Relationships Between Circulating Lipids, Lipoproteins, and Lymphocyte Subsets in the Multi-Ethnic Study of Atherosclerosis
References
- Franceschi C, Garagnani P, Parini P, Giuliani C, Santoro A. Inflammaging: A new immune-metabolic viewpoint for age-related diseases. Nat Rev Endocrinol. 2018;14(10):576–590. DOI: 10.1038/s41574-018-0059-4
- Sanada F, Taniyama Y, Muratsu J, et al. Source of chronic inflammation in aging. Frontiers in Cardiovascular Medicine. 2018;5. DOI: 10.3389/fcvm.2018.00012
- Mittelbrunn M, Kroemer G. Hallmarks of T cell aging. Nature Immunology. 2021;22(6):687–698. DOI: 10.1038/s41590-021-00927-z
- Shirakawa K, Sano M. T Cell immunosenescence in aging, obesity, and cardiovascular disease. Cells. 2021;10(9):
2435 . DOI: 10.3390/cells10092435 - Carrasco E, Gómez De Las Heras MM, Gabandé-Rodríguez E, Desdín-Micó G, Aranda JF, Mittelbrunn M. The role of T cells in age-related diseases. Nature Reviews Immunology. 2022;22(2):97–111. DOI: 10.1038/s41577-021-00557-4
- Gupta R, Sharma M, Goyal NK, Bansal P, Lodha S, Sharma KK. Gender differences in 7 years trends in cholesterol lipoproteins and lipids in India: Insights from a hospital database. Indian J Endocrinol Metab. 2016;20(2):211–8. DOI: 10.4103/2230-8210.176362
- Félix-Redondo FJ, Grau M, Fernández-Bergés D. Cholesterol and cardiovascular disease in the elderly. Facts and gaps. Aging Dis. 2013;4(3):154–69.
- Simony SB, Mortensen MB, Langsted A, Afzal S, Kamstrup PR, Nordestgaard BG. Sex differences of lipoprotein(a) levels and associated risk of morbidity and mortality by age: The Copenhagen General Population Study. Atherosclerosis. 2022;355:76–82. DOI: 10.1016/j.atherosclerosis.2022.06.1023
- Larbi A, Fortin C, Dupuis G, Berrougui H, Khalil A, Fulop T. Immunomodulatory role of high-density lipoproteins: impact on immunosenescence. AGE. 2014;36(5). DOI: 10.1007/s11357-014-9712-6
- King RJ, Singh PK, Mehla K. The cholesterol pathway: impact on immunity and cancer. Trends Immunol. 2022;43(1):78–92. DOI: 10.1016/j.it.2021.11.007
- Aguilar-Ballester M, Herrero-Cervera A, Vinue A, Martinez-Hervas S, Gonzalez-Navarro H. Impact of cholesterol metabolism in immune cell function and atherosclerosis. Nutrients. 2020;12(7):
2021 . DOI: 10.3390/nu12072021 - Kaji H. High-density lipoproteins and the immune system. Journal of Lipids. 2013;2013:1–8. DOI: 10.1155/2013/684903
- Samson S, Mundkur L, Kakkar VV. Immune response to lipoproteins in atherosclerosis. Cholesterol. 2012;2012:1–12. DOI: 10.1155/2012/571846
- Hu C, Wu H, Zhu Q, Cao N, Wang H. Cholesterol metabolism in T-cell aging: Accomplices or victims. FASEB J. 2023;37(9):
e23136 . DOI: 10.1096/fj.202300515R - Bietz A, Zhu H, Xue M, Xu C. Cholesterol metabolism in T Cells. Frontiers in Immunology. 2017;8. DOI: 10.3389/fimmu.2017.01664
- Lim SA, Su W, Chapman NM, Chi H. Lipid metabolism in T cell signaling and function. Nature Chemical Biology. 2022;18(5):470–481. DOI: 10.1038/s41589-022-01017-3
- Bazioti V, Halmos B, Westerterp M. T-cell Cholesterol accumulation, aging, and atherosclerosis. Curr Atheroscler Rep. 2023;25(9):527–534. DOI: 10.1007/s11883-023-01125-y
- Garcia C, Andersen CJ, Blesso CN. The role of lipids in the regulation of immune responses. Nutrients. 2023;15(18):
3899 . DOI: 10.3390/nu15183899 - Atehortua L, Davidson WS, Chougnet CA. Interactions between HDL and CD4+ T Cells: A novel understanding of HDL anti-inflammatory properties. Arterioscler Thromb Vasc Biol. 2024;44(6):1191–1201. DOI: 10.1161/ATVBAHA.124.320851
- Yuan J, Cai T, Zheng X, et al. Potentiating CD8+ T cell antitumor activity by inhibiting PCSK9 to promote LDLR-mediated TCR recycling and signaling. Protein & Cell. 2021;12(4):240–260. DOI: 10.1007/s13238-021-00821-2
- Gisterå A, Klement ML, Polyzos KA, et al. Low-Density Lipoprotein-reactive T Cells regulate plasma cholesterol levels and development of atherosclerosis in humanized hypercholesterolemic mice. Circulation. 2018;138(22):2513–2526. DOI: 10.1161/CIRCULATIONAHA.118.034076
- Pathan-Chhatbar S, Drechsler C, Richter K, et al. Direct regulation of the T Cell antigen receptor’s activity by cholesterol. Frontiers in Cell and Developmental Biology. 2021;8. DOI: 10.3389/fcell.2020.615996
- Olzmann JA, Carvalho P. Dynamics and functions of lipid droplets. Nature Reviews Molecular Cell Biology. 2019;20(3):137–155. DOI: 10.1038/s41580-018-0085-z
- Ma X, Bi E, Lu Y, et al. Cholesterol induces CD8+ T Cell exhaustion in the tumor microenvironment. Cell Metabolism. 2019;30(1):143–156.e5. DOI: 10.1016/j.cmet.2019.04.002
- Cui G, Qin X, Wu L, et al. Liver X receptor (LXR) mediates negative regulation of mouse and human Th17 differentiation. Journal of Clinical Investigation. 2011;121(2):658–670. DOI: 10.1172/JCI42974
- Hu X, Wang Y, Hao L-Y, et al. Sterol metabolism controls TH17 differentiation by generating endogenous RORγ agonists. Nature Chemical Biology. 2015;11(2):141–147. DOI: 10.1038/nchembio.1714
- Perucha E, Melchiotti R, Bibby JA, et al. The cholesterol biosynthesis pathway regulates IL-10 expression in human Th1 cells. Nature Communications. 2019;10(1). DOI: 10.1038/s41467-019-08332-9
- Ali AJ, Makings J, Ley K. Regulatory T Cell stability and plasticity in atherosclerosis. Cells. 2020;9(12). DOI: 10.3390/cells9122665
- Herold M, Breuer J, Hucke S, et al. Liver X receptor activation promotes differentiation of regulatory T cells. PLOS ONE. 2017;12(9):
e0184985 . DOI: 10.1371/journal.pone.0184985 - Cheng HY, Gaddis DE, Wu R, et al. Loss of ABCG1 influences regulatory T cell differentiation and atherosclerosis. Journal of Clinical Investigation. 2016;126(9):3236–3246. DOI: 10.1172/JCI83136
- Smet M, Van Hoecke L, De Beuckelaer A, et al. Cholesterol-sensing liver X receptors stimulate Th2-driven allergic eosinophilic asthma in mice. Immun Inflamm Dis. 2016;4(3):350–61. DOI: 10.1002/iid3.118
- Dunn SE, Youssef S, Goldstein MJ, et al. Isoprenoids determine Th1/Th2 fate in pathogenic T cells, providing a mechanism of modulation of autoimmunity by atorvastatin. The Journal of Experimental Medicine. 2006;203(2). DOI: 10.1084/jem.20051129
- Surls J, Nazarov-Stoica C, Kehl M, Olsen C, Casares S, Brumeanu TD. Increased membrane cholesterol in lymphocytes diverts T-cells toward an inflammatory response. PLoS One. 2012;7(6):
e38733 . DOI: 10.1371/journal.pone.0038733 - Bazioti V, La Rose AM, Maassen S, et al. T cell cholesterol efflux suppresses apoptosis and senescence and increases atherosclerosis in middle aged mice. Nat Commun. 2022;13(1):
3799 . DOI: 10.1038/s41467-022-31135-4 - Mailer RKW, Gistera A, Polyzos KA, Ketelhuth DFJ, Hansson GK. Hypercholesterolemia Induces Differentiation of Regulatory T Cells in the Liver. Circ Res. May 26 2017;120(11):1740–1753. DOI: 10.1161/CIRCRESAHA.116.310054
- Zhou X, Paulsson G, Stemme S, Hansson GK. Hypercholesterolemia is associated with a T helper (Th) 1/Th2 switch of the autoimmune response in atherosclerotic apo E-knockout mice. J Clin Invest. 1998;101(8):1717–25. DOI: 10.1172/JCI1216
- Gaddis DE, Padgett LE, Wu R, et al. Apolipoprotein AI prevents regulatory to follicular helper T cell switching during atherosclerosis. Nat Commun. 2018;9(1):
1095 . DOI: 10.1038/s41467-018-03493-5 - Lai YC, Woollard KJ, McClelland RL, et al. The association of plasma lipids with white blood cell counts: Results from the Multi-Ethnic Study of Atherosclerosis. Journal of Clinical Lipidology. 2019/09/01;13(5). DOI: 10.1016/j.jacl.2019.07.003
- Tucker B, Sawant S, McDonald H, et al. The association of serum lipid and lipoprotein levels with total and differential leukocyte counts: Results of a cross-sectional and longitudinal analysis of the UK Biobank. Atherosclerosis. 2021;319:1–9. DOI: 10.1016/j.atherosclerosis.2020.12.016
- Groenen AG, Bazioti V, van Zeventer IA, et al. Large HDL particles negatively associate with leukocyte counts independent of cholesterol efflux capacity: A cross sectional study in the population-based LifeLines DEEP cohort. Atherosclerosis. 2022;343:20–27. DOI: 10.1016/j.atherosclerosis.2022.01.008
- Harslof M, Pedersen KM, Nordestgaard BG, Afzal S. Low High-Density Lipoprotein Cholesterol and High White Blood Cell Counts: A Mendelian Randomization Study. Arterioscler Thromb Vasc Biol. 2021;41(2):976–987. DOI: 10.1161/ATVBAHA.120.314983
- Andersen CJ, Vance TM. Gender dictates the relationship between serum lipids and leukocyte counts in the National Health and Nutrition Examination Survey 1999–2004. J Clin Med. 2019;8(3):
365 . DOI: 10.3390/jcm8030365 - Schmitz T, Freuer D, Linseisen J, Meisinger C. Associations between serum cholesterol and immunophenotypical characteristics of circulatory B cells and Tregs. J Lipid Res. 2023;64(7):
100399 . DOI: 10.1016/j.jlr.2023.100399 - Bild DE, Bluemke DA, Burke GL, et al. Multi-ethnic study of atherosclerosis: Objectives and design. Am J Epidemiol. 2002;156(9):871–81. DOI: 10.1093/aje/kwf113
- Sinha A, Sitlani CM, Doyle MF, et al. Association of immune cell subsets with incident heart failure in two population-based cohorts. ESC Heart Fail. 2022;9(6):4177–4188. DOI: 10.1002/ehf2.14140
- Olson NC, Sitlani CM, Doyle MF, et al. Innate and adaptive immune cell subsets as risk factors for coronary heart disease in two population-based cohorts. Atherosclerosis. 2020;300:47–53. DOI: 10.1016/j.atherosclerosis.2020.03.011
- Olson NC, Doyle MF, Sitlani CM, et al. Associations of innate and adaptive immune cell subsets with incident Type 2 Diabetes risk: The MESA Study. J Clin Endocrinol Metab. 2020;105(3):e848–57. DOI: 10.1210/clinem/dgaa036
- Tracy RP, Doyle MF, Olson NC, et al. T-helper type 1 bias in healthy people is associated with cytomegalovirus serology and atherosclerosis: the Multi-Ethnic Study of Atherosclerosis. J Am Heart Assoc. 2013;2(3):
e000117 . DOI: 10.1161/JAHA.113.000117 - Zeb I, Jorgensen NW, Blumenthal RS, et al. Association of inflammatory markers and lipoprotein particle subclasses with progression of coronary artery calcium: The multi-ethnic study of atherosclerosis. Atherosclerosis. 2021;339:27–34. DOI: 10.1016/j.atherosclerosis.2021.11.003
- Huffman KM, Parker DC, Bhapkar M, et al. Calorie restriction improves lipid-related emerging cardiometabolic risk factors in healthy adults without obesity: Distinct influences of BMI and sex from CALERIE a multicentre, phase 2, randomised controlled trial. EClinicalMedicine. 2022;43:
101261 . DOI: 10.1016/j.eclinm.2021.101261 - Davis JR, Fresard L, Knowles DA, et al. An Efficient Multiple-Testing Adjustment for eQTL Studies that Accounts for Linkage Disequilibrium between Variants. Am J Hum Genet. Jan 7 2016;98(1):216–24. DOI: 10.1016/j.ajhg.2015.11.021
- Acton S, Rigotti A, Landschulz KT, Xu S, Hobbs HH, Krieger M. Identification of scavenger receptor SR-BI as a high density lipoprotein receptor. Science. 1996;271(5248):518–20. DOI: 10.1126/science.271.5248.518
- Kozarsky KF, Donahee MH, Rigotti A, Iqbal SN, Edelman ER, Krieger M. Overexpression of the HDL receptor SR-BI alters plasma HDL and bile cholesterol levels. Nature. 1997;387(6631):414–7. DOI: 10.1038/387414a0
- Feng H, Guo L, Wang D, et al. Deficiency of scavenger receptor BI leads to impaired lymphocyte homeostasis and autoimmune disorders in mice. Arterioscler Thromb Vasc Biol. 2011;31(11):2543–51. DOI: 10.1161/ATVBAHA.111.234716
- Kraus VB, Ma S, Tourani R, et al. Causal analysis identifies small HDL particles and physical activity as key determinants of longevity of older adults. EBioMedicine. 2022;85:
104292 . DOI: 10.1016/j.ebiom.2022.104292 - Conners KM, Shearer JJ, Joo J, et al. The Metabolic Vulnerability Index: A novel marker for mortality prediction in heart failure. JACC Heart Fail. 2024;12(2):290–300. DOI: 10.1016/j.jchf.2023.06.013
- Otvos JD, Shalaurova I, May HT, et al. Multimarkers of metabolic malnutrition and inflammation and their association with mortality risk in cardiac catheterisation patients: a prospective, longitudinal, observational, cohort study. Lancet Healthy Longev. 2023;4(2):e72–e82. DOI: 10.1016/S2666-7568(23)00001-6
- Park KH, Shin DG, Kim JR, Cho KH. Senescence-related truncation and multimerization of apolipoprotein A-I in high-density lipoprotein with an elevated level of advanced glycated end products and cholesteryl ester transfer activity. J Gerontol A Biol Sci Med Sci. 2010;65(6):600–10. DOI: 10.1093/gerona/glq034
- Park KH, Kim JY, Choi I, Kim JR, Won KC, Cho KH. Fructated apolipoprotein A-I exacerbates cellular senescence in human umbilical vein endothelial cells accompanied by impaired insulin secretion activity and embryo toxicity. Biochem Cell Biol. 2016;94(4):337–45. DOI: 10.1139/bcb-2015-0165
- Park KH, Cho KH. High-density lipoprotein (HDL) from elderly and reconstituted HDL containing glycated apolipoproteins A-I share proatherosclerotic and prosenescent properties with increased cholesterol influx. J Gerontol A Biol Sci Med Sci. 2011;66(5):511–20. DOI: 10.1093/gerona/glr016
- Xiang Q, Tian F, Xu J, Du X, Zhang S, Liu L. New insight into dyslipidemia-induced cellular senescence in atherosclerosis. Biol Rev Camb Philos Soc. 2022;97(5):1844–1867. DOI: 10.1111/brv.12866
- Newton AH, Benedict SH. Low density lipoprotein promotes human naive T cell differentiation to Th1 cells. Hum Immunol. 2014;75(7):621–8. DOI: 10.1016/j.humimm.2014.04.017
- Hermansson A, Ketelhuth DF, Strodthoff D, et al. Inhibition of T cell response to native low-density lipoprotein reduces atherosclerosis. J Exp Med. 2010;207(5):1081–93. DOI: 10.1084/jem.20092243
- Stemme S, Faber B, Holm J, Wiklund O, Witztum JL, Hansson GK. T lymphocytes from human atherosclerotic plaques recognize oxidized low density lipoprotein. Proc Natl Acad Sci U S A. 1995;92(9):3893–7. DOI: 10.1073/pnas.92.9.3893
- Kimura T, Kobiyama K, Winkels H, et al. Regulatory CD4(+) T Cells recognize major histocompatibility complex class II molecule-restricted peptide epitopes of apolipoprotein B. Circulation. 2018;138(11):1130–1143. DOI: 10.1161/CIRCULATIONAHA.117.031420
- Rajman I, Eacho PI, Chowienczyk PJ, Ritter JM. LDL particle size: an important drug target? Br J Clin Pharmacol. 1999;48(2):125–33. DOI: 10.1046/j.1365-2125.1999.00991.x
- Freigang S, Horkko S, Miller E, Witztum JL, Palinski W. Immunization of LDL receptor-deficient mice with homologous malondialdehyde-modified and native LDL reduces progression of atherosclerosis by mechanisms other than induction of high titers of antibodies to oxidative neoepitopes. Arterioscler Thromb Vasc Biol. 1998;18(12):1972–82. DOI: 10.1161/01.ATV.18.12.1972
- DeConne TM, Buckley DJ, Trott DW, Martens CR. The role of T cells in vascular aging, hypertension, and atherosclerosis. Am J Physiol Heart Circ Physiol. 2024;327(6):H1345–H1360. DOI: 10.1152/ajpheart.00570.2024
- Hinkley H, Counts DA, VonCanon E, Lacy M. T Cells in atherosclerosis: Key players in the pathogenesis of vascular disease. Cells. 2023;12(17). DOI: 10.3390/cells12172152
- Saigusa R, Winkels H, Ley K. T cell subsets and functions in atherosclerosis. Nat Rev Cardiol. 2020;17(7):387–401. DOI: 10.1038/s41569-020-0352-5
- Olson NC, Doyle MF, Jenny NS, et al. Decreased naive and increased memory CD4(+) T cells are associated with subclinical atherosclerosis: the multi-ethnic study of atherosclerosis. PLoS One. 2013;8(8):
e71498 . DOI: 10.1371/journal.pone.0071498 - Patel RD, Buzkova P, Huber S, et al. Associations of immune cell subsets with coronary artery calcium incidence and progression in the multi-ethnic study of atherosclerosis. J Am Heart Assoc. 2025;14(19):
e042502 . DOI: 10.1161/JAHA.125.042502 - Chapman MJ, Ginsberg HN, Amarenco P, et al. Triglyceride-rich lipoproteins and high-density lipoprotein cholesterol in patients at high risk of cardiovascular disease: evidence and guidance for management. Eur Heart J. 2011;32(11):1345–61. DOI: 10.1093/eurheartj/ehr112
- Bednarska-Makaruk M, Ługowska A. Rare monogenic disorders of cholesterol metabolism. Cholesterol. 2022:553–607. DOI: 10.1016/B978-0-323-85857-1.00024-9
- Sampedro MC, Motran C, Gruppi A, Kivatinitz SC. VLDL modulates the cytokine secretion profile to a proinflammatory pattern. Biochem Biophys Res Commun. 2001;285(2):393–9. DOI: 10.1006/bbrc.2001.5202
- Rhoads JP, Major AS. How oxidized low-density lipoprotein activates inflammatory responses. Crit Rev Immunol. 2018;38(4):333–342. DOI: 10.1615/CritRevImmunol.2018026483
- Ju SH, Lim JY, Song M, et al. Distinct effects of rosuvastatin and rosuvastatin/ezetimibe on senescence markers of CD8+ T cells in patients with type 2 diabetes mellitus: a randomized controlled trial. Front Endocrinol (Lausanne). 2024;15:
1336357 . DOI: 10.3389/fendo.2024.1336357 - Srichatrapimuk S, Wongsa A, Sungkanuparph S, Kiertiburanakul S, Tassaneetrithep B, Phuphuakrat A. Effects of pitavastatin on atherosclerotic-associated inflammatory biomarkers in people living with HIV with dyslipidemia and receiving ritonavir-boosted atazanavir: a randomized, double-blind, crossover study. AIDS Res Ther. 2023;20(1):
13 . DOI: 10.1186/s12981-023-00506-2 - Ma X, Liu S, Li T, Yuan H. Intensive statin treatment ameliorate the Th17/Treg functional imbalance in patients with non-ST elevation acute coronary syndrome underwent percutaneous coronary intervention. Clin Cardiol. 2020;43(4):379–385. DOI: 10.1002/clc.23326
- Yang G, Qiu Y. Effects of amlodipine combined with atorvastatin on Th17/Treg imbalance and vascular microcirculation in hypertensive patients with atherosclerosis: A double-blind, single-center randomized controlled trial. Medicine (Baltimore). 2023;102(6):
e32384 . DOI: 10.1097/MD.0000000000032384
DOI: https://doi.org/10.5334/gh.1521 | Journal eISSN: 2211-8179
Language: English
Submitted on: Sep 2, 2025
Accepted on: Jan 8, 2026
Published on: Feb 3, 2026
Published by: Ubiquity Press
In partnership with: Paradigm Publishing Services
Publication frequency: 1 issue per year
Keywords:
© 2026 Theodore M. DeConne, Colleen M. Sitlani, Joseph A. Delaney, Bruce M. Psaty, Margaret F. Doyle, James D. Otvos, Matthew J. Feinstein, Nels C. Olson, published by Ubiquity Press
This work is licensed under the Creative Commons Attribution 4.0 License.