlosOne; 2018 ICB). He also discovered novel substrate recognition sites in DPPs used in drug development and protein-protein binding sites on DPP4, which led to a recent study of DPP4 binding to SARS and similar viruses (2020 Molecules).

His team showed that DPP4, FAP and DPP9 amplify cell death signals and alter cell adhesion, and identified most of the known natural substrates of FAP and DPP9.

Professor Gorrell was first to image collagen in human liver by second harmonics (2003 J Struct Biol). He also developed the first specific enzyme assay for FAP (2014 FEBS), which he used to map the bodily distribution of FAP and discover that measuring FAP in human blood is a useful biomarker for liver fibrosis (2015 Diabetes Research).

The team found that DPP9 is essential for the survival of mice (2013 PlosOne; 2016 Expl Cell Res) and that DPP9 influences growth factor dependent cellular proliferation (2011 Mol Cancer Res).

Professor Gorrell has a keen interest in models of disease, including liver fibrosis (2017 Immunol Cell Biol). The team recently created a new model of primary liver cancer, which better resembles the current human situation of over-nutrition (2018 Scientific Reports) and better ways to examine tumour growth (2019 Cancers), and recently showed associations between the DPP4 gene family and human liver cancer (2021 Cancers).

Search amongst our repository.

For access to all Publications via Pub Med.

Australian

Flinders University
Hudson Institute of Medical Research
Monash University
University of Queensland
University of Sydney
University of Technology Sydney
University of Western Australia
Walter and Eliza Hall Institute of Medical Research

International

Tufts University, USA
University of Edinburgh, UK
University of Freiburg, Germany