Our research focuses on lipid metabolism. In one line of investigation, we study the enzymes and genes that convert cholesterol, an otherwise hydrophobic and insoluble molecule, into bile acids, which are hydrophilic derivatives that are water-soluble and readily excreted from the body. In addition to being the endproducts of cholesterol metabolism, bile acids are required for the absorption of dietary vitamins and lipids from the small intestine.
Bile acids are synthesized in the liver by several metabolic pathways that involve at least 16 enzymes located in the cytoplasmic and membrane compartments of the cell. We use biochemical and molecular methods to isolate these enzymes and their encoding genes and then use physiological methods and targeted gene disruption in mice to determine their roles in cholesterol metabolism. Our current focus includes enzymes that hydroxylate cholesterol to produce oxysterols in the liver and central nervous system. We are particularly interested in the enzyme cholesterol 24-hydroxylase, which is responsible for cholesterol turnover in the brain. Mice deficient in this enzyme and turnover pathway fail to learn and exhibit profound behavioral and electrophysiological phenotypes.
The failure to produce bile acids leads to liver disease in children. We use molecular genetic methods to identify and characterize mutations in genes that specify bile acid synthesis enzymes. The genomic DNAs of patients presenting with liver failure are screened for mutations, and if found, these are recreated in expressible cDNAs and analyzed by transfection in cultured cells. To date, the molecular bases of three different genetic diseases have been determined and we continue to screen for new causes of human liver failure.
In additional lines of investigation, we study enzymes that synthesize and break down a variety of lipids, ranging from androgens to Vitamin D to waxes. Relevant genes are cloned, the biochemical properties of the encoded enzymes are determined, and the biological roles of the lipid in question are identified through the study of knockout mice. This information is used to develop drugs for the treatment of human disease arising from impaired lipid synthesis or breakdown, to search for the causes of inherited human genetic disease, and to identify new enzymes involved in lipid metabolism. These studies have led to the identification of drugs for the treatment of prostatic disease and baldness, to the isolation of genes deficient in four human genetic diseases, and to the elucidation of several lipid biosynthetic pathways.
RESEARCH INTERESTS
Cholesterol metabolism, lipid synthesis
RECENT PUBLICATIONS
Cheng, J.B., and Russell, D.W., "Mammalian Wax Biosynthesis I: Identification of Two Fatty Acyl-Coenzyme A Reductases with Different Substrate Specificities and Tissue Distributions." J. Biol. Chem., 279:37789-97, 2004
Cheng, J.B., and Russell, D.W., "Mammalian Wax Biosynthesis II: Expression Cloning of Wax Synthase cDNAs Encoding a Member of the Acyltransferase Enzyme Family." J. Biol. Chem., 279:37798-807, 2004
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
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
SIGNIFICANT PUBLICATIONS
Andersson, S., Bishop, R.W., and Russell, D.W., "Expression Cloning and Regulation of Steroid 5alpha-Reductase, An Enzyme Essential for Male Sexual Differentiation." J. Biol. Chem., 264:16249-16255, 1989
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 5a-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 3b-Hydroxy-D5-C27-Steroid Oxidoreductase is Mutated in Progressive Intrahepatic Cholestasis." J. Clin. Invest., 106:1175-1184, 2000
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