Marshall B. Elam, PhD, MD
Professor of Pharmacology and Medicine
Director, Lipid Metabolism Clinics, VAMC
310 Crowe Research Building
- M.D., University of Tennessee Health Sciences Center, Memphis, TN, Medicine
- Ph.D., University of Tennessee Health Sciences Center, Memphis, TN, Pharmacology
- B.S., Lambuth University, Jackson, TN, Biology
Project Leader: Marshall B Elam PhD MD
Basic Research: With funding from NHLBI, VA, and American Heart, Dr Elam's laboratory is engaged in study of the cellular and molecular mechanisms that mediate hyperlipidemia in hyperinsulinemic states including obesity and type II diabetes mellitus. Our central hypothesis is that hyperinsulinemia itself contributes to hyperlipidemia in obesity and type II diabetes by increasing hepatic lipid production resulting in enhanced secretion of triglyceride rich lipoproteins (i.e. Very-Low-Density-Lipoprotein, VLDL) by the liver. As clearance mechanisms become saturated, partially metabolized remnant particles accumulate in the plasma. These particles are highly atherogenic and contribute to the high risk of atherosclerotic vascular disease observed in obesity and type II diabetes. We have demonstrated that increased VLDL secretion in animal models of hyperinsulinemia occurs as a result of increased de-novo lipogenesis, and that increased lipogenesis is, in turn, the result of upregulation of lipogenic enzymes including FAS, ACC-1 and the transcriptional regulator SREBP-1c. Currently, the laboratory component of Dr Elam's program is focused on the mechanisms through which insulin stimulates (and cAMP inhibits) transcription and posttranslational processing of this regulatory factor that plays a pivotal role in mediating the hyperlipidemia that accompanies hyperinsulinemia in insulin resistant states such as obesity and type II diabetes/Metabolic syndrome.
Clinical Research: Dr Elam participates in the design and execution of multicenter clinical trials related to cardiovascular disease and lipid metabolism. These studies, which have been funded by the National Institutes of Health, VA Cooperative Studies Program, and Pharmaceutical Industry, determine the impact of modification of multiple cardiovascular risk factors including lipids, blood pressure, and blood glucose on cardiovascular outcomes in patients with hyperlipidemia, coronary heart disease, peripheral arterial disease and diabetes. Dr Elam has participated on a national level in many landmark cardiovascular risk reduction studies including VA-HIT, ADMIT, TNT, ALLIANCE, and ACES. Dr Elam is currently the Principal Investigator of the Memphis VA Medical Center site for the NHLBI-funded ACCORD (Action to Control Cardiovascular Risk in Diabetes) study, a landmark clinical trial that tests the hypothesis that intensive treatment of cardiovascular risk factors (glucose, blood pressure, and lipids) will reduce risk of cardiovascular disease in patients with type II diabetes. He is also the Memphis VA PI of the AIM-HIGH study (Atherothombosis Intervention in Metabolic Syndrome with low HDL/high triglycerides and Impact on Global Health Outcomes) which tests the hypothesis that HDL raising with ER-Niacin in addition to LDL-reduction with an HMG-CoA Reductase Inhibitor will reduce cardiovascular morbidity and mortality in patients with Metabolic Syndrome and existing cardiovascular disease. This study is also funded by NHLBI.
Translational Research: Dr Elam is the PI of a CRC-funded study of hepatic gene expression in morbidly obese humans. This study, conducted in collaboration with the Department of Surgery Obesity Center, involved hepatic gene profiling using microarray (Genome Explorations Inc) technology coupled with metabolic profiling of patients undergoing gastric bypass surgery for morbid obesity and those undergoing abdominoplasty (tummy tuck) following weight loss. Over 150 differentially expressed genes have been identified, many of which are novel genes related to inflammatory response, lipid metabolism, xenobiotic metabolism, and signaling pathways. Dr Elam and his colleagues in ACCORD have identified a subpopulation of participants who experience a paradoxical lowering of HDL with combined rosiglitazone (PPAR-g) and fenofibrate (PPAR-a) therapy. He is proposing an ancillary study to identify gene polymorphi
Pathogenesis of dyslipidemia in Obesity and Type II Diabetes Mellitus
Lipid Metabolism, Obesity, Type II Diabetes, Gene expression, hepatic, lipogenesis, Sterol-Regulatory-Element-Binding-Protein-1c, Transcriptional Regulation, Posttranslational Modification of Proteins, Statin Pharmacology, Pharmacogenomics
- Elam, MB, Cowan, GS, Rooney, RJ, Hiler, ML, Yellaturu, CR, Deng, X, Howell, GE, Park, EA, Gerling, IC, Patel, D, Corton, JC, Cagen, LM, Wilcox, HG, Gandhi, M, Bahr, MH, Allan, MC, Wodi, LA, Cook, GA, Hughes, TA, Raghow, R. Hepatic Gene Expression in Morbidly Obese Women: Implications for Disease Susceptibility. Obesity (Silver Spring), 2009.
- Yellaturu, CR, Deng, X, Cagen, LM, Wilcox, HG, Mansbach, CM, Siddiqi, SA, Park, EA, Raghow, R, Elam, MB. Insulin Enhances Post-translational Processing of Nascent SREBP-1c by Promoting Its Phosphorylation and Association with COPII Vesicles. J Biol Chem, 284 (12), 7518-32, 2009.
- Raghow, R, Yellaturu, C, Deng, X, Park, EA, Elam, MB. SREBPs: the crossroads of physiological and pathological lipid homeostasis. Trends Endocrinol Metab, 19 (2), 65-73, 2008.
- Deng, X, Yellaturu, C, Cagen, L, Wilcox, HG, Park, EA, Raghow, R, Elam, MB. Expression of the rat sterol regulatory element-binding protein-1c gene in response to insulin is mediated by increased transactivating capacity of specificity protein 1 (Sp1). J Biol Chem, 282 (24), 17517-29, 2007.
- Sadana, P, Zhang, Y, Song, S, Cook, GA, Elam, MB, Park, EA. Regulation of carnitine palmitoyltransferase I (CPT-Ialpha) gene expression by the peroxisome proliferator activated receptor gamma coactivator (PGC-1) isoforms. Mol Cell Endocrinol, 267 (1-2), 6-16, 2007.
- Aligeti, VR, Gandhi, M, Braden, R, Rezk, A, Elam, MB. Effect of combination lipid-modifying therapy on the triglyceride lowering effect of fish oil. Am J Med Sci, 333 (3), 168-72, 2007.
- Zhang, Y, Ma, K, Sadana, P, Chowdhury, F, Gaillard, S, Wang, F, McDonnell, DP, Unterman, TG, Elam, MB, Park, EA. Estrogen-related receptors stimulate pyruvate dehydrogenase kinase isoform 4 gene expression. J Biol Chem, 281 (52), 39897-906, 2006.
- Ma, K, Zhang, Y, Elam, MB, Cook, GA, Park, EA. Cloning of the rat pyruvate dehydrogenase kinase 4 gene promoter: activation of pyruvate dehydrogenase kinase 4 by the peroxisome proliferator-activated receptor gamma coactivator. J Biol Chem, 280 (33), 29525-32, 2005.
- Yellaturu, CR, Deng, X, Cagen, LM, Wilcox, HG, Park, EA, Raghow, R, Elam, MB. Posttranslational processing of SREBP-1 in rat hepatocytes is regulated by insulin and cAMP. Biochem Biophys Res Commun, 332 (1), 174-80, 2005.
- Cagen, LM, Deng, X, Wilcox, HG, Park, EA, Raghow, R, Elam, MB. Insulin activates the rat sterol-regulatory-element-binding protein 1c (SREBP-1c) promoter through the combinatorial actions of SREBP, LXR, Sp-1 and NF-Y cis-acting elements. Biochem J, 385 (Pt 1), 207-16, 2005.
- Zhang, Y, Ma, K, Song, S, Elam, MB, Cook, GA, Park, EA. Peroxisomal proliferator-activated receptor-gamma coactivator-1 alpha (PGC-1 alpha) enhances the thyroid hormone induction of carnitine palmitoyltransferase I (CPT-I alpha). J Biol Chem, 279 (52), 53963-71, 2004.
- Deng, X, Elam, MB, Wilcox, HG, Cagen, LM, Park, EA, Raghow, R, Patel, D, Kumar, P, Sheybani, A, Russell, JC. Dietary olive oil and menhaden oil mitigate induction of lipogenesis in hyperinsulinemic corpulent JCR:LA-cp rats: microarray analysis of lipid-related gene expression. Endocrinology, 145 (12), 5847-61, 2004.
- Song, S, Zhang, Y, Ma, K, Jackson-Hayes, L, Lavrentyev, EN, Cook, GA, Elam, MB, Park, EA. Peroxisomal proliferator activated receptor gamma coactivator (PGC-1alpha) stimulates carnitine palmitoyltransferase I (CPT-Ialpha) through the first intron. Biochim Biophys Acta, 1679 (2), 164-73, 2004.
- Deng, X, Cagen, LM, Wilcox, HG, Park, EA, Raghow, R, Elam, MB. Regulation of the rat SREBP-1c promoter in primary rat hepatocytes. Biochem Biophys Res Commun, 290 (1), 256-62, 2002.
- Elam, MB, Wilcox, HG, Cagen, LM, Deng, X, Raghow, R, Kumar, P, Heimberg, M, Russell, JC. Increased hepatic VLDL secretion, lipogenesis, and SREBP-1 expression in the corpulent JCR:LA-cp rat. J Lipid Res, 42 (12), 2039-48, 2001.
- Chesney, CM, Elam, MB, Herd, JA, Davis, KB, Garg, R, Hunninghake, D, Kennedy, JW, Applegate, WB. Effect of niacin, warfarin, and antioxidant therapy on coagulation parameters in patients with peripheral arterial disease in the Arterial Disease Multiple Intervention Trial (ADMIT). Am Heart J, 140 (4), 631-6, 2000.
- Elam, MB, Hunninghake, DB, Davis, KB, Garg, R, Johnson, C, Egan, D, Kostis, JB, Sheps, DS, Brinton, EA. Effect of niacin on lipid and lipoprotein levels and glycemic control in patients with diabetes and peripheral arterial disease: the ADMIT study: A randomized trial. Arterial Disease Multiple Intervention Trial. JAMA, 284 (10), 1263-70, 2000.
- Elam, MB, von Wronski, MA, Cagen, L, Thorngate, F, Kumar, P, Heimberg, M, Wilcox, HG. Apolipoprotein B mRNA editing and apolipoprotein gene expression in the liver of hyperinsulinemic fatty Zucker rats: relationship to very low density lipoprotein composition. Lipids, 34 (8), 809-16, 1999.
- Pahor, M, Elam, MB, Garrison, RJ, Kritchevsky, SB, Applegate, WB. Emerging noninvasive biochemical measures to predict cardiovascular risk. Arch Intern Med, 159 (3), 237-45, 1999.
- Elam, MB, Heckman, J, Crouse, JR, Hunninghake, DB, Herd, JA, Davidson, M, Gordon, IL, Bortey, EB, Forbes, WP. Effect of the novel antiplatelet agent cilostazol on plasma lipoproteins in patients with intermittent claudication. Arterioscler Thromb Vasc Biol, 18 (12), 1942-7, 1998.
- von Wronski, MA, Hirano, KI, Cagen, LM, Wilcox, HG, Raghow, R, Thorngate, FE, Heimberg, M, Davidson, NO, Elam, MB. Insulin increases expression of apobec-1, the catalytic subunit of the apolipoprotein B mRNA editing complex in rat hepatocytes. Metabolism, 47 (7), 869-73, 1998.
- Hughes, TA, Elam, MB, Applegate, WB, Bond, MG, Hughes, SM, Wang, X, Tolley, EA, Bittle, JB, Stentz, FB, Kang, ES. Postprandial lipoprotein responses in hypertriglyceridemic subjects with and without cardiovascular disease. Metabolism, 44 (8), 1082-98, 1995.
- Solomon, SS, Palazzolo, MR, Elam, MB, Green, S, Raghow, R. Regulation of calmodulin gene expression by insulin is both transcriptional and post-transcriptional. J Lab Clin Med, 124 (3), 348-58, 1994.
- Thorngate, FE, Raghow, R, Wilcox, HG, Werner, CS, Heimberg, M, Elam, MB. Insulin promotes the biosynthesis and secretion of apolipoprotein B-48 by altering apolipoprotein B mRNA editing. Proc Natl Acad Sci U S A, 91 (12), 5392-6, 1994.
- Zhang, ZJ, Wilcox, HG, Castellani, L, Fungwe, TV, Elam, MB, Heimberg, M. Concentration-dependent effects of eicosapentaenoic acid on very low density lipoprotein secretion by the isolated perfused rat liver. Lipids, 28 (5), 419-25, 1993.
- Elam, MB, Wilcox, HG, Solomon, SS, Heimberg, M. In vivo growth hormone treatment stimulates secretion of very low density lipoprotein by the isolated perfused rat liver. Endocrinology, 131 (6), 2717-22, 1992.
- Zhang, ZJ, Wilcox, HG, Elam, MB, Castellani, LW, Heimberg, M. Metabolism of n-3 polyunsaturated fatty acids by the isolated perfused rat liver. Lipids, 26 (7), 504-11, 1991.
- Elam, MB, Simkevich, CP, Solomon, SS, Wilcox, HG, Heimberg, M. Stimulation of in vitro triglyceride synthesis in the rat hepatocyte by growth hormone treatment in vivo. Endocrinology, 122 (4), 1397-402, 1988.
- Elam, MB, Umstot, ES, Andersen, RN, Solomon, SS, Heimberg, M. Deprivation and repletion of androgen in vivo modifies triacylglycerol synthesis by rat hepatocytes. Biochim Biophys Acta, 921 (3), 531-40, 1987.
- Huch, KM, Elam, MB, Chesney, CM. Oral contraceptive steroid induced platelet coagulant hyperactivity: dissociation of in vivo and in vitro effects. Thromb Res, 48 (1), 41-50, 1987.