Profile

John S. Parks, Ph.D.Wake Forest School of Medicine

Education & Training

  • B.S., North Carolina State University , 1973
  • M.S., Wake Forest University , 1976
  • Ph.D., Wake Forest University , 1979
  • Fellowship, Boston University School of Me, 1981

Memberships

  • Aha - Council On Arteriosclero
John S. Parks, Ph.D.

John S. Parks, Ph.D.

Section Chief, Molecular Medicine
Professor, Molecular Medicine
Comprehensive Cancer Center
Office of Women in Medicine and Science
Center for Diabetes Research
Center for Comparative Medicine Research
Biochemistry
Translational Science Institute

Research Interests

atherosclerosis/thrombosis, cancer/oncogenesis, diabetes, drugs/therapeutic agents pharm, education/training (all f, t,, hormones/cytokines/signalling, immunology/allergy/inflammatio, metabolism, molecular biology/molecular me, nutrition, obesity, transgenics

Contact Information

Academic: 336-716-2145 | Department: 336-716-2145

Email: jparks@wakehealth.edu

Recent Publications

Huang Y, Didonato JA, Levison BS, Schmitt D, Li L, Wu Y, Buffa J, Kim T, Gerstenecker GS, Gu X, Kadiyala CS, Wang Z, Culley MK, Hazen JE, Didonato AJ, Fu X, Berisha SZ, Peng D, Nguyen TT, Liang S, Chuang CC, Cho L, Plow EF,. An abundant dysfunctional apolipoprotein A1 in human atheroma. Nat Med. 2014;20(2):193-203.

Liu M, Seo J, Allegood J, Bi X, Zhu X, Boudyguina E, Gebre AK, Avni D, Shah D, Sorci-Thomas MG, Thomas MJ, Shelness GS, Spiegel S, Parks JS. Hepatic apolipoprotein M (apoM) overexpression stimulates formation of larger apoM/sphingosine 1-phosphate-enriched plasma high density lipoprotein. J Biol Chem. 2014;289(5):2801-2814.

Bi X, Zhu X, Gao C, Shewale S, Cao Q, Liu M, Boudyguina E, Gebre AK, Wilson MD, Brown AL, Parks JS. Myeloid cell-specific ATP-binding cassette transporter A1 deletion has minimal impact on atherogenesis in atherogenic diet-fed low-density lipoprotein receptor knockout mice. Arterioscler Thromb Vasc Biol. 2014;34(9):1888-1899.

Cao Q, Rong S, Repa JJ, Clair RS, Parks JS, Mishra N. Histone deacetylase 9 represses cholesterol efflux and alternatively activated macrophages in atherosclerosis development. Arterioscler Thromb Vasc Biol. 2014;34(9):1871-1879.

Chung S, Cuffe H, Marshall SM, McDaniel AL, Ha JH, Kavanagh K, Hong C, Tontonoz P, Temel RE, Parks JS. Dietary cholesterol promotes adipocyte hypertrophy and adipose tissue inflammation in visceral, but not in subcutaneous, fat in monkeys. Arterioscler Thromb Vasc Biol. 2014;34(9):1880-1887.

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. 2014;():.

Hasballa R, Rohrer L, Fotakis P, Zannis VI, Parks JS, von Eckardstein A. Lipoprotein metabolism and transendothelial apolipoprotein A-I transport in mice with an endothelium specific knock-out of ATP binding cassette transporter A1 [abstract]. Atherosclerosis. 2014;235(2):E21.

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.

Sene A, Khan AA, Cox D, Nakamura RE, Santeford A, Kim BM, Sidhu R, Onken MD, Harbour JW, Hagbi-Levi S, Chowers I, Edwards PA, Baldan A, Parks JS, Ory DS, Apte RS. Impaired cholesterol efflux in senescent macrophages promotes age-related macular degeneration. Cell Metab. 2013;17(4):549-561.

Westerterp M, Murphy AJ, Wang M, Pagler TA, Vengrenyuk Y, Kappus MS, Gorman DJ, Nagareddy PR, Zhu X, Abramowicz S, Parks JS, Welch C, Fisher EA, Wang N, Yvan-Charvet L, Tall AR. Deficiency of ATP-binding cassette transporters A1 and G1 in macrophages increases inflammation and accelerates atherosclerosis in mice. Circ Res. 2013;112(11):1456-1465.

Cheng HY, Wu R, Gebre AK, Hanna RN, Smith DJ, Parks JS, Ley K, Hedrick CC. Increased cholesterol content in gammadelta T lymphocytes differentially regulates their activation. PLoS One. 2013;8(5):e63746.

Forrest LM, Lough CM, Chung S, Boudyguina EY, Gebre AK, Smith TL, Colvin PL, Parks JS. Echium oil reduces plasma triglycerides by increasing intravascular lipolysis in apoB100-only low density lipoprotein (LDL) receptor knockout mice. Nutrients. 2013;5(7):2629-2645.

Zhu X, Chung S, Bi X, Chuang CC, Brown AL, Liu M, Seo J, Cuffe H, Gebre AK, Boudyguina E, Parks JS. Myeloid cell-specific ABCA1 deletion does not worsen insulin resistance in HF diet-induced or genetically obese mouse models. J Lipid Res. 2013;54(10):2708-2717.

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.

Bi X, Zhu X, Duong M, Boudyguina EY, Wilson MD, Gebre AK, Parks JS. Liver ABCA1 deletion in LDLrKO mice does not impair macrophage reverse cholesterol transport or exacerbate atherogenesis. Arterioscler Thromb Vasc Biol. 2013;33(10):2288-2296.


Miller NE, Nanjee N, Parks JS, Olszewski WL. Mechanism of the low cholesterol esterification rate in human interstitial fluid (peripheral lymph) [abstract]. Circulation. 2013;128(22 Suppl):A13029.

Liu MX, Seo JM, Allegood J, Bi X, Zhu XW, Boudyguina E, Gebre AK, Sorci-Thomas M, Thomas MS, Shelness GS, Spiegel S, Parks JS. Overexpression of apoM in liver stimulates formation of larger, apoM/S1P-enriched plasma HDL [abstract]. Circulation. 2013;128(22 Suppl):A19183.

Forrest LM, Boudyguina E, Wilson MD, Parks JS. Echium oil reduces atherosclerosis in apoB100-only LDLrKO mice. Atherosclerosis. 2012;220(1):118-121.

Lord CC, Betters JL, Ivanova PT, Milne SB, Myers DS. Madenspacher J, Thomas G, Chung S, Liu M, Davis MA, Lee RG, Crooke RM, Graham MJ, Parks JS, Brasaemle DL, Fessler MB, Brown HA, Brown JM. CGI-58/ABHD5-derived signaling lipids regulates systemic inflammation and insulin action. Diabetes. 2012;61(2):355-363.

Liu M, Chung S, Shelness GS, Parks JS. Hepatic ABCA1 and VLDL triglyceride production. Biochim Biophys Acta. 2012;1821(5):770-777.

Rong S, Cao Q, Liu M, Seo J, Jia L, Boudyguina E, Gebre AK, Colvin PL, Smith TL, Murphy RC, Mishra N, Parks JS. Macrophage 12/15 lipoxygenase expression increases plasma and hepatic lipid levels and exacerbates atherosclerosis. J Lipid Res. 2012;53(4):686-695.

Parks JS, Chung S, Shelness GS. Hepatic ABC transporters and triglyceride metabolism. Curr Opin Lipidol. 2012;23(3):196-200.

Youm Y-H, Kanneganti T-D, Vandanmagsar B, Zhu X, Ravussin A, Adijiang A, Owen JS, Thomas MJ, Francis J, Parks JS, Dixit VD. The NLRP3 inflammasome promotes age-related thymic demise and immunosenescence. Cell Rep. 2012;1(1):56-68.

Sorci-Thomas MG, Owen JS, Fulp B, Bhat S, Zhu X, Parks JS, Shah D, Jerome WG, Gerelus M, Zabalawi M, Thomas MJ. Nascent high density lipoproteins formed by ABCA1 resemble lipid rafts and are structurally organized by three apoA-I monomers. J Lipid Res. 2012;53(9):1890-1909.

Zhu X, Parks JS. New roles of HDL in inflammation and hematopoiesis. Annu Rev Nutr. 2012;32():161-182.

Brown AL, Zhu X, Rong S, Shewale S, Seo J, Boudyguina E, Gebre AK, Alexander-Miller MA, Parks JS. Omega-3 fatty acids ameliorate atherosclerosis by favorably altering monocyte subsets and limiting monocyte recruitment to aortic lesions. Arterioscler Thromb Vasc Biol. 2012;32(9):2122-2130.

Sag D, Wingender G, Nowyhed H, Wu R, Gebre AK, Parks JS, Kronenberg M, Hedrick CC. ATP-binding cassette transporter G1 intrinsically regulates invariant NKT cell development. J Immunol. 2012;189(11):5129-5138.

Zhu X, Westcott MM, Bi X, Liu M, Gowdy KM, Seo J, Cao Q, Gebre AK, Fessler MB, Hiltbold EM, Parks JS. Myeloid cell-specific ABCA1 deletion protects mice from bacterial infection. Circ Res. 2012;111(11):1398-1409.


Ma L, Mondal AK, Murea M, Sharma NK, Langberg KA, Das SK, Antinozzi PA, Parks JS, Elbein SC [deceased], Freedman BI, et al. The effect of ACACB cis-variants on gene expression and metabolic traits. PLoS ONE. 2011;6(8):e23860.

Chung S, Sawyer JK, Gebre AK, Maeda N, Parks JS. Adipose tissue ATP binding cassette transporter A1 contributes to high-density lipoprotein biogenesis in vivo. Circulation. 2011;124(15):1663-1672.

Freedman BI, Langefeld CD, Murea M, Ma L, Otvos JD, Turner J, Antinozzi PA, Rocco MV, Parks JS. Apolipoprotein L1 (APOL1) nephropathy risk variants associate with HDL subfraction concentration in African Americans [abstract]. J Am Soc Nephrol. 2011;22(Abstract Suppl):178A.

Freedman BI, Langefeld CD, Murea M, Ma L, Otvos JD, Turner J, Antinozzi PA, Divers J, Hicks PJ, Bowden DW, Rocco MV, Parks JS. Apolipoprotein L1 nephropathy risk variants associate with HDL subfraction concentration in African Americans. Nephrol Dial Transplant. 2011;26(11):3805-3810.

Armstrong AJ, Gebre AK, Parks JS, Hedrick CC. ATP-binding cassette transporter G1 negatively regulates thymocyte and peripheral lymphocyte proliferation. J Immunol. 2010;184(1):173-183.

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.

Mulya A, Seo J, Brown AL, Gebre AK, Boudyguina E, Shelness GS, Parks JS. Apolipoprotein M expression increases the size of nascent pre beta HDL formed by ATP binding cassette transporter A1. J Lipid Res. 2010;51(3):514-524.

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.

Chung S, Gebre AK, Seo J, Shelness GS, Parks JS. A novel role for ABCA1-generated large pre-beta migrating nascent HDL in the regulation of hepatic VLDL triglyceride secretion. J Lipid Res. 2010;51(4):729-742.

Cheng D, MacArthur PS, Rong S, Parks JS, Shelness GS. Alternative splicing attenuates transgenic expression directed by the apolipoprotein E promoter-enhancer based expression vector pLIV11. J Lipid Res. 2010;51(4):849-855.

Whetzel AM, Sturek JM, Nagelin MH, Bolick DT, Gebre AK, Parks JS, Bruce AC, Skaflen MD, Hedrick CC. ABCG1 deficiency in mice promotes endothelial activation and monocyte-endothelial interactions. Arterioscler Thromb Vasc Biol. 2010;30(4):809-817.

Smoak KA, Aloor JJ, Madenspacher J, Merrick BA, Collins JB, Zhu X, Cavigiolio G, Oda MN, Parks JS, Fessler MB. Myeloid differentiation primary response protein 88 couples reverse cholesterol transport to inflammation. Cell Metab. 2010;11(6):493-502.

Sturek JM, Castle JD, Trace AP, Page LC, Castle AM, Evans-Molina C, Parks JS, Mirmira RG, Hedrick CC. An intracellular role for ABCG1-mediated cholesterol transport in the regulated secretory pathway of mouse pancreatic beta cells. J Clin Invest. 2010;120(7):2575-2589.

Zhu X, Owen JS, Wilson MD, Li H, Griffiths GL, Thomas MJ, Hiltbold EM, Fessler MB, Parks JS. Macrophage ABCA1 reduces MyD88-dependent Toll-like receptor trafficking to lipid rafts by reduction of lipid raft cholesterol. J Lipid Res. 2010;51(11):3196-3206.

Murea M, Freedman BI, Parks JS, Antinozzi PA, Elbein SC [deceased], Ma L. Lipotoxicity in diabetic nephropathy: the potential role of fatty acid oxidation. Clin J Am Soc Nephrol. 2010;5(12):2373-2379.

Bi X, Boudyguina E, Maeda N, Hayden M, Parks J. Hepatic ABCA1 deficiency does not significantly influence susceptibility to atherosclerosis in C57bl/6 Ldlr(-/-) mice [abstract]. Arterioscler Thromb Vasc Biol. 2010;30(11):e253.

Chung S, Rong S, Degirolamo C, Brown AW, Bi X, Forrest L, Temel R, Shelness GS, Parks JS. Hepatocyte-specific knockout of ABCA1 alleviates liver lipid accumulation but exacerbates hepatic insulin resistance and inflammation [abstract]. Arterioscler Thromb Vasc Biol. 2010;30(11):e187.

Forrest L, Lough C, Gebre A, Boudyguina E, Chung S, Parks J. Determining the hypotriglyceridemic effect of Echium oil [abstract]. Arterioscler Thromb Vasc Biol. 2010;30(11):e248.

Seo J, Boudyguina E, Gebre AK, Mullick A, Crooke RM, Lee RG, Parks JS. Effect of apolipoprotein M expression on HDL-cholesterol concentration and subclass distribution in human ApoA-I transgenic mice [abstract]. Arterioscler Thromb Vasc Biol. 2010;30(11):e210-e211.

Brunham LR, Singaraja RR, Duong M, Timmins JM, Fievet C, Bissada N, Kang MH, Samra A, Fruchart J-C, Parks JS, et al. Tissue-specific roles of ABCA1 influence susceptibility to atherosclerosis. Arterioscler Thromb Vasc Biol. 2009;29(4):548-554.

Domoki F, Kis B, Gaspar T, Snipes JA, Parks JS, Bari F, Busija DW. Rosuvastatin induces delayed preconditioning against oxygen-glucose deprivation in cultured cortical neurons. Am J Physiol Cell Physiol. 2009;296(1):C97-C105.

Karasinska JM, Rinninger F, Lutjohann D, Ruddle P, Franciosi S, Kruit JK, Singaraja RR, Hirsch-Reinshagen V, Fan J, Parks JS, et al. Specific loss of brain ABCA1 increases brain cholesterol uptake and influences neuronal structure and function. J Neurosci. 2009;29(11):3579-3589.

Hirsch-Reinshagen V, Donkin J, Stukas S, Chan J, Wilkinson A, Fan J, Parks JS, Kuivenhoven JA, Lutjohann D, Pritchard H, et al. LCAT synthesized by primary astrocytes esterifies cholesterol on glia-derived lipoproteins. J Lipid Res. 2009;50(5):885-893.

A-Gonzalez N, Bensinger SJ, Hong C, Beceiro S, Bradley MN, Zelcer N, Deniz J, Ramirez C, Diaz M, Parks J, et al. Apoptotic cells promote their own clearance and immune tolerance through activation of the nuclear receptor LXR. Immunity. 2009;31(2):245-258.


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

Bensinger SJ, Bradley MN, Joseph SB, Zelcer N, Janssen EM, Hausner MA, Shih R, Parks JS, Edwards PA, Jamieson BD, et al. LXR signaling couples sterol metabolism to proliferation in the acquired immune response. Cell. 2008;134(1):97-111.

Brown JM, Chung S, Sawyer JK, Degirolamo C, Alger HM, Zhu X, Duong M-N, Wibley AL, Shah R, Davis MA, Kelley K, Wilson MD, Kent C, Parks JS, Rudel LL, et al. Inhibition of stearoyl-coenzyme A desaturase 1 dissociates insulin resistance and obesity from atherosclerosis. Circulation. 2008;118(14):1467-1475.

Zhu X, Lee J-Y, Timmins JM, Brown JM, Boudyguina E, Mulya A, Gebre AK, Willingham MC, Mishra N, Parks JS, et al. Increased cellular free cholesterol in macrophage-specific Abca1 knock-out mice enhances pro-inflammatory response of macrophages. J Biol Chem. 2008;283(34):22930-41.

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. 2008;19(10):655-663.

Mulya A, Lee J-Y, Gebre AK, Boudyguina EY, Chung S-K, Smith TL, Colvin PL, Jiang X-C, Parks JS. Initial interaction of apoA-I with ABCA1 impacts in vivo metabolic fate of nascent HDL. J Lipid Res. 2008;49(11):2390-2401.

Brunham LR, Kruit JK, Pape TD, Timmins JM, Reuwer AQ, Vasanji Z, Marsh BJ, Rodrigues B, Johnson JD, Parks JS, et al. Beta-cell ABCA1 influences insulin secretion, glucose homeostasis and response to thiazolidinedione treatment. Nat Med. 2007;13(3):340-347.

Lee J-Y, 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;48(5):1052-1061.

Mulya A, Lee J-Y, 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;27(8):1828-1836.

Wu Z, Wagner MA, Zheng L, Parks JS, Shy JM III, 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;14(9):861-868.

Singaraja RR, Stahmer B, Brundert M, Merkel M, Heeren J, Bissada N, Kang M, Timmins JM, Ramakrishnan R, Parks JS, et al. Hepatic ATP-binding cassette transporter A1 is a key molecule in high-density lipoprotein cholesteryl ester metabolism in mice. Arterioscler Thromb Vasc Biol. 2006;26(8):1821-1827.

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;281(30):21216-24.

Brunham LR, Kruit JK, Pape TD, Parks JS, Kuipers F, Hayden MR. Tissue-specific induction of intestinal ABCA1 expression with a liver X receptor agonist raises plasma HDL cholesterol levels. Circ Res. 2006;99(7):672-674.

Singaraja RR, Van Eck M, Bissada N, Zimetti F, Collins HL, Hildebrand RB, Hayden A, Brunham LR, Kang MH, Parks JS, et al. Both hepatic and extrahepatic ABCA1 have discrete and essential functions in the maintenance of plasma high-density lipoprotein cholesterol levels in vivo. Circulation. 2006;114(12):1301-1309.

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.

John S. Parks, Ph.D.

Current Research:

My lab has several National Institutes of Health (NIH)-funded projects that focus on the pathogenesis of complex, chronic diseases such as atherosclerosis (i.e., hardening of the arteries), diabetes, obesity, and hepatosteatosis (i.e., fatty liver). We study the effect of lipid metabolism and inflammation on the development and progression of complex metabolic diseases. To accomplish the goals of our grant projects, we use an interdisciplinary approach that includes transgenic/gene-targeted mouse models of human disease, molecular biology, cell biology, biochemistry, mass spectrometry, and vascular wall biology.

Liver ABCA1, Lipoprotein Metabolism and Atherosclerosis (HL119962)

ATP binding cassette transporter A1 (ABCA1) effluxes phospholipid and free cholesterol from cells, forming nascent high density lipoproteins (HDLs). Because ABCA1 is variably expressed in most cells, we generated hepatocyte-specific ABCA1 KO (HSKO) mice to study the role of hepatocyte ABCA1 in lipid mobilization, transport, and metabolism. Our previous studies showed that hepatocyte ABCA1 regulates the production and catabolism of all three major plasma lipoprotein classes (VLDL, LDL and HDL) that affect coronary heart disease development. In preliminary studies, we found that hepatocyte ABCA1 also reguates hepatic insulin and inflammatory signaling, suggesting the function of hepatocyte ABCA1, while not fully elucidated, is more complex than facilitating bulk cellular cholesterol export and nascent HDL formation. The goal of this project is to determine the role of hepatocyte ABCA1 in lipid mobilization and transport in HSKO mice and humans. In specific aim 1, we are examining the role of hepatocyte ABCA1 expression in hepatic insulin signaling, inflammation, and lipogenesis. Metabolic phenotype, plasma VLDL metabolism, hepatic lipid synthesis, hepatic insulin receptor signaling, and hepatic plasma membrane lipid composition are being determined in chow and high fat-fed wild type and HSKO mice. In specific aim 2, the role of hepatic ABCA1 expression on cholesterol flux from plasma HDL to feces will be examined. We are investigating the plasma decay, hepatic uptake, re-secretion into plasma, and biliary and fecal excretion of HDL FC and CE, relative to apoA-I, in HSKO vs. WT mice. In specific aim 3, the extent to which dietary polyunsaturated (poly) fat, relative to saturated (sat) and monounsaturated (mono) fat, reduces ABCA1 expression in human liver, intestine and adipose tissue will be explored. Interrelationships among tissue ABCA1 RNA and protein expression, plasma HDL cholesterol concentration, particle number and size, and plasma HDL FC efflux capacity as a function of dietary fat saturation will be determined. In specific aim 4, we will determine whether rare coding ABCA1 sequence variants unique to African Americans (AA) (absent in European Americans, EA) affect lipid efflux as well as plasma HDL cholesterol concentration, particle number and size, and plasma HDL efflux potential. Associations between these measurements and coronary artery calcified plaque score, a measure of CHD, will be examined.

Atheroprotective Mechanisms of Borage and Echium Oils (AT002782)

This project is part of the Wake Forest Center for Botanical Lipids and Inflammatory Disease Prevention. We have demonstrated that Echium oil (EO), a botanical oil enriched in stearidonic acid (18:4 n-3), the immediate downstream product of the rate-limiting delta-6 desaturation of alpha-linolenic acid (18:3 n-3), reduces plasma lipids, inflammation, and atherosclerosis similar to fish oil (FO), but we do not know the exact mechanisms for the protection. EO also contains 11% gamma-linolenic acid (GLA, 18:3 n-6), which is the delta-6 desaturation product of linoleic acid (18:2 n-6) and thus, can provide substrate for conversion to anti-inflammatory series 1 prostaglandin (PGE1). However, we do not know whether a botanical oil that is enriched in GLA, such as borage oil (BO; 25% GLA), is equally protective or less protective than EO. We are investigating whether EO and BO are equally atheroprotective and to determine anti-atherogenic mechanisms of these botanical oils. Our primary hypothesis is that both EO and BO will reduce atherosclerosis relative to palm oil (PO), by attenuating the rise of proinflammatory monocytes in blood and the trafficking of monocytes into atherosclerotic lesions (specific aim 1). Furthermore, we hypothesize that EO and BO will result in alternative activation of macrophages, relative to PO, resulting in less inflammatory macrophages (specific aim 2). Finally, we propose that the polyunsaturated fatty acid-induced macrophage alternative activation will occur through multiple mechanisms that include antagonism of proinflammatory gene transactivation, PPAR gamma-dependent transactivation of anti-inflammatory genes, and PPAR gamma-dependent transrepression of pro-inflammatory genes (specific aim 3). The proposed mechanistic studies should allow us to determine the best botanical oils or combinations to move into human trials to test for reduction of atherosclerosis risk and inflammation and to improve our basic information regarding the mechanism of action of botanical oils in chronic disease prevention.

The Role of ApoA-IV in Hepatic Lipid Mobilization (HL119983)

An emerging trend suggests that apoB lipoprotein particle number, and not LDL cholesterol, may best predict susceptibility to atherosclerotic cardiovascular disease. As very low density lipoprotein (VLDL) particle size is heterogeneous, reflecting the elasticity of the apoB lipoprotein assembly process, an unanswered question with relevance to many aspects of the metabolic syndrome is how the hepatocyte integrates particle number with particle size to achieve a given rate of hepatic lipid efflux. We are exploring the hypothesis that apolipoprotein A-IV (apoA-IV) is acutely regulated and serves an important role in hepatic lipid efflux by promoting nascent VLDL particle expansion. Defining this previously unknown role of apoA-IV in hepatic lipid metabolism and understanding the mechanism by which it functions has important translational potential, as it is likely that if VLDL-mediated lipid efflux could be achieved by a process of particle expansion at the expense of particle number, a less atherogenic lipoprotein profile may result, while still protecting the liver from steatosis. To explore and validate this hypothesis, three specific aims are being conducted. Aim 1 will define the physiologic and pathophysiologic settings that regulate apoA-IV expression in liver and will establish whether it is hepatic triglyceride (TG) accumulation that induces apoA-IV expression or whether the regulation of apoA-IV is linked to processes associated with enhanced assembly and secretion of VLDL. Aim 2 will establish the impact of apoA-IV on TG secretion and hepatic lipid content and pathophysiology. These studies are supported by preliminary data demonstrating that overexpression of apoA-IV in mouse liver both dramatically induces TG secretion, reducing hepatic lipid burden. Finally, Aim 3 will focus on the mechanism by which apoA-IV promotes TG secretion and will explore the hypothesis that a direct apoA-IV-apoB interaction alters the trafficking kinetics of apoB and promotes greater incorporation of lipid into nascent VLDL particles, while reducing total VLDL particle production.

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