Biomedical Research Centre

Colin N A Palmer Professor of Pharmacogenomics Lipid signalling in cancer and vascular disease

E-mail:nuclear-receptor@dundee.ac.uk

Many chemicals that are present in our diet and the environment promote the progression of diseases such as heart disease, diabetes, cancer and dementia. These chemicals mimic endogenous signalling molecules leading to inappropriate cellular responses. Our aim is to understand how chemicals, that mimic the actions of fatty acids, may modulate the progression of these diseases.

Fatty acids are detected at the cellular level by members of the steroid hormone/nuclear receptor superfamily known as peroxisome proliferator activated receptors (PPARs).

These receptors are responsible for the tight regulation of the intracellular concentrations of free fatty acids, which can be highly toxic; however it appears that PPARs also have important roles in modulating inflammation, cellular growth and differentiation.

Activation of PPARa by fatty acids and other chemicals causes liver cancer in the rats and mice. In contrast, we have shown that the human liver does not display a hyperplastic response to PPARa activators and contains very little functional PPARa. Our work suggests that PPARa activating chemicals such as the fibrate group of lipid lowering drugs do not represent a significant hepatocarcinogenic risk in man. These drugs do however impact on other cellular systems to provide protection from heart disease and, in collaboration with GlaxoSmithKline, we are currently investigating the role of PPARs in the development and prevention of atherosclerosis. We also collaborate with clinician scientists with the aim of translating this work into new treatments for cardiovascular disease. This collaboration has been formalised by the creation of the Institute for Cardiovascular Research, and this is the subject of a major appeal.

PPARg is a crucial factor in the development of adipocytes and is the target of insulin-sensitizing drugs known as thiazolidenediones. Thiazlidenedione drugs are effective in the management of non-insulin dependent diabetes and the PPARg gene is polymorphic in populations that have a high prevalancy of non-insulin dependent diabetes. In collaboration with the Ninewells Hospital Diabetes Centre, we are currently assessing the impact of polymorphisms in the PPAR genes on the diabetic population in Tayside.

PPARg has also been shown to be over-expressed in prostate, breast, colon and adipocytic tumours. Activation of PPARg in these cells appears to halt growth and leads to terminal differentiation. For these reasons, this receptor is a candidate target for anti-cancer drug therapy and chemoprevention. We have developed a novel screening method for the discovery of PPARg ligands and are currently screening novel compounds for their ability to bind PPARg and arrest tumour cell growth.

We are studying the interaction of non-steroidal anti-inflammatory drugs (NSAIDs) and colon cancer. NSAIDs are potent inhibitors of colon tumour growth and we are currently investigating the role of PPAR and cyclooxygenase signalling pathways in the anti-tumour action of NSAIDs. It is anticipated that this will reveal novel aspects of tumour biology that may improve cancer prevention and treatment.

We are funded by the Medical Research Council, Biotechnology and Biological Sciences Research Council, the Food Standards Agency, Association for International Cancer Research, the British Heart Foundation, GlaxoSmithKline, Sanofi Synthelabo and The Bobby Moore Memorial Fund/Cancer Research UK.

References

1. Bisgaard, H., Simpson, A., Palmer, C. N. A., et al. 2008. Gene-Environment Interaction in the Onset of Eczema in Infancy: Filaggrin Loss-of-Function Mutations Enhanced by Neonatal Cat Exposure. PLoS Med 5(6): 934-940. (12.6) Full text available.

2. Freathy, R. M., Timpson, N. J., Lawlor, D. A., et al. 2008. Common variation in the FTO gene alters diabetes-related metabolic traits to the extent expected, given its effect on BMI. Diabetes 57: 1419-1426. (8.2)

3. Nomura, T., Akiyama, M., Sandilands, A., Nemoto-Hasebe, I., Sakai, K., Nagasaki, A., Ota, M., Hata, H., Evans, A. T., Palmer, C. N. A., Shimizu, H., McLean, W. H. 2008. J Invest Dermatol 128: 1436-1441. (4.8)

4. Zeggini, E., Scott, L. J., Saxena, R., et al. 2008. Meta-analysis of genome-wide association data and large-scale replication identifies several additional susceptibility loci for type 2 diabetes. Nat Genetics 40: 438-645. (25.5)

5. McLean, W. H., Palmer, C. N. A., Henderson, J., Kabesch, M., Weidinger, S., Irvine, A. D., 2008. Filaggrin variants confer susceptibility to asthma. J Allergy Clin Immunol 121: 1294-1295. (8.1)

References (continued)