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Liver Enzymes in Metabolism and Inflammation Program

The Molecular Hepatology team is focused on understanding the roles played by a key enzyme family in chronic liver diseases. We have clear indications from following successful targeting for type 2 diabetes therapy that related approaches may also combat fatty liver diseases.

We are working to understanding what makes chronic liver diseases wax and wane. Chronic liver disease often causes inflammation, high blood pressure and cancer.

Current Projects:

  1. 1  Circulating dipeptidyl peptidase 4 activity correlates with NAFLD severity in type 2 diabetes and obesity.
  2.  Dipeptidyl peptidase 4 is a driver of fatty liver and liver fibrosis.
  3.  Dipeptidyl peptidase 4 slows anti-tumour T cells getting into a tumour.
  4. Fibroblast activation protein in humans: Circulating levels rise with liver fibrosis and cirrhosis but not Rheumatoid Arthritis or Systemic Sclerosis.
  5. Fibroblast activation protein functions: what are the important substrates.
  6.  Dipeptidyl Peptidase 9 functions: Targeted inactivation of Dipeptidyl Peptidase 9 enzyme activity as a cause of death in newborn mice and immune dysfunction in adult mice.
  7.  Homology modeling of human Kynurenine Aminotransferase III and binding by its inhibitors using molecular docking.

Professor Mark Gorrell, Head of Program

Phone: +61 2 9565 6152
Mobile: +61 419 933 474
Email: m.gorrell@centenary.org.au

Professor Mark Gorrell heads the Liver Enzymes in Metabolism and Inflammation Program. He trained in cell biology, virology, immunology and protein biochemistry at Australian National University, University of Melbourne and Johns Hopkins University. 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 144 publications attracting H index 43, i10 index 91 and > 6,500 citations. His research experience also includes small RNA viruses, transcriptomics, proteomics and cell biology. His research was important in the development of DPP4-targetted therapies for type 2 diabetes, which are now used to treat millions of patients. Inside Centenary Institute, he chairs the postgraduate research and equipment grants committees, is Academic Advisor for postgraduate research and a Commercialisation Committee member. Outside Centenary Institute, he is active in the International Proteolysis Society, the Gastroenterological Society of Australia, NHMRC grant reviews, and editorial boards of Journals including Scientific Reports.

Research:
With colleagues, he 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 Scand J Immunol; 2013 PlosOne]. He also discovered novel substrate recognition sites in DPPs used in drug development, ligand binding sites on DPP4 that are binding sites of MERS virus, and constructed the first DPP4 protein structure prediction [1999 FEBS J; 1999 FEBS Lett].

His team showed that DPP4, FAP and DPP9 amplify cell death signals and alter cell adhesion [2006 FEBS J; 2005 Hepatology; 2011 Mol Cancer Res; 2015 BBA-MCR], and identified most of the known natural substrates of FAP [2011 FEBS J] and DPP9 [2015 FEBS J]. Using novel 2-photon microscopy, showed that harmful collagen is near FAP in cirrhotic liver [2003 J Struct Biol]. He found that measuring FAP in human blood is useful for assessing whether people have 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. His 2017 paper showing the importance of DPP4 in liver fibrosis is the best on that topic [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].

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