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Research in Lipid Sciences
Dr. John Parks

John S. Parks, PhD

Professor of Pathology (Lipid Sciences)
Tel: (336) 716-2145
Fax: (336) 716-6279
jparks@wfubmc.edu

Education:
  • Undergraduate: North Carolina State University, BS, 1973
  • Postgraduate: Wake Forest University, MS 1976; PhD, 1979
  • Fellowship: Boston University School of Medicine, 1979-81
Interests:
  • Teaching: Lipoprotein Metabolism and Structure, Lipoprotein Modifying Enzymes
  • Research: High Density Lipoprotein (HDL) Formation and Catabolism, Molecular Mechanisms by which Lecithin:Colesterol Acyltransferase (LCAT) Prevents Atherosclerosis, Molecular Mechanisms by which Botanical Oils and Fish Oil Impact Atherosclerosis and Inflammation 
Current Research: 1)The Role of ABCA1 in HDL Subfraction Formation and Catabolism; 2) Lecithin:Cholesterol Acyltransferase, Lipids, and Atherosclerosis; and 3) Echium Oil, Triglyceride Metabolism and Atherosclerosis 

My lab has three National Institutes of Health (NIH)-funded projects that focus on the interrelationships of lipoprotein metabolism, dietary fat type, inflammation, and atherosclerosis (i.e., hardening of the arteries). To accomplish the goals of our grant projects we use an interdisciplinary approach that includes transgenic/gene targeted mouse models, molecular biology, cell biology, biochemistry, mass spectrometry, and vascular wall biology.

In the first project, which is part of a Program Project Grant from the National Heart, Lung, and Blood Institute (NHLBI) of the NIH, we seek to understand the role of tissue specific expression of ATP binding cassette transporter A1 (ABCA1) in high density lipoprotein (HDL) metabolism and atherosclerosis development. HDLs are referred to as the “good cholesterol” and are protective against the development of atherosclerosis. HDLs are formed by the interaction of apoA-I, the major protein on HDL particles, with a lipid transporter on cell surfaces known as ABCA1. Individuals with a genetic deficiency of ABCA1 have Tangier disease, which is characterized by plasma HDL concentrations that are <5% of normal and accumulation of cholesterol in peripheral tissues. Using gene targeting techniques, we have developed tissue specific deletions of ABCA1 protein. We are currently studying the effect of tissue specific deletion of ABCA1 on HDL formation and catabolism, and on atherosclerosis development. [See Press Releases 3/16/2006 and 4/8/2005 and publications listed below].

In the second project, which is funded by an R01 grant from NHLBI of the NIH, we are investigating the molecular mechanisms by which LCAT expression influences atherosclerosis development. LCAT is an enzyme that makes cholesterol esters in plasma; cholesterol esters are the lipid that accumulates in arteries during atherosclerosis, leading to lumen stenosis. We have found in previous studies that elimination of LCAT activity in plasma by gene targeting increases arterial cholesterol ester deposition in a mouse model of atherosclerosis, which is a paradox since LCAT makes cholesterol esters. The goal of this grant is to elucidate the molecular mechanisms that account for the protective effect of LCAT with regard to atherosclerosis. We are testing a novel hypothesis that LCAT is athero-protective by multiple mechanisms that include altering the fatty acid composition of cholesterol esters in plasma and in arterial plaques as well a decreasing the inflammatory response of cells in arteries. Experiments in this project rely extensively on gene targeted and transgenic mouse models as well as molecular and cell biology techniques.

The third project is part of an NIH-funded Botanical Research Center, one of only five in the United States. The goal of the Center for Botanical Lipids is to explore the molecular mechanisms by which botanical lipid supplements affect the development of chronic diseases, such as asthma and atherosclerosis. My project is designed to elucidate the molecular mechanism by which a botanical oil (Echium oil) that is enriched in n-3 fatty acids reduces plasma triglycerides concentrations and whether supplementation with Echium oil will reduce atherosclerosis and arterial inflammation to a degree similar to that observed with fish oil. This project will also rely heavily on an interdisciplinary approach to experimentation that makes use of molecular and cell biology techniques and in vivo studies in gene targeted and transgenic mice. [Link] 

Verhoeff-van Gieson-stained cross-sections of aortas from mice of the indicated genotypes after 16 weeks of atherogenic diet consumption.

Figure Legend: Verhoeff-van Gieson-stained cross-sections of aortas from mice of the indicated genotypes after 16 weeks of atherogenic diet consumption. A 3-mm section was taken from the aorta just distal to the origin of the left subclavian artery for histological evaluation. Sections are representative of the extent and severity of atherosclerosis among the four experimental groups. LDLr-/-, low density lipoprotein receptor knockout mouse; apoE-/-, apolipoprotein E knockout mouse; LCAT-/-, lecithin:cholesterol acyltransferase knockout mouse. Double knockout mice of the indicated genotypes are shown in the bottom panel. Note the more extensive aortic artery blockage by atherosclerotic plaque in the double knockout mice compare to its single knockout control (i.e., apoE-/- LCAT-/- vs. apoE-/-).
Recent Publications:

Bensinger SJ, Bradley MN, Joseph SB, Zelcer N, Janssen EM, Hausner MA, Shih R, Parks JS, Edwards PA, Jamieson BD, Tontonoz P. LXR Signaling Couples Sterol Metabolism to Proliferation in the Acquired Immune Response. Cell. 2008 Jul 11;134(1):97-111.

Mulya A, Lee JY, Gebre AK, Boudyguina EY, Chung SK, Smith TL, Colvin PL, Jiang XC, Parks JS. Initial interaction of ApoA-I with ATP binding cassette transporter A1 (ABCA1) impacts in vivo metabolic fate of nascent HDL. J Lipid Res; 2008 Jun 25; [Epub ahead of print].

Zhu X, Lee JY, Timmins JM, Brown JM, Boudyguina E, Mulya A, Gebre AK, Willingham MC, Hiltbold EM, Mishra N, Maeda N, Parks JS. Increased cellular free cholesterol in macrophage-specific Abca1 knockout mice enhances pro-inflammatory response of macrophages. J Biol Chem. 2008 Jun 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.

Zhang P, Boudyguina E, Wilson MD, Gebre AK, Parks JS. Echium oil reduces plasma lipids and hepatic lipogenic gene expression in apoB100-only LDL receptor knockout mice. J Nutr Biochem. 2007 Dec 20; [Epub ahead of print]

Wu Z, Wagner MA, Zheng L, Parks JS, Shy JM 3rd, Smith JD, Gogonea V, Hazen SL. The refined structure of nascent HDL reveals a key functional domain for particle maturation and dysfunction.  Nat Struct Mol Biol. 2007 Sep;14(9):861-8.

Mulya A, Lee JY, Gebre AK, Thomas MJ, Colvin PL, Parks JS. Minimal Lipidation of Pre-{beta} HDL by ABCA1 Results in Reduced Ability to Interact with ABCA1. Arterioscler Thromb Vasc Biol. 2007 Aug;27(8):1828-36.

Brunham LR, Kruit JK, Pape TD, Timmins JM, Reuwer AQ, Vasanji Z, Marsh BJ, Rodrigues B, Johnson JD, Parks JS, Verchere CB, Hayden MR. beta-cell ABCA1 influences insulin secretion, glucose homeostasis and response to thiazolidinedione treatment. Nat Med. 2007 Mar;13(3):340-7. 

Lee JY, Badeau RM, Mulya A, Boudyguina E, Gebre AK, Smith TL, Parks JS. Functional LCAT deficiency in human apolipoprotein A-I transgenic, SR-BI knockout mice. J Lipid Res. 2007 May;48(5):1052-61.

Brunham LR, Kruit JK, Pape TD, Parks JS, Kuipers F, Hayden MR. Tissue-Specific Induction of Intestinal ABCA1 Expression With a Liver X ReceptorAgonist Raises Plasma HDL Cholesterol Levels. Circ Res. 2006 Sep 29;99(7):672-4.

Singaraja RR, Van Eck M, Bissada N, Zimetti F, Collins HL, Hildebrand RB, Hayden A, Brunham LR, Kang MH, Fruchart JC, Van Berkel TJ, Parks JS, Staels B, Rothblat GH, Fievet C, Hayden MR.  Both Hepatic and Extrahepatic ABCA1 Have Discrete and Essential Functions in the Maintenance of Plasma High-Density Lipoprotein Cholesterol Levels In Vivo. Circulation. 2006 Sep 19;114(12):1301-9.

Singaraja RR, Stahmer B, Brundert M, Merkel M, Heeren J, Bissada N, Kang M, Timmins JM, Ramakrishnan R, Parks JS, Hayden MR, Rinninger F. Hepatic ATP-Binding Cassette Transporter A1 Is a Key Molecule in High-Density Lipoprotein Cholesteryl Ester Metabolism in Mice. Arterioscler Thromb Vasc Biol. 2006 Aug;26(8):1821-7.

Mauldin JP, Srinivasan S, Mulya A, Gebre A, Parks JS, Daugherty A, Hedrick CC. Reduction in ABCG1 in type 2 diabetic mice increases macrophage foam cell formation. J Biol Chem. 2006 Jul 28:281(30):21216-24.

Brunham LR, Kruit JK, Iqbal J, Fievet C, Timmins JM, Pape TD, Coburn BA, Bissada N, Staels B, Groen AK, Hussain MM, Parks JS, Kuipers F, Hayden MR. Intestinal ABCA1 directly contributes to HDL biogenesis in vivo. J Clin Invest. 2006 Apr;116(4):1052-62.

Lee JY, Timmins JM, Mulya A, Smith TL, Zhu Y, Rubin EM, Chisholm JW, Colvin PL, Parks JS. HDLs in apoA-I transgenic Abca1 knockout mice are remodeled normally in plasma but are hypercatabolized by the kidney. J Lipid Res. 2005 Oct;46(10):2233-45.

Timmins JM, Li JY, Boudyguina E, Kluckman KD, Brunham LR, Mulya A, Gebre AK, Coutinho JM, Colvin PL, Smith TL, Hayden MR, Maeda N, Parks JS. Targeted inactivation of hepatic Abca1 causes profound hypoalphalipoproteinemia and kidney hypercatabolism of apoA-I. J Clin Invest. 2005 May;115(5):1333-42.

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

Zhao Y, Thorngate FE, Weisgraber KH, Williams DL, Parks JS. Apolipoprotein E Is the Major Physiological Activator of Lecithin-Cholesterol Acyltransferase (LCAT) on Apolipoprotein B Lipoproteins. Biochemistry. 2005 Jan 25;44(3):1013-1025.

Lee JY, Parks JS. ATP-binding cassette transporter AI and its role in HDL formation. Curr Opin Lipidol. 2005 Feb;16(1):19-25.

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.

Matthan NR, Welty FK, Barrett PH, Harausz C, Dolnikowski GG, Parks JS, Eckel RH, Schaefer EJ, Lichtenstein AH. Dietary hydrogenated fat increases high-density lipoprotein apoA-I catabolism and decreases low-density lipoprotein apoB-100 catabolism in hypercholesterolemic women. Arterioscler Thromb Vasc Biol. 2004 Jun;24(6):1092-7.

Lee JY, Lanningham-Foster L, Boudyguina EY, Smith TL, Young ER, Colvin PL, Thomas MJ, Parks JS. Pre-beta high density lipoprotein has two metabolic fates in human apolipoprotein A-I transgenic mice. J Lipid Res. 2004 Apr;45(4):716-728.

Zhao Y, Wang J, Gebre AK, Chisholm JW, Parks JS. Negative charge at amino acid 149 is the molecular determinant for substrate specificity of lecithin: cholesterol acyltransferase for phosphatidylcholine containing 20-carbon sn-2 fatty acyl chains. Biochemistry. 2003 Dec 2;42(47):13941-9.

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.

Malloy SI, Altenburg MK, Knouff C, Lanningham-Foster L, Parks JS, Maeda N. Harmful effects of increased LDLR expression in mice with human APOE*4 but not APOE*3. Arterioscler Arterioscler Thromb Vasc Biol. 2004 Jan; 24(1): 91-7.

Shelness GS, Hou L, Ledford AS, Parks JS, Weinberg RB. Identification of the lipoprotein initiating domain of apolipoprotein BI. J Biol Chem. 2003 278: 44702-44707.

Dawson PA, Haywood J, Craddock AL, Wilson M, Tietjen M, Kluckman K, Maeda N, Parks JS. Targeted deletion of the ileal bile acid transporter eliminates enterohepatic cycling of bile acids in mice. J Biol Chem. 2003 Sep 5;278(36):33920-7.

Temel RE, Parks JS, Williams DL. Enhancement of scavenger receptor class B type I-mediated selective cholesteryl ester uptake from apoA-I(-/-) high density lipoprotein (HDL) by apolipoprotein A-I requires HDL reorganization by lecithin cholesterol acyltransferase. J Biol Chem. 2003 Feb 14;278(7):4792-9.

Huggins KW, Burleson ER, Sawyer JK, Kelly K, Rudel LL, Parks JS. Determination of the tissue sites responsible for the catabolism of large high density lipoprotein in the African green monkey. J Lipid Res. 2000;41:384-394.

Huggins KW, Colvin PL, Burleson ER, Kelley K, Sawyer JK, Barrett PHR, 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; 42:1457-1466.

Furbee JW, Francone O, Parks JS. Alteration of plasma HDL cholesteryl ester composition with transgenic expression of a point mutation (E149A) of human lecithin:cholesterol acyltransferase (LCAT). J Lipid Res, 2001; 42:1626-1635.

Chisholm, JW, Burleson ER, Shelness GS and Parks JS. Apo A-I secretion from HepG2 cells: Evidence for the secretion of both lipid-poor apo A-I and intracellularly assembled nascent HDL. J Lipid Res 2002; 43(1):36-44.

Furbee JW Jr., Francone O, Parks JS. In vivo contribution of lecithin: cholesterol acyltransferase (LCAT) to ApoB lipoprotein cholesteryl esters in low density lipoprotein receptor and apolipoprotein E knockout mice. J Lipid Res 2002; 43(3):428-37.

Furbee JW Jr., Sawyer JK, Parks JS. Lecithin:cholesterol acyltransferase (LCAT) deficiency increases atherosclerosis in the low density lipoprotein receptor (LDLr) and apolipoprotein E (apoE) knockout mice. J Biol Chem 2002; 277:3511-3519.