Apply to Graduate School | Library | Jobs & Volunteers | Visitor Information | Department Index | News      
Research in Lipid Sciences
Dr. Larry Rudel

Lawrence L. Rudel, PhD

Professor of Pathology (Lipid Sciences) and Biochemistry
Tel: (336) 716-2821
Fax: (336) 716-6279
lrudel@wfubmc.edu

Education:
  • Undergraduate: Colorado State University, BS, 1963
  • Postgraduate: University of Arkansas, MS, 1965; University of Arkansas for Medical Sciences, PhD, 1969
  • Fellowships: University of Toronto, 1970-71; University of California (San Francisco), 1972-73  
Interests:
  • Teaching: Disturbances in Plasma Lipoprotein Metabolism, Cholesterol Biosynthesis and Metabolism, Atherosclerosis and Nutrition, Pathophysiology of Cholesterol and Bile Acids
  • Research: Nutrition in Atherosclerosis, Dietary Fatty Acids in Cardiovascular Disease, Hepatic Cholesterol Metabolism and Gene Regulation, Primate Liver Perfusion, Plasma Lipoprotein Metabolism, Cholesterol Ester Formation 
Current Research: Cholesterol Metabolism, Lipoproteins, Primates 

Complications arising from coronary heart disease are the number one cause of death in our country. Atherosclerosis is the underlying disease process. We have developed nonhuman primate (monkey) models of diet-induced coronary artery atherosclerosis (CAA). We are attempting to define molecular mechanisms through which dietary fatty acids modify plasma lipoprotein distribution and composition and their respective roles in CAA. Increased blood plasma concentrations of low density lipoproteins (LDL) and decreased concentrations of high density lipoproteins (HDL) both contribute to increased CHD in man and monkeys.

Pathways regulating plasma lipoprotein concentrations are under study. In addition, increased LDL cholesteryl oleate content has been associated with increased CAA. Isolated, perfused primate livers have been used to demonstrate that hepatic cholesteryl oleate secretion rate is correlated with LDL cholesteryl oleate enrichment and increased CAA. The enzyme in the liver responsible for cholesteryl oleate formation and secretion has been identified as acyl-CoA:cholesterol acyltransferase 2 (ACAT2). This enzyme has been cloned, expressed, and regulation by cholesterol and fatty acids is under investigation. Intrahepatic metabolism of cholesterol determines the type and extent of lipoprotein particle secretion by the liver, so we are quantifying entry and exit pathways for cholesterol in the liver. To accomplish this, we are examining transcriptional regulation of the genes controling hepatic cholesterol metabolism, particularly ACAT2 and cholesterol 7-a-hydroxylase, as this regulation is influenced by cholesterol and fatty acid type.

In sum, by delineating molecular aspects of diet responsiveness of cholesterol and lipoprotein metabolism in a nonhuman primate model of CAA, we are providing information that can eventually be helpful in development of strategies for prevention of coronary heart disease. 

Figure Legend: The role of ACAT1 and ACAT2 in cholesterol metabolism.

Figure Legend: The role of ACAT1 and ACAT2 in cholesterol metabolism.
Recent Publications:

Das A, Davis MA, Tomoda H, Omura S, Rudel LL. Identification of the interaction site within acyl Coenzyme A (CoA): cholesterol acyltransferase - 2 (ACAT2) for the isoform-specific inhibitor pyripyropene A. J Biol Chem. 2008 Feb 19; [Epub ahead of print]

Brown JM, Bell TA 3rd, Alger HM, Sawyer JK, Smith TL, Kelley KD, Shah RA, Wilson MD, Davis MA, Lee RG, Graham MJ, Crooke RM, Rudel LL. Targeted depletion of hepatic ACAT2-driven cholesterol esterification reveals a non-biliary route for fecal sterol loss. J Biol Chem. 2008 Feb 14; [Epub ahead of print]

Chilton FH, Rudel LL, Parks JS, Arm JP, Seeds MC. Mechanisms by which botanical lipids affect inflammatory disorders. Am J Clin Nutr. 2008 Feb;87(2):498S-503S.

Temel RE, Rudel LL. Diet effects on atherosclerosis in mice. Curr Drug Targets. 2007 Nov;8(11):1150-60.

Jiang ZY, Parini P, Eggertsen G, Davis MA, Hu H, Suo GJ, Zhang SD, Rudel LL, Han TQ, Einarsson C. Increased expression of LXRalpha , ABCG5, ABCG8 and SRBI in the liver from normolipidemic nonobese chinese gallstone patients. J Lipid Res. 2007 Nov 15; [Epub ahead of print]

Zhao B, Song J, Chow WN, St Clair RW, Rudel LL, Ghosh S. Macrophage-specific transgenic expression of cholesteryl ester hydrolase significantly reduces atherosclerosis and lesion necrosis in Ldlr mice. J Clin Invest. 2007 Oct;117(10):2983-92.

Brown JM, Chung S, Das A, Shelness GS, Rudel LL, Yu L. CGI-58 facilitates the mobilization of cytoplasmic triglyceride for lipoprotein secretion in hepatoma cells. J Lipid Res. 2007 Oct;48(10):2295-305.

Kavanagh K, Jones KL, Sawyer J, Kelley K, Carr JJ, Wagner JD, Rudel LL. Trans fat diet induces abdominal obesity and changes in insulin sensitivity in monkeys. Obesity (Silver Spring). 2007 Jul;15(7):1675-84.

Kavanagh K, Fairbanks LA, Bailey JN, Jorgensen MJ, Wilson M, Zhang L, Rudel LL, Wagner JD. Characterization and heritability of obesity and associated risk factors in vervet monkeys. Obesity (Silver Spring). 2007 Jul;15(7):1666-74.

Temel RE, Tang W, Ma Y, Rudel LL, Willingham MC, Ioannou YA, Davies JP, Nilsson LM, Yu L. Hepatic Niemann-Pick C1-like 1 regulates biliary cholesterol concentration and is a target of ezetimibe. J Clin Invest. 2007 Jul;117(7):1968-78.

Brown JM, Rudel LL, Yu L. NPC1L1 (Niemann-Pick C1-like 1) mediates sterol-specific unidirectional transport of non-esterified cholesterol in McArdle-RH7777 hepatoma cells. Biochem J. 2007 Sep 1;406(2):273-83.

Temel RE, Hou L, Rudel LL, Shelness GS. ACAT2 stimulates cholesteryl ester secretion in apoB-containing lipoproteins. J Lipid Res. 2007 Jul;48(7):1618-27.
 
Bell TA 3rd, Kelley K, Wilson MD, Sawyer JK, Rudel LL. Dietary fat-induced alterations in atherosclerosis are abolished by ACAT2-deficiency in ApoB100 only, LDLr-/- mice. Arterioscler Thromb Vasc Biol. 2007 Jun;27(6):1396-402.

Ohshiro T, Rudel LL, Omura S, Tomoda H. Selectivity of microbial acyl-CoA: cholesterol acyltransferase inhibitors toward isozymes. J Antibiot (Tokyo). 2007 Jan;60(1):43-51.

Bell TA 3rd, Wilson MD, Kelley K, Sawyer JK, Rudel LL. Monounsaturated fatty acyl-coenzyme A is predictive of atherosclerosis in human apoB-100 transgenic, LDLr-/- mice. J Lipid Res. 2007 May;48(5):1122-31.

Ohshiro T, Namatame I, Nagai K, Sekiguchi T, Doi T, Takahashi T, Akasaka K, Rudel LL, Tomoda H, Omura S. Absolute stereochemistry of fungal beauveriolide III and ACAT inhibitory activity of four stereoisomers. J Org Chem. 2006 Sep 29;71(20):7643-9. 

Rudel LL, Farese RV Jr. ACAT inhibition and the progression of coronary atherosclerosis. N Engl J Med. 2006 Jun 15;354(24):2616-7; author reply 2616-7.

Bell TA 3rd, Brown JM, Graham MJ, Lemonidis KM, Crooke RM, Rudel LL. Liver-specific inhibition of acyl-coenzyme a:cholesterol acyltransferase 2 with antisense oligonucleotides limits atherosclerosis development in apolipoprotein B100-only low-density lipoprotein receptor-/- mice. Arterioscler Thromb Vasc Biol. 2006 Aug;26(8):1814-20.

Yu L, Bharadwaj S, Brown JM, Ma Y, Du W, Davis MA, Michaely P, Liu P, Willingham MC, Rudel LL. Cholesterol-regulated translocation of Niemann-pick C1-like 1 to the cell surface facilitates free cholesterol uptake. J Biol Chem. 2006 Mar 10;281(10):6616-24.

Shelness GS, Rudel LL. A role for the pregnane X receptor in high-density lipoprotein metabolism. Arterioscler Thromb Vasc Biol. 2005 Oct;25(10):2016-7.

Temel RE, Lee RG, Kelley KL, Davis MA, Shah R, Sawyer JK, Wilson MD, Rudel LL. Intestinal cholesterol absorption is substantially reduced in mice deficient in both ABCA1 and ACAT2. J Lipid Res. 2005 Nov;46(11):2423-31.

Zhao B, Fisher BJ, St Clair RW, Rudel LL, Ghosh S. Redistribution of macrophage cholesteryl ester hydrolase from cytoplasm to lipid droplets upon lipid loading. J Lipid Res. 2005 Oct;46(10):2114-21.

Pramfalk C, Davis MA, Eriksson M, Rudel LL, Parini P. Control of ACAT2 liver expression by HNF1. J Lipid Res. 2005 Sep;46(9):1868-76.

Rudel LL, Lee RG, Parini P. ACAT2 is a target for treatment of coronary heart disease associated with hypercholesterolemia. Arterioscler Thromb Vasc Biol. 2005 Jun;25(6):1112-8.

Lee RG, Shah R, Sawyer JK, Hamilton RL, Parks JS, Rudel LL. ACAT2 contributes cholesteryl esters to newly secreted VLDL, whereas LCAT adds cholesteryl ester to LDL in mice. J Lipid Res. 2005 Jun;46(6):1205-12.

Wallace JM, Schwarz M, Coward P, Houze J, Sawyer JK, Kelley KL, Chai A, Rudel LL. Effects of peroxisome proliferator-activated receptor alpha/delta agonists on HDL-cholesterol in vervet monkeys. J Lipid Res. 2005 May;46(5):1009-16.

Edwards IJ, Berquin IM, Sun H, O'flaherty JT, Daniel LW, Thomas MJ, Rudel LL, Wykle RL, Chen YQ. Differential effects of delivery of omega-3 fatty acids to human cancer cells by low-density lipoproteins versus albumin. Clin Cancer Res. 2004 Dec 15;10(24):8275-83.

Lee RG, Kelly KL, Sawyer JK, Farese RV Jr, Parks JS, Rudel LL. Plasma cholesteryl esters provided by lecithin:cholesterol acyltransferase and acyl-coenzyme A:cholesterol acyltransferase 2 have opposite atherosclerotic potential. Circ Res. 2004 Nov 12;95(10):998-1004.

Parini P, Davis M, Lada AT, Erickson SK, Wright TL, Gustafsson U, Sahlin S, Einarsson C, Eriksson M, Angelin B, Tomoda H, Omura S, Willingham MC, Rudel LL. ACAT2 is localized to hepatocytes and is the major cholesterol-esterifying enzyme in human liver. Circulation. 2004 Oct 5;110(14):2017-23.

Lada AT, Rudel LL. Associations of low density lipoprotein particle composition with atherogenicity. Curr Opin Lipidol. 2004 Feb;15(1):19-24.

Lada AT, Davis M, Kent C, Chapman J, Tomoda H, Omura S, Rudel LL. Identification of ACAT1- and ACAT2-specific inhibitors using a novel, cell-based fluorescent assay: evidence defining uniqueness for individual ACATs. J Lipid Res. 2004 Feb;45(2):378-86.

Temel RE, Gebre AK, Parks JS, Rudel LL. Compared with Acyl-CoA:cholesterol O-acyltransferase (ACAT) 1 and lecithin:cholesterol acyltransferase, ACAT2 displays the greatest capacity to differentiate cholesterol from sitosterol. J Biol Chem. 2003 Nov 28;278(48):47594-601.

Thorngate FE, Yancey PG, Kellner-Weibel G, Rudel LL, Rothblat GH, Williams DL. Testing the role of apoA-I, HDL, and cholesterol efflux in the atheroprotective action of low-level apoE expression. J Lipid Res. 2003 Dec; 44(12): 2331-8.

Ghosh S, St Clair RW, Rudel LL. Mobilization of cytoplasmic CE droplets by overexpression of human macrophage cholesteryl ester hydrolase. J Lipid Res. 2003 Oct;44(10):1833-40.

Parini P, Rudel LL. Is there a need for cholesteryl ester transfer protein inhibition? Arterioscler Thromb Vasc Biol. 2003 Mar 1;23(3):374-5.

Lada AT, Rudel LL, St Clair RW. Effects of LDL enriched with different dietary fatty acids on cholesteryl ester accumulation and turnover in THP-1 macrophages. J Lipid Res. 2003 Apr;44(4):770-9

Lada AT, Rudel LL. Dietary monounsaturated versus polyunsaturated fatty acids: which is really better for protection from coronary heart disease? Curr Opin Lipidol. 2003 Feb;14(1):41-6.

Willner EL, Tow B, Buhman KK, Wilson M, Sanan DA, Rudel LL, Farese RV Jr. Deficiency of acyl CoA:cholesterol acyltransferase 2 prevents atherosclerosis in apolipoprotein E-deficient mice. Proc Natl Acad Sci U S A. 2003 Feb 4;100(3):1262-7.

Schwenke DC, Rudel LL, Sorci-Thomas MG, Thomas MJ. alpha-Tocopherol protects against diet induced atherosclerosis in New Zealand white rabbits. J Lipid Res. 2002 Nov;43(11):1927-38.

Rudel LL, Davis M, Sawyer J, Shah R, Wallace J. Primates highly responsive to dietary cholesterol ip-regulate hepatic ACAT2, and less responsive primates do not. J Biol Chem. 2002 Aug 30;277(35):31401-6.

Rudel LL. Preclinical and clinical pharmacology of a new class of lipid management agents. Am J Manag Care. 2002 Feb;8(2 Suppl):S33-5; discussion S45-7. Review.

Fusegawa Y, Kelley KL, Sawyer JK, Shah RN, Rudel LL. Influence of dietary fatty acid composition on the relationship between CETP activity and plasma lipoproteins in monkeys. J Lipid Res. 2001 Nov;42(11):1849-57.

Edwards IJ, Rudel LL, Terry JG, Kemnitz JW, Weindruch R, Zaccaro DJ, Cefalu WT. Caloric restriction lowers plasma lipoprotein (a) in male but not female rhesus monkeys. Exp Gerontol. 2001 Aug;36(8):1413-8.

Huggins KW, Colvin PL, Burleson ER, Kelley K, Sawyer JK, Barrett PH, Rudel LL, Parks JS. Dietary n-3 polyunsaturated fat increases the fractional catabolic rate of medium-sized HDL particles in African green monkeys. J Lipid Res. 2001 Sep;42(9):1457-66.

Thomas MJ, Chen Q, Sorci-Thomas MG, Rudel LL. Isoprostane levels in lipids extracted from atherosclerotic arteries of nonhuman primates. Free Radic Biol Med. 2001 Jun 15;30(12):1337-46.

DeMattos RB, Rudel LL, Williams DL. Biochemical analysis of cell-derived apoE3 particles active in stimulating neurite outgrowth. J Lipid Res. 2001 Jun;42(6):976-87.

Thomas MJ, Chen Q, Zabalawi M, Anderson R, Wilson M, Weinberg R, Sorci-Thomas MG, Rudel LL. Is the oxidation of high-density lipoprotein lipids different than the oxidation of low-density lipoprotein lipids? Biochemistry. 2001 Feb 13;40(6):1719-24.

Kris-Etherton P, Daniels SR, Eckel RH, Engler M, Howard BV, Krauss RM, Lichtenstein AH, Sacks F, St Jeor S, Stampfer M, Grundy SM, Appel LJ, Byers T, Campos H, Cooney G, Denke MA, Kennedy E, Marckmann P, Pearson TA, Riccardi G, Rudel LL, Rudrum M, Stein DT, Tracy RP, Ursin V, Vogel RA, Zock PL, Bazzarre TL, Clark J. AHA scientific statement: summary of the Scientific Conference on Dietary Fatty Acids and Cardiovascular Health. Conference summary from the Nutrition Committee of the American Heart Association. J Nutr. 2001 Apr;131(4):1322-6.

Rudel LL, Lee RG, Cockman TL. Acyl coenzyme A: cholesterol acyltransferase types 1 and 2: structure and function in atherosclerosis. Curr Opin Lipidol. 2001 Apr;12(2):121-7.