Untitled Document

Research

Alan D. Attie

Ph.D., University of California-San Diego
Professor, Department of Biochemistry
attie@biochem.wisc.edu
http://www.biochem.wisc.edu/faculty/attie/lab/

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

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
Blasiole, D.A., Oler, A.T., & Attie, A.D. (2008). Regulation of ApoB secretion by the low density lipoprotein receptor requires exit from the endoplasmic reticulum and interaction with ApoE or ApoB. J. Biol. Chem., 283(17), 11374-11381.

Blasiole, D.A., Oler, A.T., & Attie, A.D. (2008). Regulation of ApoB secretion by the low density lipoprotein receptor requires exit from the endoplasmic reticulum and interaction with ApoE or ApoB. J. Biol. Chem., 283(17), 11374-11381.

Ferrara, C.T., Wang, P., Neto, E.C., Stevens, R.D., Bain, J.R., Wenner, B.R., Ilkayeva, O.R., Keller, M.P., Blasiole, D.A., Kendziorski, C., Yandell, B.S., Newgard, C.B., & Attie, A.D. (2008). Genetic networks of liver metabolism revealed by integration of metabolic and transcriptional profiling. PLoS Genet., 4(3), e10000034.

Flowers, M.T., Keller, M..P, Choi, Y., Lan, H., Kendziorski, C., Ntambi, J.M., & Attie, A.D. (2008). Liver gene expression analysis reveals endoplasmic reticulum stress and metabolic dysfunction in SCD1-deficient mice fed a very low-fat diet. Physiol. Genomics, 33(3), 361-372.

Oler, A.T., & Attie, A.D. (2008). A rapid, microplate SNP genotype assay for the leptinob allele. J. Lipid Res. 49(5), 1126-1129.

Chaibub Neto, E., Ferrara, C.T., Attie, A.D., Yandell, B.S. (2008). Inferring causal phenotype networks from segregating populations. Genetics, 179(2), 1089-1100.

Nassoury, N., Blasiole, D., Oler, A.T., Hamelin, J., Prat, A., Attie, A.D., & Seidah, N.G. (2007). The cellular trafficking of the secretory proprotein convertase PCSK9 and its dependence on the LDLR. Traffic, 8, 718-732.

Goodarzi, M.O., Lehman, D.M., Taylor, K.D., Guo, X., Cui, J., Qui�ones, J.J., Clee, S.M., Hsueh, W.A., Yang, H., Attie, A.D., Stern, M.P., & Rotter, J.I. (2007). SORCS1: A novel human type 2 diabetes susceptibility gene suggested by the mouse. Diabetes, 56, 1922-1929.

Blasiole, D.A., Davis, R.A., & Attie, A.D. (2007). The physiological and molecular regulation of lipoprotein assembly and secretion. Mol. Biosyst., 3(9), 608-19.

Clee, S.M. , & Attie, A.D. (2007). The genetic landscape of type 2 diabetes in mice. Endocrine Reviews, 28(1), 48-83.

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., & Attie, A.D. (2006). Combined expression trait correlations and expression quantatative trait locus mapping. PLoS Genetics, 2, 52-61.

Rabagia, M.E., Gray-Keller, M.P., & Attie, A.D. (2005). a-Ketoisocaproate-induced Hypersecretion of Insulin by Islets from Diabetes-susceptible Mice: A Role for a‑ketoglutarate as a direct insulin secretagogue. Am. J. Physiol. 289, E218-E224.

Jin, C., Lan, H., Attie, A.D., Bulutuglo, D., Churchill, G.A., & Yandell, B.S. (2004). Selective phenotyping for increased efficiency in mapping studies. Genetics, 168, 2285-93.

Stoehr, J.P., Byers, J.E., Clee, S.M., Lan, H., Boronenkov, I., Schueler, K.M., Yandell, B.S., & Attie, A.D. (2004). Identification of major quantitative trait loci controlling body weight variation in ob/ob mice. Diabetes 53, 245-249.

Lan, H., Rabaglia, M.E., Stoehr, J.P., Nadler, S.T., Schueler, K.L., Zou, F., Yandell, B.S., & Attie, A.D. (2003). Gene expression profiles of non-diabetic and diabetic obese mice suggest a role of hepatic lipogenic capacity in diabetes susceptibility. Diabetes, 52(3), 688-700.

Gillian-Daniel, D.L., Bates, P.W., Tebon, A., & Attie, A.D.Gillian-Daniel, D.L., Bates, P.W., Tebon, A., & Attie, A.D. (2002). Endoplasmic reticulum localization of the LDL receptor mediates pre-secretory degradation of apolipoprotein B. Proc. Natl. Acad. Sci. USA, 43, 4337-4342.

Ntambi, J.M., Miyazaki, M., Stoehr, J.P., Lan, H., Kendziorski, C.M., Yandell, B.S., Cohen, P., Friedman, J.M., & Attie, A.D. (2002). Loss of Stearoyl CoA Desaturase-1 Function protects mice against adiposity. Proc. Natl. Acad. Sci. USA, 99, 11482-11486.

Attie, A.D., Krauss, R.M., Gray-Keller, M.P., Brownlie, A., Miyazaki, M., Kastelein, J.J., Lusis, A.J., Stalenhoef, A.F.H., Stoehr, J.P., Hayden, M.R., & Ntambi, J.M. (2002). Relationship between stearoyl-CoA desaturase activity and plasma triglycerides in human and mouse hypertriglyceridemia. J. Lipid Res., 43, 1899 - 1907.

Attie, A.D., Hamon, Y., Brooks-Wilson, A.R., Gray-Keller, M.P., Rigot, V., Tebon, A., Zhang, L.-H., Mulligan, J., Singaraja, R.R., Bitgood, J.J., Cook, M.E., Kastelein, J.J.P., Chimini, G., & Hayden, M.R. (2002). Identification and functional analysis of a naturally occurring E89K mutation in the ABCA1 gene of the WHAM chicken. J. Lipid Res., 43, 1610-1617.

Lin, Y., Nadler, S.T., Lan, H., Attie, A.D., & Yandel, B.S. (2002). Adaptive gene picking with microarray data: Detecting important low abundance signals. In G. Parmigiani, E.S. Garrett, R.A. Irizarry, & S.L. Zeger (Eds.), The analysis of gene expression data: Methods and software. Springer-Verlag.

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