Marshall B. Elam, M. D., Ph.D., FAHA
Professor and Chief
Departments of Pharmacology and Medicine (Cardiovascular Diseases)

Staff Cardiologist and Director
Lipid Meabolism Clinics
Memphis VAMC

Room 310 Crowe Research Building
(901) 448-6011
FAX (901) 448-7206
melam@utmem.edu

Research Interest:

Funded by the American Heart Association and by the VA Merit Review Research Program, my 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. Specifically, insulin increases de novo fatty acid synthesis (lipogenesis) and promotes incorporation of fatty acid into triglyceride by transcriptional upregulation of key enzymes involved in both processes. These include fatty acid synthase (FAS), acetyl-CoA-carboxylase (ACC-1), long-chain fatty acyl elongase, and glycerol phosphate acyltransferase (GPAT). Increased hepatic triglyceride synthesis results 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. The prevalence of both diabetes and obesity is rapidly increasing in the U.S. population. Understanding the mechanisms underlying hyperlipidemia in diabetes and obesity is of critical importance to the development of effective treatment strategies.

We are currently examining the mechanisms underlying enhanced lipid and lipoprotein production by the liver in hyperinsulinemia. Our studies are conducted using both animal models (Zucker fatty rat and JCR:LA/cp corpulent rat) and in vitro models (primary rat hepatocyte cultures). 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. The effect of insulin to increase hepatic expression of FAS and ACC-1 is mediated via transcriptional upregulation of SREBP-1c. Conversely, glucagon (via cAMP) reduces FAS and ACC-1 expression by reducing transcription of SREBP-1c. Currently, our work is focused on the mechanisms through which insulin stimulates (and cAMP inhibits) transcription of this pivotal factor. We have cloned the promoter region for rat SREBP-1c and have demonstrated that this promoter responds to insulin (positive) and to both cAMP and polyunsaturated fatty acids (PUFA) (negative) in transient transfections of primary rat hepatocyte cultures. We have localized the primary insulin-responsive region of the SREBP-1c promoter to the proximal 412 bp. This region of the SREBP-1c promoter contains binding sites for the transcription factors LXRa, Sp1, NF-Y, and for SREBP-1c itself. We have found that over-expression of LXRa, Sp1, and SREBP-1c mimics the effect of insulin on the SREBP-1c promoter and that conversely, disabling the binding sites for each of these factors reduces the ability of the promoter to respond to insulin. We have proposed the hypothesis that the insulin response element (IRE) of the SREBP-1c consists of the LXRa, Sp1, and SREBP-1c binding sites and that these factors act in a cooperative manner to mediate the effect of insulin to stimulate SREBP-1c transcription. Conversely, cAMP prevents activation of LXRa , Sp1 and SREBP-1c by insulin.

Clinical Research:

I participate in the design and execution of multicenter clinical trials related to my basic and clinical research interests in cardiovascular disease and lipid metabolism. These studies, which are 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. I have played key roles in the design and conduct of many national studies including the VA-HDL Intervention Trial (VA-HIT) and Atherosclerotic Disease Multiple Intervention Trial (ADMIT). I am currently the UT/VA clinical site Principal Investigator for four major national studies, Aggressive Control of Cardiovascular Risk in Diabetes (ACCORD, NHLBI/VA), Azithromycin Cardiovascular Event Trial (ACES, NHLBI), Treating to New Targets (TNT, private industry sponsored) and Aggressive Lipid Lowering In preventing New Cardiovascular Events (ALLIANCE, private industry sponsored).

Selected Publications:

Basic Science Publications

Von Wronski, M.A., Cagen, L.M., Wilcox, H.G., Raghow, R., Thorngate, F.E., Heimberg, M., Elam, M.B. "Insulin Increases Expression of Apobec-1, the Catalytic Subunit of the Apolipoprotein B mRNA Editing Complex in Rat Heptocytes. Metabolism 47:869-873, 1998.

Elam MB. Wilcox HG, Von-Wronski MA, Cagen L, Thorngate F, Kumar P, Heimberg M. Expression of Apobec-1, Apolipoprotein B mRNA editing, and Altered VLDL Composition in the Hyperinsulinemic Fatty Zucker Rat. Lipids 34:809-816, 1999.

Elam MB, Wilcox HG, Cagen L, Deng, X. Russell, JC, Raghow R, Kumar P, Heimberg M. Increased Hepatic VLDL secretion, lipogenesis, and SREBP-1 Expression in the Corpulent JCR:LA-cp Rat. J. Lipid Res. 42:2039-2048, 2001.

Deng, X., Cagen, L.M., Wilcox, H.G., Park, E.S., Raghow, R., Elam, M.B. Regulation of the Rat SREBP-1c Promoter in Primary Rat Hepatocytes. Biochem. Biophys. Res. Comm. 290:256-262, 2002

Deng X, Elam MB, Wilcox HG, Cagen LM, Park E, Raghow R, Patel D, Kumar P, Russell JC.  Dietary Fatty Acids Mitigate Induction of Lipogenic Enzymes in the Hyperinsulinemic Corpulent JCR:LA-cp Rat: Microarray Profiling of Lipid Related Gene Expression.  Endocrinology. 145:5847-5861, 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

Zhang Yi, Ma K, Song S, Elam MB, Cook G, Park EA.  Peroxisomal proliferator activated receptor gamma coactivator (PGC-1a ) enhances the thyroid hormone induction of carnitine palmitoyltransferase I (CPT-Ia). J. Biol. Chem. 279:53963-53971, 2004

Cagen LM, Deng X, Wilcox HG, Park EA, Raghow R, Elam MB.  Insulin Activates the Rat SREBP-1c Promoter Through the Acitons of SREBP, LXR, Sp-1 and NF-Y cis-Acting Elements. Biochemical Journal.  385: 207-216, 2005.

Ke Ma, Yi Zhang, Marshall B Elam, George A Cook and Edwards A. Park.  Cloning of the rat pyruvate dehydrogenase kinase 4 (PDK4) gene promoter:  Activation of PDK4 by the peroxisome proliferator-activated receptor gamma coactivator (PGC-1a).  In Press J. Biol Chem. 2005.

Yellaturu CR, Deng X, Cagen LM, Wilcox HG, Park EA, Raghow R, and Elam MB.  Posttranslational Processing of SREBP-1 in Rat Hepatocytes is Regulated by Insulin and cAMP.  Biochem. Biophys. Res. Comm.332:174-180, 2005.

Clinical Research Publications:

Elam, M.B., Heckman, J., Crouse, R., Hunninghake, D., Herd, A., Davidson, M., Forbes, B. for the Cilostozol Lipid Investigators Study Group. "Modification of Plasma Lipoproteins by the Vasodilator Cilostozol in Patients with Intermittant Claudication". Arteriosclerosis Thrombosis Vascular Biology 18:1942-1947, 1998.

Rubins HB, Robins SJ, Collins D, Anderson JW, Elam MB, Faas FH, Linares EL, Schaefer EJ, Schectman G, Wilt TJ, Wittes J, for the VA-HIT Study Group. Gemfibrozil for the Secondary Prevention of Coronary Heart Disease in Men with Low Levels of High-Density-Lipoprotein Cholesterol. New England Journal of Medicine: 341:410-418, 1999

Garg R., Elam, M.B., R., Hunninghake, D.B., Davis, K.B., Applegate, W.B., Crouse, J.R., Herd, J.A., Sheps, D.S., Kostis, J.B., Egan, D.A., Pettinger, M.B., Johnson, C. "Effective and Safe Modification of multiple atherosclerotic risk factors in patients with peripheral arterial disease. American Heart Journal 140:792-803, 2000.

Chesney, C., Elam, M.B., Herd, A., Davis, K., Garg, R., Hunninghake, D., Kennedy, J.W., Applegate, W.B. "Effect of Niacin, Warfarin, and Antioxidant Therapy on Coagulation Parameters in Subjects with Peripheral Arterial Disease in the Arterial Disease Multiple Intervention Trial (ADMIT). Am Heart J 140:631-636, 2000.

Elam M.B., Hunninghake D.B., Davis K.B., Brinton E.B., Sheps D.S., Garg R, Johnson C, Egan D. Kostis JB, On Behalf of the ADMIT Investigators. "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. JAMA, 284:1263-1270, 2000.

Rubins HB, Robins SJ, Collins D, Nelson DB, Elam MB, Schaefer EJ, Faas FH, Anderson JW. for the VA-HIT Study Group.  Diabetes, Plasma Insulin and Cardiovascular Disease: Subgroup Analysis from the VA-HDL Intervention Trial (VA-HIT).  Arch. Int. Med. 162:2597-2604, 2002.

Robins SJ, Rubins HB, Faas FH, Schaefer EJ, Elam MB, Anderson JW, Collins D. Insulin resistance and cardiovascular events with low HDL cholesterol: the Veterans Affairs HDL Intervention Trial (VA-HIT).  Diabetes Care 26:1513-1517, 2003

Laboratory roster

Lauren Cagen PhD
Research Assistant Professor
901-448-6077
lcagen@utmem.edu

Xiong Deng PhD.
Postdoctoral Research Fellow
901-448-5825
xdeng@utmem.edu

Poonam Kuman , B.S.
Senior Research Assistant
901-448-5825
pkumar@utmem.edu