Physiology and Pharmacology : Sonia M. Najjar

Professor Director, Center for Diabetes and Endocrine Research (CeDER) Phone: (419) 383-5196 FAX: (419) 383-2871 E-mail: sonia.najjar@utoledo.edu

Training

• B.A., Biochemistry, 1980, San Francisco State University
• M.S., Chemistry, 1983, San Francisco State University
• Ph.D., Physiology, 1989, Stanford University

Appointments

• Intramural Research Training Assistant Fellow, Diabetes Branch, NIDDK, National Institutes of Health, Bethesda, Maryland, 1989-1994
• Assistant Professor of Pharmacology and Therapeutics, Medical College of Ohio, 1994-1999
• Associate Professor of Pharmacology and Therapeutics, Medical College of Ohio, 2000-2005
• Professor of Pharmacology and Therapeutics, Department of Physiology and Pharmacology, University of Toledo College of Medicine, Health Science Campus, 2005-
• Director, Molecular Basis of Disease Graduate Program, University of Toledo College of Medicine, Health Science Campus, 2001-2007
• Director, Center for Diabetes and Endocrine Research (CeDER), Medical University of Ohio, 2006-

Research Interests

Understanding the mechanisms of obesity, type 2 diabetes and fatty liver disease.

Research 

Dr. Najjar's laboratory focuses on the role of insulin clearance in the pathogenesis of obesity, fatty liver disease and type 2 diabetes, and on the genetic and dietary basis of these diseases.  The laboratory is also interested in investigating the molecular basis of the increase in the rate of death of common types of cancer with increased obesity.The laboratory is accredited by identifying CEACAM1, as a molecular player in the insulin clearance in liver, and by finding that secreted insulin pulse's acutely decrease de novo lipogenesis in liver to maintain insulin sensitivity in this organ in the presence of high physiologic levels of insulin in the portal circulation.  During the last 15 years, Dr. Najjar has published seminal research papers on lipid and insulin metabolism and action in leading journals such as Science, Cell Metabolism, J. Clinical Investigations, Nature Genetics and others.The laboratory uses genetically engineered mice in addition to tissue culture, molecular techniques and several phenotyping analysis assays.

Representative Publications

• Najjar, S.M., Accili, D., Philippe, N., Margolis, R. and Taylor, S.I. (1993): pp120/ecto-ATPase, an endogenous substrate of the insulin receptor tyrosine kinase, is expressed as two variably spliced isoforms. J. Biol. Chem. 268:1201-6.
• Najjar, S.M., Philippe, N., Suzuki, Y., Formisano, P., Accili, D. and Taylor, S.I. (1995): Insulin-stimulated phosphorylation of recombinant pp120/HA4, an endogenous substrate of the insulin receptor tyrosine kinase. Biochemistry 34:9341-9.
• Formisano, P., Najjar, S.M., Gross, C.N., Philippe, N., Accili, D. and Gorden, P. (1995): Receptor-mediated internalization of insulin: potential role of pp120/HA4, a substrate of the insulin receptor kinase. J. Biol. Chem. 270:24073-7.
• Najjar, S.M., Boisclair, Y.R., Nabih, Z.T., Suh, D-S. and Ooi, G. T. (1996): Cloning and characterization of a functional promotor of the rat pp120 gene, encoding a substrate of the insulin receptor tyrosine kinase. J. Biol. Chem. 271:8809-8817.
• McInerney, M.F., Flynn, J.C., Goldblatt, P.J., Najjar, S.M., Sherwin, R.S., and Janeway, C.A., Jr. (1996): High density insulin receptor positive T lymphocytes from nonobese diabetic mice transfer insulitis and diabetes. J. Immunology 157:3716-3726.
• Najjar, S.M., Blakesley, V.A., Li Calzi, S., Kato, H., LeRoith, D., and Choice, C.V. (1997): Differential phosphorylation of pp120 by insulin and insulin-like growth factor-1 receptors: Role for the C-terminal domain of the beta-subunit. Biochemistry 36:6827-6834.
• Li Calzi, S., Choice, C.V., and Najjar, S.M. (1997): Differential effect of pp120 on insulin internalization via the spliced isoforms of the receptor. Am. J. Physiol. 273 (Endocrinol. Metab. 36):E801-E808.
• Najjar, S.M., Choice, C.V., Soni, P., Whitman, C., and Poy, M.N. (1998): Effect of pp120 on receptor-mediated insulin endocytosis is regulated by the juxtamembrane domain of the insulin receptor. J. Biol. Chem. 273:12923-12928.
• Najjar, S.M. (1998): pp120, a substrate of the insulin receptor tyrosine kinase, is associated with phosphatase activity. Biochem. Biophys. Res. Commun. 247:457-461.
• Choice, C.V., Howard, M.J., Poy, M.N., Hankin, M.H., and Najjar, S.M. (1998): Insulin stimulates pp120 endocytosis in cells co-expressing insulin receptors. J. Biol. Chem. 273:22194-22200.
• Najjar, S.M. and Lewis, R.E. (1999): Persistent expression of foreign genes in cultured hepatocytes: expression vectors. Gene 230:41-45.
• Soni, P., Al-Hosaini, K.A., Fernström, M.A., and Najjar, S.M. (1999): Cell adhesion properties and effects on receptor-mediated insulin endocytosis are independent properties of pp120, a substrate of the insulin receptor tyrosine kinase. Mol. Cell. Biol. Res. Commun. 1:102-108.
• Choice, C.V., Poy, M.N., Formisano, P., and Najjar, S.M. (1999): Differential intracellular trafficking of the two spliced isoforms of pp120, a substrate of the insulin receptor tyrosine kinase. J. Cell. Biochem. 76:133- 142.
• Beauchemin, N., Draber, P., Dveksler, G., Gold, P., Gary-Owen, S., Grunert, F., Hammarstrom, S., Holmes, K.V., Karlsson, A., Kuroki, M., Lin, S- H., Lucka, L., Najjar, S.M., Neumaier, M., Obrink, B., Shively, J.E., Skubitz, K.M., Stanners, C.P., Thomas, P., Thompson, J.A., Virji, M., von Kleist, S., Wagener, C., Watts, S., and Zimmerman, W. (1999): Redefined nomenclature for members of the carcinoembryonic antigen family. Exp. Cell. Res. 252:243-249.
• Xie, Z., Li, H., Liu, L., Kahn, B.B., Najjar, S.M., and Shah, W. (2000): Metabolic regulation of Na+/Pi-cotransporter-1 gene expression in H4IIE cells. Am. J. Physiol. Endocrinol. Metab. 278:E648-E655.
• Soni, P., Lakkis, M., Poy, M.N., Fernström, A.M., and Najjar, S.M. (2000) The Differential Effects of pp120 (Ceacam-1) on the mitogenic action of insulin and insulin-like growth factor-1 are regulated by the nonconserved tyrosine 1316 in the insulin receptor. Mol. Cell. Biol. 20: 3896-3905
• Najjar, S.M., Broyart, J-P, Hampp, L.T., and Gray, G.M. (2001): Intestinal aminooligopeptidase in diabetic BioBreed rat: altered posttranslational processing and trafficking. Am. J. Physiol. Gastrointest. Liver Physiol. 280: G104-G112
• Najjar, S.M., Broyart, J-P., Hampp, L.T., and Gray, G.M. (2001) Abnormal intracellular assembly of sucrase-alpha-dextrinase in spontaneous diabetes. J. Cell. Biochem. 81:252-261.
• Han, E., Phan, D., Lo, P., Poy, M.N., Behringer, R., Najjar, S.M., and Lin, S.-H. (2001) Differences in tissue-specific and embryonic expression of mouse Ceacam1 and Ceacam2 genes. Biochem. J. 355:417-423.
• Phan, D., Sui, X., Luo, W., Najjar, S.M., Jenster, G., and Lin, S-H. (2001) Androgen regulation of the cell-cell adhesion molecule-1 (C-CAM1) gene. Mol. Cell. Endocrinol. 184:115-123.
• Poy, M.N., Ruch R.J., Fernström, M.A., Okabayashi, Y., and Najjar, S.M. (2002) Shc and CEACAM1 interact to regulate the mitogenic action of insulin. J. Biol. Chem 277: 1076-1084.
• Poy, M.N., Yang, Y., Rezaei, K., Fernström, M.A., Lee, A.D., Kido, Y., Erickson, S.K., and Najjar, S.M. (2002) CEACAM1 regulates insulin clearance in liver. Nature Genetics 30: 270-276.
• Najjar, S.M. (2002) Regulation of insulin action by CEACAM1. Trends Endocrinol. Metab. 13:240-245.
• Northcott, C.A., Poy, M.N., Najjar, S.M. and Watts, S.W. (2002) PI-3-kinase mediates enhanced spontaneous and agonist-induced contraction in aorta of DOCA-salt hypertensive rats. Circ. Res. 91:360-369.
• Phan, D., Cheung, C.-J., Galfione, M., Vakar-Lopez, F., Tunstead, J., Thompson, N.E., Burgess, R.R., Najjar, S.M., Yu-Lee, L.-Y., and Lin, S.-H. (2004) Identification of Sp2 as a transcriptional repressor of CEACAM1 in tumorigenesis. Cancer Res. 64:3072-3078.
• Abou-Rjaily, G.A., Lee, S.J., May, D., Al-Share, Q.Y., Ruch, R.J., Neumaier, M., Kalthoff, H., Lin, S-H., and Najjar, S.M. (2004) CEACAM1 modulates epidermal growth factor receptor-mediated cell proliferation. J. Clin. Invest. 114:944-952.
• Dai, T., Abou-Rjaily, G.A., Al-Share, Q.Y., Yang, Y., Fernstrom, M.A., DeAngelis, A.M., Lee, A.D., Sweetman, L., Amato, A., Pasquale, M., Lopaschuk, G.D., Erickson, S.K., and Najjar, S.M. (2004) Interaction between altered insulin and lipid metabolism in CEACAM1-inactive transgenic mice. J. Biol. Chem. 279: 45155-45161.
• McInerney, M.F., Najjar, S.M., Brickley, D., Lutzke, M., Abou-Rjaily, G.A., Reifsnyder, P., Haskell, B.D., Flurkey, K., Zhang, Y.J., Pietropaolo, S.L., Pietropaolo, M., Byers, J.P., and Leiter, E.H. (2004) Anti-insulin receptor autoantibodies are not required for type 2 diabetes pathogenesis in NZL/Lt mice, a New Zealand obese (NZO)-derived mouse strain. Exp. Diabesity Res. 5:177-185.
• Wisloff, U.*, Najjar, S.M.*, Ellingsen, O., Haram, Per M., Swoap, S., Fernstrom, M.A., Lee, S.J., Rezaei, K., Al-Share, Q., Koch, L.G., and Britton, S.L. (2005) Metabolic syndrome X emerges from artificial selection for aerobic capacity. Science 207:418-420. *Equal contribution.
• Najjar, S.M., Yang, Y., Fernstrom, M.A., Abou-Rjaily, G.A., Lee, S.J., DeAngelis, M.A., Al-Share, Q., Miller, T., Dai, T., Ratnam, S., Smith, S., Lin, S.-H., Beauchemin, N., and Oyarce, A.M. (2005) Insulin acutely decreases hepatic fatty acid synthase activity. Cell Metabolism 2:43-53.
• Park, S.Y., Cho,Y.R., Kim, H.J., Hong, E.G., Higashimori, T., Lee, S.J., Goldberg, I.J., Shulman, G.I., Najjar, S.M., and Kim, J.K. (2006) Mechanism of glucose intolerance in mice with dominant-negative mutation of CEACAM1.  Am. J. Physiol. Endocrinol. Metab. 291 (3):E517-E524.    
• Wisløff, U., Støylen, A., Loennechen, J.P., Bruvold,M., Rognmo, Ø., Haram, P.H., Tjønna, A.E., Helgerud, J., Slørdahl, S.A., Lee, S.J., Videm, V., Bye, A., Smith, G.L., Najjar, S.M., Ellingsen, Ø., and Skjærpe, T. (2007)  Superior cardiovascular effect of aerobic interval-training versus moderate continuous training in elderly heart failure patients: A randomized controlled study.  Circulation. 115(24): 3086-3094.
• Bye A, Langaas M, Høydal MA, Kemi OJ, Heinrich G, Koch LG, Britton SL, Najjar SM, Ellingsen Ø, Wisløff U.  (2008) Aerobic capacity-dependent differences in cardiac gene expression.  Physiol Genomics. Mar 14;33(1):100-109.
• Schjerve IE, Tyldum GA, Tjønna AE, Stølen TO, Loennechen JP, Hansen HE, Haram PM, Heinrich G, Bye A, Najjar SM, Smith GL, Slørdahl SA, Kemi OJ, Wisløff U.  (2008) Both aerobic endurance and strength training programs improve cardiovascular health in obese adults.  Clin Sci (Lond). Mar 13. [Epub ahead of print].
• Bye A, Sørhaug S, Ceci M, Høydal MA, Stølen T, Heinrich G, Tjønna AE, Najjar SM, Nilsen OG, Catalucci D, Grimaldi S, Contu R, Steinshamn S, Condorelli G, Smith GL, Ellingsen O, Waldum H, Wisløff U.  (2008)  Carbon monoxide levels experienced by heavy smokers impair aerobic capacity and cardiac contractility and induce pathological hypertrophy.  Inhal Toxicol. May;20(7):635-646.   
• DeAngelis AM, Heinrich G, Dai T, Bowman TA, Patel PR, Jun Lee S, Hong EG, Young Jung D, Assmann A, Kulkarni RN, Kim JK, Najjar, SM, (2008) CEACAM1: A Link Between Insulin and Lipid Metabolism.  Diabetes.  June 10.  [Epub ahead of print].      
• Arnt Erik TjØnna, MSc; Sang Jun Lee, PhD;  Øivind Rognmo, MSc; Tomas O. StØlen, MSc; Anja Bye, MSc; Per Magnus Haram, PhD; Jan Pål Loennechen, PhD; Qusai Y. Al-Share, MSc; Eirik Skogvoll, PhD; Stig a SlØrdahl, PhD; Ole J. Kemi, PhD; Sonia M. Najjar, PhD; Ulrik WislØff, PhD. (2008) Aerobic Interval Training Versus Continuous Moderate Exercise as a Treatment for the Metabolic Syndrome A Pilot Study. Circulation. 118:346-354.
• Lee SJ, Heinrich G, Federova L, Al-Share QY, Ledford KJ, Fernstrom MA, McInerney MF, Erickson SK, Gatto-Weis C, Najjar SM. (2008) Development of Nonalcoholic Steatohepatitis in Insulin-Resistant Liver-Specific S503A Carcinoembryonic Antigen-Related Cell Adhesion Molecule Mutant Mice. Gastroenterology. Aug 20 [Epub ahead of print].
• Haram PM, Kemi OJ, Lee SJ, Bendheim MØ, Al-Share QY, Waldum HL, Gilligan LJ, Koch LG, Britton SL, Najjar SM, Wisløff U.  (2009) Aerobic interval training vs. continuous moderate exercise in the metabolic syndrome of rats artificially selected for low aerobic capacity.  Cardiovasc Res. Mar 1; 81(4):723-32. Epub 2008 Dec 1.