FATTT Lab: Fatty Acid Transport, Trafficking and Transcriptional Regulation

Telephone: (518) 641-6460
Fax: (518) 641-6304
cdirusso@ordwayresearch.org

Research Focus

The research in our laboratory focuses on the simplest class of biological lipids, the fatty acids. Fatty acids are essential structural components of membrane lipids, cholesterol esters and storage lipids called triglycerides. It is now commonly known that certain classes of fatty acids including saturated and trans unsaturated fatty acids can lead to disease states including obesity, diabetes, atherosclerosis and cancers of the breast and colon. Less commonly known is that these fatty acids or their metabolic byproducts are also involved in chronic inflammation and pain, sudden infant death syndrome and neurodegenerative disorders such as Alzheimers, adrenoleukodystrophy and macular degeneration. In contrast, polyunsaturated cis omega 3 fatty acids are protective against many of these same diseases. However, the detailed molecular mechanisms by which these fatty acids either cause or prevent disease remain to be elucidated so that we can formulate preventive measures and develop medications. Toward this end three research projects supported by grants from the National Institutes of Health and the Charitable Leadership Foundation are currently underway in our laboratory:

•  Metabolomics of lipid genes. Currently, this work focuses on the acyl-CoA synthetase and FATP enzyme families as well as enzymes that synthesize or degrade fatty acids. These enzymes are essential for a broad range of processes including fatty acid transport, esterification reactions involving fatty acids, foam cell formation in atherogenesis, polyketide synthesis in microorganisms and in the synthesis of substrates required for formation of microbial bioplastics. We use biochemical, biophysical and structural approaches to distinguish the structures and functions of related family members from diverse organisms including bacteria, fungi and mammals.

•  Drug Discovery , high throughput screens for small molecular inhibitors and selective activators of fatty acid import. We are exploiting our well-defined yeast system and human cells in culture to target the FATP-dependent human fatty acid transport system. Humanized yeast ( i.e. human FATP genes replace the yeast counterpart) are being used in a high throughput robotics platform to identify compounds from large structurally diverse chemical libraries that inhibit the uptake of fatty acids which are identified as detrimental to health ( i.e. saturated and trans- unsaturated fatty acids). The same approach is expected to be useful in identifying compounds that promote uptake of fatty acids deemed protective and therapeutic (polyunsaturated w -3 fatty acids).

III. Nutrigenomics . Lipids obtained in the diet are very efficiently and non-selectively absorbed in the gastrointestinal tract. The typical western diet is high in saturated and trans fatty acids that are known to cause metabolic syndrome, diabetes, cardiovascular disease and some cancers. To understand the pathways of fatty acid trafficking from the GI tract and to determine the regulatory and metabolic consequences of dietary fat, we are performing nutritional, metabolic and biochemical studies on mice fed specific diets that vary in the fatty acid composition. The mice have been genetically engineered to either overexpress or underexpress specific genes hypothesized to be important in disease promotion and progression. These animal studies are essential to understand complex diseases of humans resulting from poor nutritional status including high caloric intake.

Collaborations

Paul N. Black, Ph.D., Ordway Research Institiue, Inc. and Albany Medical College , Albany , NY . Co-Principal investigator of the FATTT Lab (Fatty Acid Transport, Trafficking and Transcriptional Regulation).

Rosalind Coleman, M.D., University of North Carolina , expression and characterization of mammalian acyl-CoA synthetase enzymes in E. coli and yeast.

Keith Derbyshire, Ph.D., Wadsworth Laboratories, David Axelrod Institute, New York State Department of Public Health, Albany , NY . Fatty acid analysis of Mycobacterium smegmatis.

Jeannie Dubnau, Ph.D., and Issar Smith, Ph.D., Public Health Research Institute, Newark, New Jersey. Analysis of Mycobacterium tuberculosis strains carrying a mutations in fatty acid metabolic and regulatory genes.

José M. Luengo, Ph. D., Department of Biochemistry and Molecular Biology, University of Leon, Spain. Synthesis of biological plastics from fatty acid ß-oxidation intermediates in bacteria.

Paul Watkins, M.D., Ph.D., Senior scientist Kennedy Krieger Institute and Professor of Neurology, Johns Hopkins University School of Medicine. Structure and function of the human FATP proteins.

Xinxin Ding, Ph.D., Senior Scientist, Wadsworth Laboratories, New York State Department of Public Health, Albany, NY. Lipid analysis in POR null mice.

Selected Publications

www.pubmed.com

Li., H., Black, P. N. and DiRusso , C. C . 2005. A live cell high throughput screening assay for identification of fatty acid uptake inhibitors. Analytical Biochemistry, 336:11-19 .

DiRusso, C. C., Li, H., Darwis, D., Watkins, P.A., Berger, J. and Black, P.N., 2005. Comparative biochemical studies of the murine fatty acid transport proteins (FATP) expressed in yeast. The Journal of Biological Chemistry , 280(17):16829-16837

Marszalek, J. R., Kitidis, C., DiRusso, C. C. and Lodish, H. F., 2005. Long-chain Acyl CoA synthetase 6 preferentially promotes DHA metabolism. The Journal of Biological Chemistry , 280(11):10817-10826

Black, P. N., Li, H., Tong, F. and DiRusso, C. C., 2005. The cell biology fatty acids. In: Cell Biology and Dynamics of Yeast Lipids , (Guenther Daum, ed.), pp.1-20, Research Signpost, Kerala India .

Weng, Y., DiRusso, C. C., Reilly, A.A., Black, P. N. and Ding , X., 2005, Hepatic gene expression changes in mouse models with liver-specific deletion or global suppression of the NADPH-cytochrome P450 reductse gene: Mechanistic implications for the regulation of microsomal cytochrome P450 and the fatty liver phenotype. The Journal of Biological Chemistry , 280(36):31686-31698

Tong, F., Black, P. N., Bivins, L., Quackenbush, S., Ctrnacta, V. and DiRusso , C. C. 2006, Direct interaction of S. cerevisiae Faa1p with the Omi/HtrA protease ortholog Ynm3p alters lipid homeostasis, Molecular Genetics and Genomics , 275:330-343

Tong, F., Black, P.N., Coleman, R. and DiRusso, C.C. 2006, Fatty acid transport by vectorial acylation in mammals: Roles played by different isoforms of rat long-chain acyl-CoA synthetases. Arch. Biochem. Biophys . 447: 46-52

Back to top