John S. Parks, Ph.D.
Professor, Molecular Medicine
Comprehensive Cancer Center
Office of Women in Medicine and Science
Center for Diabetes Research
Center for Comparative Medicine Research
Translational Science Institute
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
Academic: 336-716-2145 | Department: 336-716-2145
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.
Liu M, Allegood J, Zhu X, Seo J, Gebre AK, Boudyguina E, Cheng D, Chuang CC, Shelness GS, Spiegel S, Parks JS. Uncleaved ApoM signal peptide is required for formation of large ApoM/sphingosine 1-phosphate (S1P)-enriched HDL particles
. J Biol Chem. 2015;290(12):7861-7870.
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.
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.
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.
Cao Q, Wang X, Jia L, Mondal AK, Diallo A, Hawkins GA, Das SK, Parks JS, Yu L, Shi H, Shi H, Xue B. Inhibiting DNA Methylation by 5-Aza-2'-deoxycytidine ameliorates atherosclerosis through suppressing macrophage inflammation
. Endocrinology. 2014;155(12):4925-4938.
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.
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.
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.
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.
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.
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, 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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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
The Role of ApoA-IV in Hepatic Lipid
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