UCSF DIABETES, ENDOCRINOLOGY & METABOLISM TRAINING PROGRAM FACULTY RESEARCH SUMMARIES

Research in my laboratory is focused on the role of the liver in maintaining whole body homeostasis. We are especially interested in the regulation of cholesterol, lipoprotein and biliary metabolism. We have two major ongoing projects.

The first project is targeted at defining mechanisms of integrated regulation of the cholesterol, fatty acid, bile acid and carbohydrate metabolic pathways using gene knockout mouse models. Our approach is to determine the effects of specific gene knockout of key genes in the cholesterol and bile acid metabolic pathways. We study these at the physiologic, cell biology, biochemical and molecular levels. We also investigate interaction of these genes with gender, diet, aging and genetic background. At present, we are studying the effects of knocking out two genes that encode enzymes responsible for catalyzing the initial steps of cholesterol catabolism and bile acid synthesis in the liver. These genes are members of the large CYP family of genes. The first, CYP7A, encodes a protein with cholesterol 7 a -hydroxylase activity and is expressed under normal conditions only in hepatocytes. Genetic CYP7A deficiency in humans results in hypercholesterolemia. The second, CYP27A, encodes a protein with sterol 27-hydroxylase activity and is expressed in many different tissues and cell types. Genetic CYP27A deficiency in humans results in cerebrotendinous xanthomatosis (CTX). We are studying the effects of single and double gene knockouts in mice.

The second project is focused on studying the etiology(s), progression and genetics of nonalcoholic fatty liver disease (NAFLD). This disease is rapidly increasing in the human population and has become a public health problem world-wide. Little is understood about its causes or its progression. We recently have developed a diet-induced mouse model of NAFLD that closely mimics the whole range of this disease in humans. Studies with this model include: longitudinal characterization of the progression of disease at the morphological, biochemical and molecular levels and identification of genes involved in NAFLD and its progression using classic mouse genetics and quantitative trait locus (QTL) analyses.

Selected References

Erickson, SK, SR Lear, S Deane, S Dubrac, S Huling, L Nguyen, JS Bollineni, S Shefer, H Hyogo, DE Cohen, B Shneider, E Sehayek, M Ananthanarayan, N Balasubramanian, FJ Suchy, AK Batta, G Salen. Hypercholesterolemia and changes in lipid and bile acid metabolism in male and female cyp7A1 deficient mice. J Lipid Res, 44:1001-9, 2003.

Dai, T, GA Abou-Rjaily, QY Al-Share, Y Yang, MA Fernstrom, AM DeAngelis, AD Lee, L Sweetman, A Amato, M Pasquale, G Lopaschuk, SK Erickson, SM Najjar. Interaction between altered insulin and lipid metabolism in CEACAM1-inactive transgenic mice. J Biol Chem 279:45155-61, 2004.

Dubrac, S, SR Lear, M Ananthananarayan,N Balasubramaniyan, J Bollineni, S Shefer, H Hyogo, DE Cohen, P Blanche, RM Krauss, AK Batta, G Salen, FJ Suchy, N Maeda, SK Erickson. Role of CYP27A in cholesterol and bile acid metabolism. J Lipid Res 46:76-85, 2005.

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