Profile

Lawrence L. Rudel, Ph.D.Wake Forest School of Medicine

Lawrence L. Rudel, Ph.D.

Professor,

Contact Information

Academic: 336-716-2823 | Department: 336-716-2823

Email: lrudel@wakehealth.edu

Education & Training

  • B.S., Colorado State University, 1963
  • M.S., Univ Of Arkansas For Medical Sci, 1965
  • Ph.D., Univ Of Arkansas For Medical Sci, 1969
  • Fellowship, University Toronto Med-Canada, 1971
  • Fellowship, University of California-San F, 1973

Memberships

  • Am Assn Of Advancement Of Scie
  • Am Assn Of Pathologists
  • Aha - Council On Arteriosclero
Lawrence L. Rudel, Ph.D.

Lawrence L. Rudel, Ph.D.

Professor, Molecular Medicine

Research Interests

atherosclerosis/thrombosis, drugs/therapeutic agents pharm, metabolism, model development, molecular biology/molecular me

Contact Information

Academic: 336-716-2823 | Department: 336-716-2823

Email: lrudel@wakehealth.edu

Recent Publications

Warrier M, Zhang J, Bura K, Kelley K, Wilson MD, Rudel LL, Brown JM. Sterol o-acyltransferase 2-driven cholesterol esterification opposes liver X receptor-stimulated fecal neutral sterol loss. Lipids. 2016;51(2):151-157.

Ma L, Shelness GS, Snipes JA, Murea M, Antinozzi PA, Cheng D, Saleem MA, Satchell SC, Banas B, Mathieson PW, Kretzler M, Hemal AK, Rudel LL, Petrovic S, Weckerle A, Pollak MR, Ross MD, Parks JS, Freedman BI. Localization of APOL1 protein and mRNA in the human kidney: nondiseased tissue, primary cells, and immortalized cell lines. J Am Soc Nephrol. 2015;26(2):339-348.

Jones PJ, MacKay DS, Senanayake VK, Pu S, Jenkins DJ, Connelly PW, Lamarche B, Couture P, Kris-Etherton PM, West SG, Liu X, Fleming JA, Hantgan RR, Rudel LL. High-oleic canola oil consumption enriches LDL particle cholesteryl oleate content and reduces LDL proteoglycan binding in humans. Atherosclerosis. 2015;238(2):231-238.

Melchior JT, Olson JD, Kelley KL, Wilson MD, Sawyer JK, Link KM, Rudel LL. Targeted knockdown of hepatic SOAT2 with antisense oligonucleotides stabilizes atherosclerotic plaque in ApoB100-only LDLr-/- mice. Arterioscler Thromb Vasc Biol. 2015;35(9):1920-1927.

Lopez AM, Chuang JC, Posey KS, Ohshiro T, Tomoda H, Rudel LL, Turley SD. PRD125, a potent and selective inhibitor of sterol O-acyltransferase 2 markedly reduces hepatic cholesteryl ester accumulation and improves liver function in lysosomal acid lipase-deficient mice. J Pharmacol Exp Ther. 2015;355(2):159-167.

Ohshiro T, Ohtawa M, Nagamitsu T, Matsuda D, Yagyu H, Davis M, Rudel L, Ishibashi S, Tomoda H. New pyripyropene A derivatives, highly SOAT2-selective inhibitors, improve hypercholesterolemia and atherosclerosis in atherogenic mouse models. J Pharmacol Exp Ther. 2015;355(2):299-309.

Marshall SM, Kelley KL, Davis MA, Wilson MD, McDaniel AL, Lee RG, Crooke RM, Graham MJ, Rudel LL, Brown JM, Temel RE. Reduction of VLDL secretion decreases cholesterol excretion in niemann-pick C1-like 1 hepatic transgenic mice. PLoS One. 2014;9(1):e84418.

Marshall SM, Gromovsky AD, Kelley KL, Davis MA, Wilson MD, Lee RG, Crooke RM, Graham MJ, Rudel LL, Brown JM, Temel RE. Acute sterol o-acyltransferase 2 (SOAT2) knockdown rapidly mobilizes hepatic cholesterol for fecal excretion. PLoS One. 2014;9(6):e98953.

Iqbal J, Boutjdir M, Rudel LL, Hussain MM. Intestine specific MTP deficiency with global ACAT2 gene ablation lowers acute cholesterol absorption with chylomicrons and HDLs. J Lipid Res. 2014;55(11):2261-2275.

Medina MW, Bauzon F, Naidoo D, Theusch E, Stevens K, Schilde J, Schubert C, Mangravite LM, Rudel LL, Temel RE, Runz H, Krauss RM. Transmembrane protein 55B is a novel regulator of cellular cholesterol metabolism. Arterioscler Thromb Vasc Biol. 2014;34(9):1917-1923.

Zhang J, Sawyer JK, Marshall SM, Kelley KL, Davis MA, Wilson MD, Brown JM, Rudel LL. Cholesterol esters (CE) derived from hepatic sterol O-acyltransferase 2 (SOAT2) are associated with more atherosclerosis than CE from intestinal SOAT2. Circ Res. 2014;115(10):826-833.

Jones P, Rudel L, Sawyer J, Hantgan R, Rempel J, Pu SH, Kris-Etherton P, Liu XR, West S, Couture P, Lamarche B, Jenkins D. Effects of high oleic canola oil-rich feeding on in vitro LDL proteoglycan binding affinity in individuals with at least two criteria for metabolic syndrome [abstract]. FASEB J. 2014;28(1 Suppl):269.5.

Rong JX, Blachford C, Feig JE, Bander I, Mayne J, Kusunoki J, Miller C, Davis M, Wilson M, Dehn S, Thorp E, Tabas I, Taubman MB, Rudel LL, Fisher EA. ACAT inhibition reduces the progression of preexisting, advanced atherosclerotic mouse lesions without plaque or systemic toxicity. Arterioscler Thromb Vasc Biol. 2013;33(1):4-12.

Ma L, Murea M, Snipes JA, Marinelarena A, Kruger J, Hicks PJ, Langberg KA, Bostrom MA, Cooke JN, Suzuki D, Babazono T, Uzu T, Tang SC, Mondal AK, Sharma NK, Kobes S, Antinozzi PA, Davis M, Das SK, Rasouli N, Kern PA,. An ACACB variant implicated in diabetic nephropathy associates with body mass index and gene expression in obese subjects. PLoS One. 2013;8(2):e56193.

Ohtawa M, Yamazaki H, Ohte S, Matsuda D, Ohshiro T, Rudel LL, Omura S, Tomoda H, Nagamitsu T. Synthesis and structure-activity relationship of pyripyropene A derivatives as potent and selective acyl-CoA:cholesterol acyltransferase 2 (ACAT2) inhibitors: part 1. Bioorg Med Chem Lett. 2013;23(5):1285-1287.

Bura KS, Lord C, Marshall S, McDaniel A, Thomas G, Warrier M, Zhang J, Davis MA, Sawyer JK, Shah R, Wilson MD, Dikkers A, Tietge UJ, Collet X, Rudel LL, Temel RE, Brown JM. Intestinal SR-BI does not impact cholesterol absorption or transintestinal cholesterol efflux in mice. J Lipid Res. 2013;54(6):1567-1577.

McDaniel AL, Alger HM, Sawyer JK, Kelley KL, Kock ND, Brown JM, Temel RE, Rudel LL. Phytosterol feeding causes toxicity in ABCG5/G8 knockout mice. Am J Pathol. 2013;182(4):1131-1138.

Ohtawa M, Yamazaki H, Matsuda D, Ohshiro T, Rudel LL, Omura S, Tomoda H, Nagamitsu T. Synthesis and structure-activity relationship of pyripyropene A derivatives as potent and selective acyl-CoA:cholesterol acyltransferase 2 (ACAT2) inhibitors: part 2. Bioorg Med Chem Lett. 2013;23(9):2659-2662.

Ohtawa M, Yamazaki H, Ohte S, Matsuda D, Ohshiro T, Rudel LL, Omura S, Tomoda H, Nagamitsu T. Synthesis and structure-activity relationship of pyripyropene A derivatives as potent and selective acyl-CoA:cholesterol acyltransferase 2 (ACAT2) inhibitors: part 3. Bioorg Med Chem Lett. 2013;23(13):3798-3801.

Voruganti VS, Jorgensen MJ, Kaplan JR, Kavanagh K, Rudel LL, Temel R, Fairbanks LA, Comuzzie AG. Significant genotype by diet (G X D) interaction effects on cardiometabolic responses to a pedigree-wide, dietary challenge in vervet monkeys (Chlorocebus aethiops sabaeus). Am J Primatol. 2013;75(5):491-499.

Ma L, Snipes JA, Murea M, Antinozzi PA, Shelness GS, Saleem M, Satchell SC, Banas B, Mathieson PW, Kretzler M, Petrovic S, Ross MD, Pollak MR, Rudel L, Parks JS, Freedman BI. ApoL1 protein in non-diseased human podocytes: endogenous synthesis versus uptake? [abstract]. J Am Soc Nephrol. 2013;24(Abstract Suppl):557A.

Melchior JT, Sawyer JK, Kelley KL, Shah R, Wilson MD, Hantgan RR, Rudel LL. LDL particle core enrichment in cholesteryl oleate increases proteoglycan binding and promotes atherosclerosis. J Lipid Res. 2013;54(9):2495-2503.

Nguyen TM, Sawyer JK, Kelley KL, Davis MA, Rudel LL. Cholesterol esterification by ACAT2 is essential for efficient intestinal cholesterol absorption: evidence from thoracic lymph duct cannulation. J Lipid Res. 2012;53(1):95-104.

Owens AP III, Passam RH, Antoniak S, Marshall SM, McDaniel AL, Rudel L, Williams JC, Hubbard BK, Dutton J-A, Wang J, Tobias PS, Curtiss LK, Daugherty A, Kirchhofer D, Luyendyk JP, Moriarty PM, Nagarajan S, Furie BC, Furie B, Johns DG, Temel RE, Mackman N. Monocyte tissue factor-dependent activation of coagulation in hypercholesterolemic mice and monkeys is inhibited by simvastatin. J Clin Invest. 2012;122(2):558-568.

Miller CD, Thomas MJ, Hiestand B, Samuel MP, Wilson MD, Sawyer J, Rudel LL. Cholesteryl esters associated with acyl-CoA:cholesterol acyltransferase-2 predict coronary arter stenosis in patients with symptoms of acute coronary syndrome [abstract]. Acad Emerg Med. 2012;19(Suppl 1):S150.

Baum SJ, Kris-Etherton PM, Willett WC, Lichtenstein AH, Rudel LL, Maki KC, Whelan J, Ramsden CE, Block RC. Fatty acids in cardiovascular health and disease: a comprehensive update. J Clin Lipidol. 2012;6(3):216-234.

Miller CD, Thomas MJ, Hiestand B, Samuel MP, Wilson MD, Sawyer J, Rudel LL. Cholesteryl esters associated with Acyl-CoA:cholesterol acyltransferase predict coronary artery disease in patients with symptoms of acute coronary syndrome. Acad Emerg Med. 2012;19(6):673-682.

Zhang J, Kelley KL, Marshall SM, Davis MA, Wilson MD, Sawyer JK, Farese RV Jr, Brown JM, Rudel LL. Tissue-specific knockouts of ACAT2 reveal that intestinal depletion is sufficient to prevent diet-induced cholesterol accumulation in the liver and blood. J Lipid Res. 2012;53(6):1144-1152.

Nguyen TM, Sawyer JK, Kelley KL, Davis MA, Kent CR, Rudel LL. ACAT2 and ABCG5/G8 are both required for efficient cholesterol absorption in mice: evidence from thoracic lymph duct cannulation. J Lipid Res. 2012;53(8):1598-1609.

Jorgensen MJ, Rudel LL, Kavanagh K, Jasinska AJ, Freimer NB, Jentsch JD, Fairbanks LA, Fallon MT, Kaplan JR. The vervet research colony as a biomedical resource [abstract]. Am J Primatol. 2012;74(Suppl 1):68.

Jorgensen MJ, Rudel LL, Nudy M, Kaplan JR, Clarkson TB, Pajewski NM, Schnatz PF. 25(OH)D3 and cardiovascular risk factors in female nonhuman primates. J Womens Health. 2012;21(9):959-965.

Brown JM, Martinez K, Betters J, Shores N, Rudel LL, McIntosh MK, Thomas G. Regulation of the alpha beta hydrolase domain (ABHD) protein family in murine and human obesity [abstract]. FASEB J. 2012;26():597.4.

Shores NJ, Fernandez AZ, Tam NC, DAvis M, Wilson M, Sawyer JK, Rudel L. Hepatic cholesterol ester--not free cholesterol--is associated with steatohepatitis (NASH) in human beings [abstract]. Hepatology. 2012;56(Suppl 1):845A.

Medina MW, Gao F, Naidoo D, Rudel LL, Temel RE, McDaniel AL, Marshall SM, Krauss RM. Coordinately regulated alternative splicing of genes involved in cholesterol biosynthesis and uptake. PLoS ONE. 2011;6(4):e19420.

Sun H, Hu Y, Gu Z, Wilson MD, Chen YQ, Rudel LL, Willingham MC, Edwards IJ. Endogenous synthesis of n-3 polyunsaturated fatty acids in fat-1 mice is associated with increased mammary gland and liver syndecan-1. PLoS ONE. 2011;6(5):e20502.

Ohshiro T, Matsuda D, Sakai K, Degirolamo C, Yagyu H, Rudel LL, Omura S, Ishibashi S, Tomoda H. Pyripyropene A, an acyl-coenzyme A:cholesterol acyltransferase 2-selective inhibitor, attenuates hypercholesterolemia and atherosclerosis in murine models of hyperlipidemia. Arterioscler Thromb Vasc Biol. 2011;31(5):1108-1115.

Shores NJ, Link K, Fernandez A, Geisinger KR, Davis M, Nguyen T, Sawyer J, Rudel L. Non-contrasted computed tomography for the accurate measurement of liver steatosis in obese patients. Dig Dis Sci. 2011;56(7):2145-2151.

Voruganti V, Jorgensen MJ, Kaplan JR, Kauanagh K [sic] [Kavanagh K], Rudel LL, Temel R, Fairbanks LA, Comuzzie AG. Significant genotype by diet (GXD) interaction effects on cardiometabolic responses to a pedigree-wide, dietary challenge in Vervet monkeys (Chlorocebus aethiops sabaeus) [abstract]. Am J Primatol. 2011;73(Suppl 1):84.

Jorgensen MJ, Schnatz PF, Rudel LL, Nudy M, Kaplan JR, Clarkson TB. Low plasma concentrations of vitamin D3 are associated with increased cardiovascular risk factors in a female nonhuman primate model [abstract]. Menopause. 2011;18(12):1345.

Pedrelli M, Davoodpour P, Degirolamo C, Gomaraschi M, Larsson L, Rudel LL, Calabresi L, Gustafsson JA, Steffensen K, Eriksson M, Parini P. The inhibition of hepatic acyl coenzyme A:cholesterol acyltransferase (ACAT) 2 positively affects HDL metabolism and functionality in mice [abstract]. Atheroscler Suppl. 2011;12(1):39.

Brown JM, Chung S, Sawyer JK, Degirolamo C, Alger HM, Zhu X, Brown AL, Shah R, Davis MA, Kelley K, Wilson MD, Parks JS, Rudell LL, et al. Combined therapy of dietary fish oil and stearoyl-CoA desaturase 1 inhibition prevents the metabolic syndrome and atherosclerosis. Arterioscler Thromb Vasc Biol. 2010;30(1):24-30.

Chung S, Timmins JM, Duong M, Degirolamo C, Rong S, Sawyer JK, Singaraja RR, Rudel LL, Shelness GS, Parks JS, et al. Targeted deletion of hepatocyte ABCA1 leads to very low density lipoprotein triglyceride overproduction and low density lipoprotein hypercatabolism. J Biol Chem. 2010;285(16):12197-209.

Alger HM, Brown JM, Sawyer JK, Kelley KL, Shah R, Wilson MD, Willingham MC, Rudel LL. Inhibition of acyl-coenzyme A:cholesterol acyltransferase 2 (ACAT2) prevents dietary cholesterol-associated steatosis by enhancing hepatic triglyceride mobilization. J Biol Chem. 2010;285(19):14267-74.

Brown JM, Rudel LL. Stearoyl-coenzyme A desaturase 1 inhibition and the metabolic syndrome: considerations for future drug discovery. Curr Opin Lipidol. 2010;21(3):192-197.

Kavanagh K, Sajadian S, Jenkins KA, Wilson MD, Carr JJ, Wagner JD, Rudel LL. Neonatal and fetal exposure to trans-fatty acids retards early growth and adiposity while adversely affecting glucose in mice. Nutr Res. 2010;30(6):418-426.

Degirolamo C, Kelley KL, Wilson MD, Rudel LL. Dietary n-3 LCPUFA from fish oil but not alpha-linolenic acid-derived LCPUFA confers atheroprotection in mice. J Lipid Res. 2010;51(7):1897-1905.

Temel RE, Sawyer JK, Yu L, Lord C, Degirolamo C, McDaniel A, Marshall S, Wang N, Shah R, Rudel LL, Brown JM. Biliary sterol secretion is not required for macrophage reverse cholesterol transport. Cell Metab. 2010;12(1):96-102.

Madenspacher JH, Draper DW, Smoak KA, Li H, Griffiths GL, Suratt BT, Wilson MD, Rudel LL, Fessler MB. Dyslipidemia induces opposing effects on intrapulmonary and extrapulmonary host defense through divergent TLR response phenotypes. J Immunol. 2010;185(3):1660-1669.

Degirolamo C, Rudel LL. Dietary monounsaturated fatty acids appear not to provide cardioprotection. Curr Atheroscler Rep. 2010;12(6):391-396.

Degirolamo C, Kelley KL, Wilson MD, Rudel LL. Dietary omega-3 fatty acids shift plasma and hepatic lipid metabolism in a mouse model of atherosclerosis within the first day of treatment [abstract]. Arterioscler Thromb Vasc Biol. 2010;30(11):e248.

All Publications

For a listing of recent publications, refer to PubMed, a service provided by the National Library of Medicine.

For a list of earlier publications, visit the Carpenter Library Publication Search.

Lawrence L. Rudel, Ph.D.

Lawrence L. Rudel, Ph.D.

Professor, Molecular Medicine

Contact Information

Academic: 336-716-2823 | Department: 336-716-2823

Email: lrudel@wakehealth.edu

Current Research:

Cholesterol and Lipoprotein Metabolism Studies using Primate and Mouse Models

Complications arising from coronary heart disease (CHD) 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 have followed these studies by developing genetically engineered mouse models that allow us to evaluate selected gene targets.  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 in our animal models.  Other factors in cholesterol metabolism also contribute. 

Pathways regulating plasma lipoprotein concentrations as affected by dietary cholesterol and fatty acid type are under study. Further, the monkey experiments have shown that lipoprotein particle composition, i.e. increased LDL cholesteryl oleate content, is consistently 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 to be acyl-CoA:cholesterol acyltransferase 2 (ACAT2), also termed steryl 0-acyl transferase 2 (SOAT2). This enzyme has been cloned, expressed, and its regulation by cholesterol and fatty acids is under investigation. Mouse models of SOAT2 deletion and tissue specific expression have been valuable in defining the essential role of this enzyme in lipoprotein metabolic pathways associated with atherogenesis.  Promotion of LDL particle retention in the intima of arteries has been a demonstrated consequence of cholesterol oleate enrichment. 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 controlling hepatic cholesterol metabolism, particularly SOAT2, 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, and subsequently evaluating the role of specific enzymes and pathways in genetically engineered mouse models, we are providing information that hopefully will be helpful in development of strategies for prevention and treatment of coronary heart disease. We have begun translational studies by evaluating selective small molecule SOAT2 inhibitors with the hope that compounds will be identified that can eventually prove useful in treatment of CHD patients. 

LL Rudel: Figure 1

Figure 1: The role of ACAT1 and ACAT2 in cholesterol metabolism

Publications:

Link to PubMed Database

 

 

  

 

Lawrence L. Rudel, Ph.D.

Lawrence L. Rudel, Ph.D.

Professor, Molecular Medicine

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