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

Sterol O-Acyltransferase; Cholesterol; Cholesterol Esters; Atherosclerosis; Liver
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Contact Information

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

Email: lrudel@wakehealth.edu

Recent Publications

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

Localization of APOL1 protein and mRNA in the human kidney: nondiseased tissue, primary cells, and immortalized cell lines. 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.. J Am Soc Nephrol. 2015;26(2):339-348.

High-oleic canola oil consumption enriches LDL particle cholesteryl oleate content and reduces LDL proteoglycan binding in humans. 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.. Atherosclerosis. 2015;238(2):231-238.

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

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. Lopez AM, Chuang JC, Posey KS, Ohshiro T, Tomoda H, Rudel LL, Turley SD.. J Pharmacol Exp Ther. 2015;355(2):159-167.

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

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

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

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

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

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

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]. 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.. FASEB J. 2014;28(1 Suppl):269.5.

ACAT inhibition reduces the progression of preexisting, advanced atherosclerotic mouse lesions without plaque or systemic toxicity. 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.. Arterioscler Thromb Vasc Biol. 2013;33(1):4-12.

An ACACB variant implicated in diabetic nephropathy associates with body mass index and gene expression in obese subjects. 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,.. PLoS One. 2013;8(2):e56193.

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

Intestinal SR-BI does not impact cholesterol absorption or transintestinal cholesterol efflux in mice. 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.. J Lipid Res. 2013;54(6):1567-1577.

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

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

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

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

ApoL1 protein in non-diseased human podocytes: endogenous synthesis versus uptake? [abstract]. 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.. J Am Soc Nephrol. 2013;24(Abstract Suppl):557A.

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

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

Monocyte tissue factor-dependent activation of coagulation in hypercholesterolemic mice and monkeys is inhibited by simvastatin. 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.. J Clin Invest. 2012;122(2):558-568.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Combined therapy of dietary fish oil and stearoyl-CoA desaturase 1 inhibition prevents the metabolic syndrome and atherosclerosis. 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.. Arterioscler Thromb Vasc Biol. 2010;30(1):24-30.

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

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

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

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

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

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

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

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

Dietary omega-3 fatty acids shift plasma and hepatic lipid metabolism in a mouse model of atherosclerosis within the first day of treatment [abstract]. Degirolamo C, Kelley KL, Wilson MD, Rudel LL.. 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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