The goal of the proposed research is to investigate the hypothesis that saturated fatty acids are important mediators of disease progression in NAFLD and do so via the induction of ER stress. Specifically, we plan to examine the hypothesis that saturated fatty acids promote ER stress and loss of cellular integrity in the hepatocytes via upregulation of SERCA truncated isoform protein 1 and redistribution of ER luminal calcium stores. I have the expertise, leadership and experience necessary to carry out the proposed work. This is evidenced by a proven track record with past NIH funding and multiple publications using in vitro and in vivo models, as well as metabolic, cellular and molecular techniques. As a result of my previous experience with NIH funded projects, I am aware of the importance of communication among project members and consultants, and of constructing a realistic research plan, timeline and budget. The current application builds logically on previous NIH-funded work and I have assembled a research team that can accomplish the proposed goals. Finally, I have a long standing interest and track record of training undergraduate, graduate and post-graduate students.
Bachelor of Science, California State University, Northridge, 1982.
Master of Arts, California State University, Northridge, 1983.
Doctor of Philosophy, University of Southern California, 1988.
Post-Doctoral Fellowship, Vanderbilt University Medical School, Dept. of Molecular Physiology and Biophysics, 1988-1992.
Positions and Employment
Research Assistant, Department of Exercise Science, University of Southern California, 1986-1988.
Post-doctoral fellow, Department of Molecular Physiol & Biophysics, Vanderbilt University School of Medicine, 1988-1993.
Assistant Professor, Department of Pediatrics, University of Colorado Health Science Center, 1993-1997.
Associate Professor, Departments of Exercise Science and Biology (with tenure), Arizona State University, 1998-2000.
Associate Professor, Department of Medicine, University of Colorado Health Sciences Center, 2001-2003.
Professor, Department of Food Science and Human Nutrition, Colorado State University, 2003-present.
Lillian Fountain Smith Endowed Chair in Nutrition, Colorado State University, 2003-present.
Other Experience and Professional Memberships
Co-Director, Pediatric Resident Academic Track, University of Colorado Health Science Center, 1995-1998.
Director of Research Training, University of Colorado Health Sciences Center, Center for Human Nutrition, 1994-1998.
Co-Director, NIH Nutrition Training Grant, Center for Human Nutrition, 1996-1998.
Editorial Board, Metabolism: Clinical and Experimental, 2002-present.
Editorial Board, J. Nutrition, 2004-2008.
Editorial Board, Am. J. Physiology: Reg, Integrative and Comparative, 2009-present.
Editorial Board, Am. J. Physiology: Endocrinology and Metabolism, 2010-present.
Adjoint Professor, Department of Medicine, University of Colorado and Denver Health Sciences Center, 2006-present.
Member, American Diabetes Association, 1988-present.
Member, American Physiological Society, 1993-present.
Member, American Society for Nutrition, 2003-present.
Honors
Juvenile Diabetes Foundation International Post-Doctoral Award, 1991-1993.
Bristol Meyers Squibb/Mead Johnson Research Award, 1993 and 1994.
American Physiological Society Career Development Award, 1994.
New Investigator Award, Colorado CNRU, 1994.
NIH FIRST Award, 1994 (DK47416).
Scholarly Excellence Award, College of Applied Human Sciences, Colorado State University, 2009.
Most relevant to the current application
D. Wang, Y. Wei, M.J. Pagliassotti. Saturated fatty acids promote endoplasmic reticulum stress and liver injury in rats with hepatic steatosis. Endocrinology 147:943-951, 2006.
D. Wang, Y. Wei, D. Schmoll, K.N. Maclean, M.J. Pagliassotti. Endoplasmic reticulum stress increases glucose-6-phosphatase and glucose cycling in liver cells. Endocrinology 147:350-358, 2006.
Y. Wei, D. Wang, F. Topczewski, M.J. Pagliassotti. Saturated fatty acids induce endoplasmic reticulum stress and apoptosis independently of ceramide in liver cells. Am. J. Physiol. 291:E275-E281, 2006.
M.J. Pagliassotti, Y. Wei, D. Wang. Insulin protects liver cells from saturated fatty acid-induced apoptosis via inhibition of c-Jun NH2 terminal kinase activity. Endocrinology 148:3338-3345, 2007.
J.C. Gonzales, C.L. Gentile, K.T. Pfaffenbach, Y. Wei, D. Wang, M.J. Pagliassotti. Chemical induction of the unfolded protein response in the liver increases glucose production and is activated during insulin-induced hypoglycemia in rats. Diabetologia 51:1920-1929, 2008.
Y. Wei, D. Wang, C.L. Gentile, M.J. Pagliassotti. Reduced endoplasmic reticulum calcium links saturated fatty acid-mediated endoplasmic reticulum stress and cell death in liver cells. Molecular and Cellular Biochemistry 331:31-40, 2009.
K.T. Pfaffenbach, C.L. Gentile, A.M. Nivala, D. Wang, Y. Wei, M.J. Pagliassotti. Linking endoplasmic reticulum stress to cell death in hepatocytes: roles of C/EBP homologous protein and chemical chaperones in palmitate-mediated cell death. Am. J. Physiol. 298:E1027-E1035, 2010.
W.L. Holland, B.T. Bikman, L-P Wang, G. Yuguang, K.M. Sargent, S. Bulchand, T.A. knots, G. Shui, D.J. Clegg, M.R. Wenk, M.J. Pagliassotti, P.E. Scherer, S.A. Summers. Mechanism of inflammation-induced insulin resistance: Reliance of Toll-Like Receptor-4 (TLR4) action on ceramide synthesis reveals roles for saturated fatty acids. J. Clin. Invest. 121:1858-1870, 2011.
C.L. Gentile, A. Nivala, J. Gonzales, K. Pfaffenbach, D. Wang, Y. Wei, H. Jiang, D. Orlicky, D. Peterson, M.J. Pagliassotti, K.N. Maclean. Experimental evidence for therapeutic potential of taurine in the treatment of non-alcoholic fatty liver disease. Am. J. Physiol. (In Press).
Additional publications of importance to the field (in chronological order)
Pagliassotti MJ, PA Prach, TA Koppenhafer, DA Pan. Changes in insulin action, triglycerides and lipid composition during sucrose feeding in rats. Am. J. Physiol. 271:R1319-R1326, 1996.
Pagliassotti MJ, LC Holste, MC Moore, DW Neal, AD Cherrington. Comparison of the time courses of insulin and the portal signal on hepatic glucose and glycogen metabolism in the conscious dog. J. Clin. Invest. 97:81-91, 1996.
Horton TJ, MJ Pagliassotti, K Hobbs, JO Hill. Fuel metabolism in men and women during and after long-duration exercise. J. Appl. Physiol. 85:1823-1832, 1998.
Commerford SR, JB Ferniza, ME Bizeau, JS Thresher, WT Willis, MJ Pagliassotti. Diets enriched in sucrose or fat increase gluconeogenesis and G6Pase but not basal glucose production in rats. Am. J. Physiol. 283:E545-E555, 2002.
Y. Wei and M.J. Pagliassotti. Hepato-specific effects of fructose on c-jun N-terminal kinase: Implications for hepatic insulin resistance. Am. J. Physiol. 287:E926-E933, 2004.
Y. Wei, D. Wang, M.J. Pagliassotti. Fructose selectively modulates c-jun N-terminal kinase and insulin signaling in primary rat hepatocytes. J. Nutrition 135:1642-1646, 2005.
ACTIVE:
R01 DK072017-05 (Pagliassotti, PI), 09/01/11-8/30/16
NIH, NIDDK - $200,000 per year - 1.5 calendar months
Obesity and Hepatic Steatosis
Major goal: To elucidate how saturated fatty acids in the steatotic liver lead to increased liver cell injury.
CSREES COL00759 (Pagliassotti, PI), 07/01/07-06/30/2012
Dept. of Agriculture - $50,000 per year - 0.5 calendar months
Plants as a source of bioactive molecules for the treatment of obesity and diabetes
Major goal: To identify bioactive compounds in plant root exudates using LCMS.
R01 (DK47416-14), 12/1/05-1/30/12
NIH, NIDDK - 200,000 per year - 1.5 calendar months
Nutrient Effects on Insulin Action
Major goals: To determine the cellular effectors of fructose-induced activation of JNK and insulin resistance and to examine the link between ER stress and fructose-induced insulin resistance.
Relevant Completed Grants:
NIH FIRST Award (DK47416(1-5)), “Nutrient Effects on Insulin Action”, 3/1/94-2/28/99. Principal Investigator.
NIH R01 (DK 42549), “The Influence of Diet on Nutrient Balance in Humans”, 8/1/94-7/31/98. Co-Investigator.
NIH R01 (DK 38088), “Utilization of Ingested Energy during Underfeeding”, 4/1/96-3/31/98. Co-Investigator.
The Sugar Association, “Postprandial Nutrient Partitioning in Humans”, 10/1/95-12/31/98. Principal Investigator.
NIH R01 (DK 55386), “Dietary Nutrients as Modulators of Hepatic Metabolism”, 6/1/98-5/31/02, Principal Investigator.
NIH R01 (DK47416(6-10)), “Nutrient Effects on Insulin Action”, 9/1/01-8/30/05. Principal Investigator.
NIH R03 (HD048902), “Prenatal hypoxia and development of insulin resistance”, 07/01/2005-06/03/2007. Co-Investigator.
NIH 3R01 (DK072017-01S1), “Obesity and Hepatic Steatosis: Research Supplement to Promote Diversity in Health-Related Research” 3/1/2006-5/30/2008. Principal Investigator.
NIHR01 (DK072017), “Obesity and Hepatic Steatosis”, 09/01/05-8/30/2010. Principal Investigator.