Our research focuses on lipid metabolism. In general, we study enzymes that synthesize or break down different types of lipids and examine the roles these enzymes play in whole body lipid metabolism. A variety of experimental approaches are taken to accomplish these goals, including protein purification, electrophysiology, mass spectrometry, molecular cloning, and whole animal physiology. In several instances, we have linked our findings in the laboratory to the clinic and in so doing have elucidated the molecular bases of six human genetic diseases.
A current focus in the laboratory includes enzymes that hydroxylate cholesterol to produce oxysterols in the brain and macrophage. We are particularly interested in the enzyme cholesterol 24-hydroxylase, which is responsible for cholesterol turnover in the brain. Mice deficient in this enzyme fail to learn and exhibit profound deficiencies in synaptic plasticity. A second oxysterol synthesizing enzyme that we study is cholesterol 25-hydroxylase. This enzyme is expressed in macrophages and therein regulates important aspects of the immune system.
In additional lines of investigation, we study enzymes that break down ether lipids and we develop mass spectrometric methods for metabolite profiling and the elucidation of new substrates and products for enzymes of unknown function. In these studies, relevant enzymes are purified and their genes cloned, the biochemical properties of the encoded enzymes are determined, and the biological roles of the enzyme and lipid in question are identified through the study of knockout mice.
RESEARCH INTERESTS
Cholesterol metabolism, lipid synthesis
RECENT PUBLICATIONS
Ramirez, D.M.O., Andersson, S., and Russell, D.W., "Neuronal Expression and Subcellular Localization of Cholesterol 24-Hydroxylase in the Mouse Brain." J. Comp. Neurol., 507:1676-1693, 2008
Shea, H.C., Head, D.D., Setchell, K.D.R., and Russell, D.W., "Analysis of HSD3B7 Knockout Mice Reveals that a 3a-Hydroxyl Stereochemistry is Required for Bile Acid Function." Proc. Natl. Acad. Sci. USA, 104:11526-11533:11526-11533, 2007
Chen, W., Chen, G., Head, D.L., Mangelsdorf, D.J., Russell, D.W., "Enzymatic reduction of oxysterols impairs LXR signaling in cultured cells and the livers of mice." Cell Metabolism, 5:73-9, 2007
Yildiz, Y., Matern, H., Thompson, B., Allegood, J.C., Warren, R.L., Ramirez, D.M., Hammer, R.E., Hamra, F.K., Matern, S., Russell, D.W., "Mutation of beta-glucosidase 2 causes glycolipid storage disease and impaired male fertility." J. Clin. Invest., 116:2985-94, 2006
Kotti, T.J., Ramirez, D.M., Pfeiffer, B.E., Huber, K.M., Russell, D.W., "Brain cholesterol turnover required for geranylgeraniol production and learning in mice." Proc. Natl. Acad. Sci. USA, 103:3869-74, 2006
SIGNIFICANT PUBLICATIONS
Cali, J.J., Hsieh, C-L., Francke, U., and Russell, D.W., "Mutations in the Bile Acid Biosynthetic Enzyme Sterol 27-Hydroxylase Underlie Cerebrotendinous Xanthomatosis." J. Biol. Chem., 266:7779-7783, 1991
Thigpen, A.E., Davis, D.L., Milatovich, A., Mendonca, B.B., Imperato-McGinley, J., Griffin, J.E., Francke, U., Wilson, J.D., and Russell, D.W., "The Molecular Genetics of Steroid 5alpha-Reductase 2 Deficiency." J. Clin. Invest., 90:799-809, 1992
Setchell, K.D.R., Schwarz, M., O'Connell, N.C., Lund, E.G., Davis, D.L., Lathe, R., Thompson, H.R., Tyson, R.W., Sokol, R.J., and Russell, D.W., "Identification of a New Inborn Error in Bile Acid Synthesis: Mutation of the Oxysterol 7alpha-Hydroxylase Gene Causing Severe Neonatal Liver Disease." J. Clin. Invest., 102:1690-1703, 1998
Schwarz, M., Wright, A.C., Davis, D.L., Nazer, H., Bjorkhem, I., and Russell, D.W., "The Bile Acid Synthetic Gene 3beta-Hydroxy-D5-C27-Steroid Oxidoreductase is Mutated in Progressive Intrahepatic Cholestasis." J. Clin. Invest., 106:1175-1184, 2000
Cheng, J.B., Levine, M.A., Bell, N.H., Mangelsdorf, D.J., and Russell, D.W., "Genetic Evidence that the Human CYP2R1 Enzyme Is A Key Vitamin D 25-Hydroxylase." Proc. Natl. Acad. Sci. USA., 101:7711-7715, 2004
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