Molecular Hepatology

Project Leader: Associate Professor Mark Gorrell

Molecular hepatology research is focussed upon understanding the functions and functioning of enzymes of the dipeptidyl peptidase IV [DPIV] gene family and an unrelated gene, discoidin domain receptor 1 [DDR1] and harnessing that knowledge to improve human health, particularly liver diseases and disorders. In addition, we work with the Pharmacy Faculty at the University of Sydney on ways to better understand and use the liver/brain enzyme Kynurenine Aminotransferase 1 [KAT-1] and we work with organ transplantation researchers of the Bosch Institute on certain lymphocyte cell surface proteins.

Research focus

The DPIV family
The DPIV family of enzymes consists of DPIV, DP8, DP9 and fibroblast activation protein (FAP). We previously found that:

• FAP levels increase in human liver in proportion to the extent of scarring;
• FAP causes cells to become less adherent and less motile
• Using mouse strains genetically unable to make either FAP or DPIV (called gene knockout or deficient), we saw that FAP deficient mice and DPIV deficient mice exhibit less liver scarring and inflammation than normal mice. We found this reduced scarring relates to the presence of fewer B lymphocytes. This discovery suggests that FAP and DPIV drive liver B cell numbers. We have now progressed on to examining the resistance of DPIV deficient mice to depositing fat in the liver.

Functions of DP8 and DP9
We cloned DP8 and DP9 in the late 1990s. The value of these genes primarily relates to using DP8 and DP9 to reduce risks of drug side-effects by ensuring that DPIV inhibitory drugs are DPIV selective. The major use for DPIV inhibitors such as sitagliptin (Januvia) is as a new therapy for type 2 diabetes and we continue to work with pharmaceutical companies to evaluate DPIV inhibitor selectivity.

Our group is continuing to improve methods of producing and purifying DPIV, FAP, DP8 and DP9 in quantity. Large quantities of pure enzyme are needed to make antibodies and perform full biochemical analyses and enzymological profiling.

We discovered that DP8, like DPIV, inactivates some chemokines. Chemokines are small proteins made by various cells in the body to attract specific lymphoid cells to locations of injury. We found the chemokines called CXCL10, CXCL11 and CXCL12 are inactivated by DP8. This work was a collaboration with Professor Chris Overall of the University of British Columbia.

We found that DP8 and DP9 are made by certain lymphoid cells and hepatocytes. Both cell types are crucial in the development of chronic liver disease.

Additionally, we discovered that, like FAP, DP9 makes cells less adherent and slower. Cell adhesion and movement are crucial in organ development, inflammation, tumour growth and wound healing.

Roles of DDR1 in liver biology
DDR1 is a cell surface protein activated by collagen, which is the major component of the liver scarring resulting from long-term liver injury. We have found that hepatocytes express more DDR1 when injured and that differing forms are made in scarred versus non-diseased human liver. We found that DDR1 can make cells of a liver cell line more adherent and slower.