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Alan D. Attie

Professor of Biochemistry

Lab Home Page:

Attie Lab

Address:

534A Biochemistry Addn

Telephone:

262-1372

Email:

attie@biochem.wisc.edu

Research Fields:

Genomics

Gene Expression

Human and Mammalian

Research Interests

Molecular genetics of diabetes & insulin resistance; cell biology of lipoprotein assembly, cholesterol trafficking

Research Description

Diabetes:

About 15 million Americans suffer from type II diabetes mellitus. This disease involves an impaired response to insulin (insulin resistance) and the failure of pancreatic beta-cells to compensate with sufficient insulin to titrate blood glucose. Diet and obesity collaborate with genetics to produce diabetes. We have created a mouse model for identifying genes that determine whether obesity will result in diabetes. Through a genome-wide mapping study, we mapped several gene loci that contribute to diabetes and to obesity. Interestingly, the obesity loci influence the penetrance of the diabetes loci. We are using the genetics to reveal new biochemical mechanisms underlying the key features of diabetes. This involves the positional cloning of the relevant gene loci and biochemical studies to elucidate the molecular basis of insulin resistance and beta-cell failure.

Lipoprotein Assembly:

Lipoproteins package water-insoluble lipids for transport through the bloodstream. Overproducation of lipoproteins is the leading cause of hyperlipidemia, a major risk factor for premature heart disease. Lipoproteins are constitutively synthesized. The rate of lipoprotein production is determined by the post-translational fate of the newly-synthesized proteins.

We have discovered that the LDL receptor mediates presecretory degradation of lipoproteins and re-uptake of newly-secreted lipoproteins. This finding opens many new questions relating to lipoprotein trafficking through the secretory pathway.

Cholesterol trafficking:

Cells take up cholesterol through receptor-mediated endocytosis of plasma lipoproteins. To get rid of cholesterol, cells must efflux cholesterol back to lipoprotein acceptors. We are studying defects in this transport pathway that lead to human disease. In one project, we are studying a specific cholesterol/phospholipid transporter, ABCA1. Mutations in ABCA1 result in HDL deficiency and premature heart disease.

Representative Publications

• Clee, S.M. and Attie, A.D. 2007. The genetic landscape of type 2 diabetes in mice. Endocrine Reviews. 28:48-83.
• Clee, S.M., Yandell, B.S., Schueler, K.M., Rabaglia, M.E., Richards, O.C., Raines, S.M., Kabara, E.A., Klass, D.M., Stapleton, D.S., Gray-Keller, M.P., Boronenkov, I., Raess, P.W., Flowers, M.T. and Attie, A.D. 2006. Positional cloning of a type 2 diabetes quantitative trait locus. Nature Genetics. 38:688-693.
• Lan, H., Chen, M., Byers, J.E., Yandell, B.S., Stapelton, D.S., Mata, C.M., Mui, E.T., Flowers, M.T., Scheuler, K.L., Manly, K.F., Williams, R.W., Kendziorski, C.M. and Attie, A.D. 2006. Combined expression trait correlations and expression quantitative trait locus mapping. PLoS Genetics. 2:52-61.
• Attie, A.D. 2007. ABCA1: at the nexus of cholesterol, HDL and atherosclerosis. Trends Biochem Sci. 32:172-9. .
• Clee, S.M, Nadler, S.T. and Attie. A.D. 2005. Genetic and genomic studies of the BTBR ob/ob mouse model of type 2 diabetes. Am J Ther. 12:491-8.