Concetta C DiRusso
Fatty acids and higher lipids are essential to cellular and organismal structure and function. These compounds include structural components of biological membranes, mediators of signal transduction within cells, physiological regulators in higher organisms and ligands of specific transcription factors. Fatty acids also serve as biological energy sources and current research seeks methods to harvest these abundant biofuels as an alternative to fossil fuels. Lipid metabolism is closely tied to synthesis of other macromolecules required for cell growth and differentiation. Many of the fatty acid transport and metabolic enzymes are evolutionarily conserved. Common disease states associated with abnormalities in lipid metabolism include obesity, diabetes, coronary heart disease, sudden infant death syndrome and neurodegenerative disorders such as Alzheimers and adrenoleukodystrophy. Elevation of fatty acid synthetic capacity of cells is a common phenotype of cancerous tissues and pharmacological inhibitors of the anabolic fatty acid synthase enzyme, including cerulenin, are selectively cytotoxic to cancer cells. High fat diets have been associated clinically with a number of neoplasias including, specifically, colorectal types. However, the details of the molecular mechanisms linking lipid metabolism with these disease states remains to be elucidated.
Our interests lie  in understanding how lipid metabolism is coordinated to meet the nutritional, structural and regulatory needs of cells and organisms;  in comparative genomics of lipid enzymes;  in determining the molecular mechanisms by which lipid metabolism and regulation are altered in disease states; and  in exploiting fatty acids synthesized and stored by microalgae for use as biofuels. Five research projects are currently underway:
- Development of small molecular inhibitors of fatty acid import. Recently, we identified 5 structural families (out of 100,000 compounds screened) that inhibited fatty acid uptake into yeast expressing human fatty acid transport protein 2 (FATP2). Secondary screens of these lead hits were conducted in cell lines that are models for intestine (Caco2), liver (HepG2), pancreatic ß-cells (INS-1E), skeletal muscle (C2C12) and adipose tissue (primary human and mouse 3T3-L). Additionally, the compounds are being evaluated in mice to test their ability to prevent fat absorption and lipotoxicity of organs. To determine structure activity relationships, we are analyzing derivatives of our compounds designed and synthesized by The Vanderbilt University Specialized Chemistry Center for Accelerate Probe Development.
- Analysis of fatty acid transport, metabolism and transcriptional regulation. This project focuses on proteins required for fatty acid transport and activation. The proteins include Fatty Acid transport Proteins and acyl-CoA synthetases. We are using a variety of molecular genetic and biochemical approaches to define the mechanisms and factors involved in fatty acid uptake, activation and signaling using yeast, mammalian cells and microalgae as a model systems.
- Comparative genomics of lipid metabolic genes. Currently, this work focuses on the acyl-CoA synthetase and thioesterase family members. These enzymes are essential for a broad range of processes including 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 biofuels. We use molecular genetic, enzymatic and biophysical approaches to determine the functions and structures of related family members.
- Algal Biofuels. One of the most exciting new projects in the lab seeks to exploit lipids produced in microalgae for use as biofuels. Our lab has joined a consortium of UNL and external collaborators in efforts to modify genetically tractable strains, to identify as yet uncharacterized algal strains that produce high levels of storage lipids, and to develop methods and tools to identify, enrich and concentrate these lipids for use in fuel production. We are employing high throughput screening, metabolomics and proteomics approaches to investigate mechanisms and to identify factors that lead to lipid production and storage.
- Dietary fatty acids, trafficking patterns, metabolism and regulation. Recently, we demonstrated using in studies in mice that polyunsaturated fatty acids C18:2 and C18:3 from plants did not have the same regulatory or physiological impact on liver as providing dietary C20:4 and C22:6, even though the shorter chain less saturated fatty acids were efficiently converted to the longer more highly unsaturated fatty acids in vivo. This led us to current studies evaluating other physiological factors impacted by dietary fat composition including immune function and the profile of the gut microbiome.