mimmunМедицинская иммунологияMedical Immunology (Russia)1563-06252313-741XSPb RAACI10.15789/1563-0625-PEO-2222mimmun-2222Research ArticleОБЗОРЫREVIEWSПлейотропные свойства PPAR-α: от экспериментов к клиникеPleiotropic effects of PPAR-α – from benchside to bedsidehttps://orcid.org/0000-0002-8603-3406ШиринскийИ. В.ShirinskyI. V.

Иван Валерьевич Ширинский — доктор медицинских наук, врач-ревматолог, ведущий научный сотрудник, заведующий лабораторией клинической иммунофармакологии.

Новосибирск

Shirinsky Ivan V., PhD, MD (Medicine), Clinical Rheumatologist, Leading Research Associate, Head, Laboratory of Clinical Immunopharmacology.

Novosibirsk

ishirinsky@mail.ruhttps://orcid.org/0000-0002-4922-9303ШиринскийВ. С.ShirinskyV. S.

Валерий Степанович Ширинский — доктор медицинских наук, профессор, главный научный сотрудник лаборатории клинической иммунофармакологии.

630047, Новосибирск, ул. Залесского, 6. Тел.: 8 (923) 107-51-00. Факс: 8 (383) 228-25-47

Shirinsky Valery S., PhD, MD (Medicine), Professor, Consulting Rheumatologist, Main Research Associate, Laboratory of Clinical Immunopharmacology.

630047, Novosibirsk, Zalessky str., 6. Phone: 7(923) 107-51-00. Fax: 7(383) 228-25-47

valery.shirinsky@gmail.comФГБНУ Научно-исследовательский институт фундаментальной и клинической иммунологииРоссияResearch Institute of Fundamental and Clinical ImmunologyRussian Federation202120062021233439454Copyright © Ширинский И.В., Ширинский В.С., 20212021Ширинский И.В., Ширинский В.С.Shirinsky I.V., Shirinsky V.S.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.mimmun.ru/mimmun/article/view/2222

В обзоре анализируются данные литературы, посвященные характеристике представителя суперсемейства ядерных гормональных рецепторов PPARα — рецептору, активируемому перок-сисомным пролифератором α. Показано, что PPARa экспрессируется в различных клетках организма, включая дендритные клетки, макрофаги, В- и Т-лимфоциты. Представлены данные о структуре естественных и синтетических лигандов PPARα, охарактеризованы молекулярные и клеточные механизмы контроля PPARα за липидным и углеводным обменом клеток. Модуляция активности PPARα может изменять множественные биологические эффекты глюкокортикостероидов и инсулинорезистентность. Приведен анализ результатов нескольких рандомизированных исследований, метаанализов, посвященных оценке эффективности и безопасности применения агониста PPARα фенофибрата у больных сахарным диабетом 2 с высоким риском микрососудистых и сердечно-сосудистых осложнений. Показана хорошая переносимость монотерапии фибратами, в комбинации со статинами, эзе-тимибом, снижение частоты сердечно-сосудистых осложнений и общей смертности. Представлены данные, свидетельствующие о том, что метаболизм глюкозы и липидов играет важную роль в судьбе клеток врожденного и адаптивного иммунитета. Показано, что гранулоциты, дендритные клетки и макрофаги Ml-типа при активации зависят от метаболизма глюкозы, в то время как макрофаги M2-типа зависят от FAO. В отличие от лимфоцитов, активированные миелоидные клетки пролиферируют слабо, характеризуются повышенным гликолитическим метаболизмом, который необходим для приобретения их эффекторных функций. Подчеркивается, что модуляция метаболизма клеток иммунной системы, путем воздействия на PPARα, открывает новые возможности управления интенсивностью и продолжительностью воспаления и иммунного ответа при хронических заболеваниях. Представлен анализ работ, проведенных на моделях хронических заболеваний животных, у больных ревматоидным артритом, остеоартритом. В большинстве исследований показана клиническая эффективность агонистов PPARα и их многоцелевые эффекты: противовоспалительные, иммуномодулирующие, эффект снижения содержания липидов, в первую очередь триглицеридов, и повышение холестерина липопротеинов высокой плотности. Приведенные данные литературы позволяют считать, что применение агонистов PPARα при полиморбидных заболеваниях будет эффективно в отношении основного и сопутствующих болезней, что позволит снизить частоту полипрагмазии, уменьшить затраты на лечение, поможет предупредить присоединение новых заболеваний у больного.

Here we review literature data on properties of a member of nuclear hormone receptors - peroxisome proliferator-activated receptor-α. It was shown that PPARα was expressed on different cells including dendritic cells, macrophages, B- and T-cells. We discuss structure of natural and synthetic ligands of PPARa, molecular and cellular mechanisms of PPARa regulation of lipid and carbohydrate cellular metabolism. PPARa activity in hepatocytes results in decrease of intracellular concentrations of lipid acids. This leads to reduction of VLDL cholesterol, increase in HDL-cholesterol and decrease in triglycerides in plasma of patients taking PPARα agonists. Modulation of PPARa activity may change multiple biological effects of glucocorticoids (GCS) and insulin resistance. It is assumed that PPARα agonists reduce side effects of GCS and at the same time enhance their anti-inflammatory activity due to transrepression of NF-kB. We analyzed the results of several randomized studies, meta-analyses devoted to assessment of efficacy and safety of PPARa agonist fenofibrate in patients with type 2 diabetes mellitus with high risk of micro- and macrovascular events. The studies showed good safety profile of monotherapy with fibrates as well as of their combinations with statins, ezetimibe. Fibrates reduced not only cardiovascular events but also overall mortality. We present the data on the role of PPARa in control of glucose and lipid metabolism in subpopulations of innate and adaptive immunity cells. The data show that glucose and lipid metabolism play an important role in the fate of cells of innate and adaptive immunity. The metabolic state of lymphocytes has dynamic nature and depends on their functional activity. Transition from dormant cells with relatively low metabolism rate to activated and proliferating cells is accompanied with increase of metabolic demands. This transition is supported with the switch from oxidative metabolism to anaerobic glycolysis (Warburg effect) after antigen recognition by T-cells and B-cells. It was shown that granulocytes, dendritic cells and M1 macrophages were dependent on glucose metabolism during their activation while M2 macrophages were dependent on fatty acids oxidation. In contrast with lymphocytes, activated myeloid cells do not proliferate well but still have increased glycolysis which is necessary for their effector function. It is stressed that modulation of immune cells metabolism via PPARα gives new opportunities to modulate intensity and duration of immune responses in chronic diseases. We analyze studies performed on animal models of some chronic diseases, human patients with rheumatoid arthritis and different phenotypes of osteoarthritis. Most of the studies showed clinical efficacy and pleiotropic effects of PPARα agonists: antiinflammatory, immunomodulating and lipid modulating, primarily reduction of triglycerides and increase in HDL-C. The presented literature data suggest efficacy of PPARα agonists against individual components of polypathies. This could reduce risk of polypharmacy and reduce direct treatment costs. It is not unlikely that the use of PPARα agonists in a patient with multimorbidity could prevent acquiring a new disease. These are merely suggestions and much effort and time is required to perform large-scale randomized controlled studies evaluating new indications for the use of PPARa agonists.

PPARαметаболизмлипидыглюкозавоспалениеплейотропностьфенофибратфагоцитылимфоцитыPPARαmetabolismlipidsglucoseinflammationpleiotropicfenofibratephagocyteslymphocytesReferencesЕвин И. А. Введение в теорию сложных сетей // Компьютерные исследования и моделирование, 2010. Т. 2, № 2. С. 121-141.Yevin I.A. Introduction to the theory of complex networks. Kompyuternye issledovaniya i modelirovanie = Computer Research and Modeling, 2010, Vol. 2, no. 2, pp. 121-141. (In Russ.)Пузырев В.П. Генетический взгляд на феномен сочетанной патологии у человека // Медицинская генетика, 2008. № 9. С. 3-9.Puzyrev V.P. Genetic view on the phenomenon of combined pathology in human. Meditsinskaya genetika = Medical Genetics, 2008, no. 9, pp. 3-9. (In Russ.)Саркисов Д.С., Пальцев М.А., Хитров Н.К. Общая патология человека. М.: Медицина, 1997. 608 с.Sarkisov D.S., Paltsev M.A., Hitrov N.K. General human pathology. Moscow: Meditsina, 1997. 608 p.Тарловская Е.И. Коморбидность и полиморбидность - современная трактовка и насущные задачи, стоящие перед терапевтическим сообществом // Кардиология, 2018. № 58 (9S). С. 29-38.Tarlovskaya E.I. Comorbidity and polymorbidity - a modern interpretation and urgent tasks facing the therapeutic community. Kardiologiya = Cardiology, 2018, no. 58 (9S), pp. 29-38. (In Russ.)]Ширинский В.С., Казыгашева Е.В., Калиновская Н.Ю., Ширинский И.В. Клиническая эффективность и безопасность применения агониста PPARa фенофибрата у больных с диабет-ассоциирован-ным остеоартритом: перекрестное пилотное исследование // Медицинская иммунология, 2017. Т. 19, № 2. С. 165-174. doi: 10.15789/1563-0625-2017-2-165-174.Shirinsky V.S., Kazygasheva E.V, Kalynovskaya N.Yu. Shirinsky I.V Clinical efficiency and safety of Fenofibrate, a PPARa agonist, in the patients with diabetes-associated osteoarthritis: a cross-over pilot study. Meditsinskaya immunologiya = Medical Immunology (Russia), 2017, Vol. 19, no. 2, pp. 165-174. (In Russ.) doi: 10.15789/1563-0625-2017-2-165-174.Ширинский В.С., Половникова О.А., Калиновская Н.Ю., Ширинский И.В. Клиническая эффективность и безопасность применения агониста рецептора пероксисомного пролифератора альфа у больных ревматоидным артритом - открытое контролируемое исследование // Медицинская иммунология, 2014. Т. 16, № 1. C. 71-80. doi: 10.15789/1563-0625-2014-1-71-80.Shirinsky VS., Polovnikova O.A., Kalinovskaya N.Yu., Shirinsky I.V. Clinical efficacy and safety of peroxisome proliferator-activated receptor alpha agonists in rheumatoid arthritis:an open-label controlled study. Meditsinskaya immunologiya = Medical Immunology (Russia), 2014, Vol. 16, no. 1, pp. 71-80. (In Russ.) doi: 10.15789/1563-0625-2014-1-71-80.Ширинский В.С., Ширинский И.В. Полиморбидность, старение иммунной системы и системное вялотекущее воспаление - вызов современной медицине // Медицинская иммунология, 2020. Т. 22, № 4. С. 609-624. doi: 10.15789/1563-0625-PAO-2042.Shirinsky V.S., Shirinsky I.V. Polymorbidity, ageing of immune system and low-grade systemic inflammation: a challenge for modern medicine. Meditsinskaya immunologiya = Medical Immunology (Russia), 2020, Vol. 22, no. 4, pp. 609-624. (In Russ.) doi: 10.15789/1563-0625-PAO-2042.Ширинский В.С., Ширинский И.В. Коморбидные заболевания - актуальная проблема клинической медицины // Сибирский медицинский журнал, 2014. Т. 29, № 1. С. 7-12.Shirinsky V.S., Shirinsky I.V. Comorbid diseases as an important problem of clinical medicine. Sibirskiy meditsinskiy zhurnal = Siberian Journal of Medicine, 2014, Vol. 29, no. 1, pp. 7-12. (In Russ.)Ширинский В.С., Ширинский И.В. Узловая терапия - новая возможность лечения коморбидных заболеваний // Сибирский медицинский журнал, 2014. Т. 29, № 4. С. 13-21.Shirinsky V.S., Shirinsky I.V. Hub therapy as a new opportunity for treatment of comorbid diseases. Sibirskiy meditsinskiy zhurnal = Siberian Journal of Medicine, 2014, Vol. 29, no. 4, pp. 13-21. (In Russ.)Abraham J.M., Cho L. The homocysteine hypothesis: still relevant to the prevention and treatment of cardiovascular disease? Cleve. Clin. J. Med., 2010, Vol. 77, no. 12, pp. 911-918.Abraham J.M., Cho L. The homocysteine hypothesis: still relevant to the prevention and treatment of cardiovascular disease? Cleve. Clin. J. Med., 2010, Vol. 77, no. 12, pp. 911-918.Barnett K., Mercer S.W., Norbury M. Epidemiology of multimorbidity and implications for health care, research, and medical education: a cross-sectional study. Lancet, 2012, Vol. 380, pp. 37-43.Barnett K., Mercer S.W., Norbury M. Epidemiology of multimorbidity and implications for health care, research, and medical education: a cross-sectional study. Lancet, 2012, Vol. 380, pp. 37-43.Belfort R., Berria R., Cornell J., Cusi K. Fenofibrate reduces systemic inflammation markers independent of its effects on lipid and glucose metabolism in patients with the metabolic syndrome. J. Clin. Endocrinol. Metab., 2010, Vol. 95, no. 2, pp. 829-836.Belfort R., Berria R., Cornell J., Cusi K. Fenofibrate reduces systemic inflammation markers independent of its effects on lipid and glucose metabolism in patients with the metabolic syndrome. J. Clin. Endocrinol. Metab., 2010, Vol. 95, no. 2, pp. 829-836.Berglund S., Sbdergren A., Wallberg J.S., Rantapaa D.S. Atherothrombotic events in rheumatoid arthritis are predicted by homocysteine—a six-year follow-up study. Clin. Exp. Rheumatol., 2009, Vol. 27, no. 5, pp. 822-825.Berglund S., Sbdergren A., Wallberg J.S., Rantapaa D.S. Atherothrombotic events in rheumatoid arthritis are predicted by homocysteine—a six-year follow-up study. Clin. Exp. Rheumatol., 2009, Vol. 27, no. 5, pp. 822-825.Bloxham D., Bradshaw D., Cashin C., Dodge B., Lewis E., Westmacott D., Self C.R. Biologic properties of romazarit (Ro 31-3948), a potential disease-modifying antirheumatic drug. J. Pharmacol. Exp. Ther., 1990, Vol. 252, pp. 1331-1340.Bloxham D., Bradshaw D., Cashin C., Dodge B., Lewis E., Westmacott D., Self C.R. Biologic properties of romazarit (Ro 31-3948), a potential disease-modifying antirheumatic drug. J. Pharmacol. Exp. Ther., 1990, Vol. 252, pp. 1331-1340.Bougarne N., Paumelle R., Caron S., Hennuyer N., Mansouri R., Gervois P, Bart Staels, Haegeman G., de Bosscher K. PARalpha blocks glucocorticoid receptor alpha-mediated transactivation but cooperates with the activated glucocorticoid receptor alpha for transrepression on NF-kappaB. Proc. Natl Acad. Sci. USA, 2009, Vol. 106, no. 18, pp. 7397-7402.Bougarne N., Paumelle R., Caron S., Hennuyer N., Mansouri R., Gervois P, Bart Staels, Haegeman G., de Bosscher K. PARalpha blocks glucocorticoid receptor alpha-mediated transactivation but cooperates with the activated glucocorticoid receptor alpha for transrepression on NF-kappaB. Proc. Natl Acad. Sci. USA, 2009, Vol. 106, no. 18, pp. 7397-7402.Bouhlel M.A., Brozek J., Derudas B., Zawadzki C., Jude B., Staels B., Chinetti-Gbaguidi G. Unlike PPARy, PPARa or PPARp/S activation does not promote human monocyte differentiation toward alternative macrophages. Biochem. Biophys. Res. Commun., 2009, Vol. 386, pp. 459-462.Bouhlel M.A., Brozek J., Derudas B., Zawadzki C., Jude B., Staels B., Chinetti-Gbaguidi G. Unlike PPARy, PPARa or PPARp/S activation does not promote human monocyte differentiation toward alternative macrophages. Biochem. Biophys. Res. Commun., 2009, Vol. 386, pp. 459-462.Bouhlel M.A., Derudas B., Rigamonti E., Dievart R., Brozek J., Haulon S., Zawadzki C., Jude B., Torpier G., Marx N. PPARy activation primes human monocytes into alternative M2 macrophages with anti-inflammatory properties. Cell Metab., 2007, Vol. 6, pp. 137-143.Bouhlel M.A., Derudas B., Rigamonti E., Dievart R., Brozek J., Haulon S., Zawadzki C., Jude B., Torpier G., Marx N. PPARy activation primes human monocytes into alternative M2 macrophages with anti-inflammatory properties. Cell Metab., 2007, Vol. 6, pp. 137-143.Boyd C.M., Darer J., Boult C. Clinical practice guidelines and quality of care for older patients. JAMA, 2005, Vol. 294, pp. 716-724.Boyd C.M., Darer J., Boult C. Clinical practice guidelines and quality of care for older patients. JAMA, 2005, Vol. 294, pp. 716-724.Boyer J.F., Gourraud P.A., Cantagrel A., Davignon J.L., Constantin A. Traditional cardiovascular risk factors in rheumatoid arthritis: a meta-analysis. Joint Bone Spine, 2011, Vol. 78, no. 2, pp. 179-183.Boyer J.F., Gourraud P.A., Cantagrel A., Davignon J.L., Constantin A. Traditional cardiovascular risk factors in rheumatoid arthritis: a meta-analysis. Joint Bone Spine, 2011, Vol. 78, no. 2, pp. 179-183.Bruckert E., Labreuche J., Deplanque D., Touboul P.J., Amarenco P. Fibrates effect on cardiovascular risk is greater in patients with high triglyceride levels or atherogenic dyslipidemia profile: a systematic review and metaanalysis. J. Cardiovasc. Pharmacol., 2011, Vol. 57, no. 2, pp. 267-272.Bruckert E., Labreuche J., Deplanque D., Touboul P.J., Amarenco P. Fibrates effect on cardiovascular risk is greater in patients with high triglyceride levels or atherogenic dyslipidemia profile: a systematic review and metaanalysis. J. Cardiovasc. Pharmacol., 2011, Vol. 57, no. 2, pp. 267-272.Cabrero A., Laguna J.C., Vazquez M. Peroxisome proliferator-activated receptors and the control of inflammation. Curr. Drug Targets Inflamm. Allergy, 2002, Vol. 1, pp. 243-248.Cabrero A., Laguna J.C., Vazquez M. Peroxisome proliferator-activated receptors and the control of inflammation. Curr. Drug Targets Inflamm. Allergy, 2002, Vol. 1, pp. 243-248.Caro-Maldonado A., Wang R., Nichols A.G., Kuraoka M., Milasta S., Sun L.D., Gavin A.L., Abel E.D., Kelsoe G., Green D.R. Metabolic reprogramming is required for antibody production that is suppressed in anergic but exaggerated in chronically BAFF-exposed B cells. J. Immunol., 2014, Vol. 192, pp. 3626-3636.Caro-Maldonado A., Wang R., Nichols A.G., Kuraoka M., Milasta S., Sun L.D., Gavin A.L., Abel E.D., Kelsoe G., Green D.R. Metabolic reprogramming is required for antibody production that is suppressed in anergic but exaggerated in chronically BAFF-exposed B cells. J. Immunol., 2014, Vol. 192, pp. 3626-3636.Castillero E., Nieto-Bona M.P., Fernandez-Galaz C., Martin A.I., Lopez-Menduina M., Granado M., Villanua M.A., Lopez-Calderon A. Fenofibrate, a PPAR{alpha} agonist, decreases atrogenes and myostatin expression and improves arthritis-induced skeletal muscle atrophy. Am. J. Physiol. Endocrinol. Metab., 2011., Vol. 300, no. 5, pp. 790-799.Castillero E., Nieto-Bona M.P., Fernandez-Galaz C., Martin A.I., Lopez-Menduina M., Granado M., Villanua M.A., Lopez-Calderon A. Fenofibrate, a PPAR{alpha} agonist, decreases atrogenes and myostatin expression and improves arthritis-induced skeletal muscle atrophy. Am. J. Physiol. Endocrinol. Metab., 2011., Vol. 300, no. 5, pp. 790-799.Chakravarthy M.V., Pan Z., Zhu Y. “New” hepatic fat activates PPARalpha to maintain glucose, lipid, and cholesterol homeostasis. Cell Metab., 2005, Vol. 1, no. 5, pp. 309-322.Chakravarthy M.V., Pan Z., Zhu Y. “New” hepatic fat activates PPARalpha to maintain glucose, lipid, and cholesterol homeostasis. Cell Metab., 2005, Vol. 1, no. 5, pp. 309-322.Chew E., Ambrosius W, Davis M.D., Gangaputra S., Greven C.M., Hubbard L., Esser B.A., Lovato J.F., Perdue L.H., Goff D.C. Jr, Cushman W.C., Ginsberg H.N., Elam M.B., Genuth S., Gerstein H.C., Schubart U., Fine L.J.; ACCORD Study Group. Effects of medical therapies on retinopathy progression in type 2 diabetes. N. Engl. J. Med., 2010, Vol. 363, no. 3, pp. 233-244.Chew E., Ambrosius W, Davis M.D., Gangaputra S., Greven C.M., Hubbard L., Esser B.A., Lovato J.F., Perdue L.H., Goff D.C. Jr, Cushman W.C., Ginsberg H.N., Elam M.B., Genuth S., Gerstein H.C., Schubart U., Fine L.J.; ACCORD Study Group. Effects of medical therapies on retinopathy progression in type 2 diabetes. N. Engl. J. Med., 2010, Vol. 363, no. 3, pp. 233-244.Chinetti G., Griglio S., Antonucci M., Torra I.P., Delerive P., Majd Z., Fruchart J.C., Chapman J., Najib J., Staels B. Activation of proliferator-activated receptors alpha and gamma induces apoptosis of human monocyte-derived macrophages. J. Biol. Chem., 1998, Vol. 273, no. 40, pp. 25573-25580.Chinetti G., Griglio S., Antonucci M., Torra I.P., Delerive P., Majd Z., Fruchart J.C., Chapman J., Najib J., Staels B. Activation of proliferator-activated receptors alpha and gamma induces apoptosis of human monocyte-derived macrophages. J. Biol. Chem., 1998, Vol. 273, no. 40, pp. 25573-25580.Chinetti G., Fruchart J.C., Staels B. Peroxisome proliferator-activated receptors (PPARs): nuclear receptors at the crossroads between lipid metabolism and inflammation. Inflamm. Res., 2000, Vol. 49, pp. 497-505.Chinetti G., Fruchart J.C., Staels B. Peroxisome proliferator-activated receptors (PPARs): nuclear receptors at the crossroads between lipid metabolism and inflammation. Inflamm. Res., 2000, Vol. 49, pp. 497-505.Chistyakov D.V., Aleshin S.E., Astakhova A.A., Sergeeva M.G., Reiser G. Regulation of peroxisome proliferator-activated receptors (PPAR) a and -y of rat brain astrocytes in the course of activation by toll-like receptor agonists. J. Neurochem., 2015, Vol. 134, no. 1, pp. 113-124.Chistyakov D.V., Aleshin S.E., Astakhova A.A., Sergeeva M.G., Reiser G. Regulation of peroxisome proliferator-activated receptors (PPAR) a and -y of rat brain astrocytes in the course of activation by toll-like receptor agonists. J. Neurochem., 2015, Vol. 134, no. 1, pp. 113-124.Choi J.M., Bothwell A.L. The nuclear receptor PPARs as important regulators of T-cell functions and autoimmune diseases. Mol. Cells, 2012, Vol. 33, pp. 217-222.Choi J.M., Bothwell A.L. The nuclear receptor PPARs as important regulators of T-cell functions and autoimmune diseases. Mol. Cells, 2012, Vol. 33, pp. 217-222.Cipolletta D., Cohen P., Spiegelman B.M., Benoist C., Mathis D. Appearance and disappearance of the mRNA signature characteristic of Treg cells in visceral adipose tissue: age, diet, and PPARy effects. Proc. Natl Acad. Sci. USA, 2015, Vol. 112, pp. 482-487.Cipolletta D., Cohen P., Spiegelman B.M., Benoist C., Mathis D. Appearance and disappearance of the mRNA signature characteristic of Treg cells in visceral adipose tissue: age, diet, and PPARy effects. Proc. Natl Acad. Sci. USA, 2015, Vol. 112, pp. 482-487.Cipolletta D., Feuerer M., Li A., Kamei N., Lee J., Shoelson S.E., Benoist C., Mathis D. PPAR-y is a major driver of the accumulation and phenotype of adipose tissue Treg cells. Nature, 2012, Vol. 486, pp. 549-553.Cipolletta D., Feuerer M., Li A., Kamei N., Lee J., Shoelson S.E., Benoist C., Mathis D. PPAR-y is a major driver of the accumulation and phenotype of adipose tissue Treg cells. Nature, 2012, Vol. 486, pp. 549-553.Clockaerts S., Bastiaansen-Jenniskens Y.M., Feijt C., Verhaar J.A., Somville J., de Clerck L.S., van Osch G.J. Peroxisome proliferator activated receptor alpha activation decreases inflammatory and destructive responses in osteoarthritic cartilage. Osteoarthritis Cartilage, 2011, Vol. 19, no. 7, pp. 895-902.Clockaerts S., Bastiaansen-Jenniskens Y.M., Feijt C., Verhaar J.A., Somville J., de Clerck L.S., van Osch G.J. Peroxisome proliferator activated receptor alpha activation decreases inflammatory and destructive responses in osteoarthritic cartilage. Osteoarthritis Cartilage, 2011, Vol. 19, no. 7, pp. 895-902.Colville-Nash P.R., Qureshi S.S., Willis D., Willoughby D.A. Inhibition of inducible nitric oxide synthase by peroxisome proliferator-activated receptor agonists: correlation with induction of heme oxygenase 1. J. Immunol., 1998, Vol. 161, no. 2, pp. 978-984.Colville-Nash P.R., Qureshi S.S., Willis D., Willoughby D.A. Inhibition of inducible nitric oxide synthase by peroxisome proliferator-activated receptor agonists: correlation with induction of heme oxygenase 1. J. Immunol., 1998, Vol. 161, no. 2, pp. 978-984.Dana N., Vaseghi G., Haghjooy J.S. Crosstalk between peroxisome proliferator-activated receptors and tolllike receptors: a systematic review. Adv. Pharm. Bull., 2019, Vol. 1, pp. 12-21.Dana N., Vaseghi G., Haghjooy J.S. Crosstalk between peroxisome proliferator-activated receptors and tolllike receptors: a systematic review. Adv. Pharm. Bull., 2019, Vol. 1, pp. 12-21.Daste A., Domblides C., Gross-Goupil M., Chakiba C., Quivy A., Cochin V., Ide Mones E., Larmonier N., Soubeyran P., Ravaud A. Immune checkpoint inhibitors and elderly people: a review. Eur. J. Cancer., 2017, Vol. 82, pp. 155-166.Daste A., Domblides C., Gross-Goupil M., Chakiba C., Quivy A., Cochin V., Ide Mones E., Larmonier N., Soubeyran P., Ravaud A. Immune checkpoint inhibitors and elderly people: a review. Eur. J. Cancer., 2017, Vol. 82, pp. 155-166.de Bosscher K., Vanden Berghe W., Haegeman G. Mechanisms of anti-inflammatory action and of immunosuppression by glucocorticoids: negative interference of activated glucocorticoid receptor with transcription factors. J. Neuroimmunol., 2000, Vol. 109, no. 1, pp. 16-22.de Bosscher K., Vanden Berghe W., Haegeman G. Mechanisms of anti-inflammatory action and of immunosuppression by glucocorticoids: negative interference of activated glucocorticoid receptor with transcription factors. J. Neuroimmunol., 2000, Vol. 109, no. 1, pp. 16-22.Delerive P., de Bosscher K., Besnard S., Vanden Berghe W., Peters J.M., Gonzalez F.J., Fruchart J.C., Tedgui A., Haegeman G., Staels B. Peroxisome proliferator-activated receptor alpha negatively regulates the vascular inflammatory gene response by negative cross-talk with transcription factors NF-kappaB and AP-1. J. Biol. Chem., 1999, Vol. 274, no. 45, pp. 32048-32054.Delerive P., de Bosscher K., Besnard S., Vanden Berghe W., Peters J.M., Gonzalez F.J., Fruchart J.C., Tedgui A., Haegeman G., Staels B. Peroxisome proliferator-activated receptor alpha negatively regulates the vascular inflammatory gene response by negative cross-talk with transcription factors NF-kappaB and AP-1. J. Biol. Chem., 1999, Vol. 274, no. 45, pp. 32048-32054.Delerive P., Gervois P., Fruchart J.C., Staels B. Induction of IkappaBalpha expression as a mechanism contributing to the anti-inflammatory activities of peroxisome proliferator-activated receptor-alpha activators. J. Biol. Chem, 2000, Vol. 275, no. 47, pp. 36703-36707.Delerive P., Gervois P., Fruchart J.C., Staels B. Induction of IkappaBalpha expression as a mechanism contributing to the anti-inflammatory activities of peroxisome proliferator-activated receptor-alpha activators. J. Biol. Chem, 2000, Vol. 275, no. 47, pp. 36703-36707.Devchand P.R., Keller H., Peters J.M., Vazquez M., Gonzalez F.J., Wahli W. The PPARalpha-leukotriene B4 pathway to inflammation control. Nature, 1996, Vol. 384, no. 6604, pp. 39-43.Devchand P.R., Keller H., Peters J.M., Vazquez M., Gonzalez F.J., Wahli W. The PPARalpha-leukotriene B4 pathway to inflammation control. Nature, 1996, Vol. 384, no. 6604, pp. 39-43.Doughty C.A., Bleiman B.F., Wagner D.J., Dufort F.J., Mataraza J.M., Roberts M.F., Chiles T.C. Antigen receptor-mediated changes in glucose metabolism in B lymphocytes: role of phosphatidylinositol 3-kinase signaling in the glycolytic control of growth. Blood, 2006, Vol. 107, pp. 4458-4465.Doughty C.A., Bleiman B.F., Wagner D.J., Dufort F.J., Mataraza J.M., Roberts M.F., Chiles T.C. Antigen receptor-mediated changes in glucose metabolism in B lymphocytes: role of phosphatidylinositol 3-kinase signaling in the glycolytic control of growth. Blood, 2006, Vol. 107, pp. 4458-4465.Dunn S.E., Ousman S.S., Sobel R.A., Zuniga L., Baranzini S.E., Youssef S., Crowell A., Loh J., Oksenberg J., Steinman L. Peroxisome proliferator-activated receptor (PPAR)a expression in T cells mediates gender differences in development of T cell-mediated autoimmunity. J. Exp. Med., 2007, Vol. 204, pp. 321-330.Dunn S.E., Ousman S.S., Sobel R.A., Zuniga L., Baranzini S.E., Youssef S., Crowell A., Loh J., Oksenberg J., Steinman L. Peroxisome proliferator-activated receptor (PPAR)a expression in T cells mediates gender differences in development of T cell-mediated autoimmunity. J. Exp. Med., 2007, Vol. 204, pp. 321-330.Everts B., Amiel E., Huang S.C., Smith A.M., Chang C.H., Lam W.Y., Redmann V, Freitas T.C., Blagih J., van der Windt G.J. TLR-driven early glycolytic reprogramming via the kinases TBK1-IKKvarepsilon supports the anabolic demands of dendritic cell activation. Nat. Immunol., 2014, Vol. 15, pp. 323-332.Everts B., Amiel E., Huang S.C., Smith A.M., Chang C.H., Lam W.Y., Redmann V, Freitas T.C., Blagih J., van der Windt G.J. TLR-driven early glycolytic reprogramming via the kinases TBK1-IKKvarepsilon supports the anabolic demands of dendritic cell activation. Nat. Immunol., 2014, Vol. 15, pp. 323-332.Fabbri E., Zoli M., Gonzalez-Freire M., Salive M.E., Studenski S.A., Ferrucci L. Aging and multimorbidity: new tasks, priorities, and frontiers for integrated gerontological and clinical research. J. Am. Med. Dir. Assoc., 2015, Vol. 16, no. 8, pp. 640-647.Fabbri E., Zoli M., Gonzalez-Freire M., Salive M.E., Studenski S.A., Ferrucci L. Aging and multimorbidity: new tasks, priorities, and frontiers for integrated gerontological and clinical research. J. Am. Med. Dir. Assoc., 2015, Vol. 16, no. 8, pp. 640-647.Farnier M., Freeman M., Macdonell G., Perevozskaya I., Davies M.J., Mitchel Y.B., Gumbiner B. Ezetimibe Study Group Efficacy and safety of coadministration of ezetimibe with fenofibrate in patients with mixed hyperlipidemia. Eur. Heart J., 2005, Vol. 26, no. 9, pp. 897-905.Farnier M., Freeman M., Macdonell G., Perevozskaya I., Davies M.J., Mitchel Y.B., Gumbiner B. Ezetimibe Study Group Efficacy and safety of coadministration of ezetimibe with fenofibrate in patients with mixed hyperlipidemia. Eur. Heart J., 2005, Vol. 26, no. 9, pp. 897-905.Foucher C., Brugere L., Ansquer J.C. Fenofibrate, homocysteine and renal function. Curr. Vasc. Pharmacol., 2010, Vol. 8, no. 5, pp. 589-603.Foucher C., Brugere L., Ansquer J.C. Fenofibrate, homocysteine and renal function. Curr. Vasc. Pharmacol., 2010, Vol. 8, no. 5, pp. 589-603.Francois M., Richette P, Tsagris L., Fitting C., Lemay C., Benallaoua M., Tahiri K., Corvol M.T. Activation of the peroxisome proliferator-activated receptor alpha pathway potentiates interleukin-1 receptor antagonist production in cytokine-treated chondrocytes. Arthritis Rheum., 2006, Vol. 54, pp. 1233-1245.Francois M., Richette P, Tsagris L., Fitting C., Lemay C., Benallaoua M., Tahiri K., Corvol M.T. Activation of the peroxisome proliferator-activated receptor alpha pathway potentiates interleukin-1 receptor antagonist production in cytokine-treated chondrocytes. Arthritis Rheum., 2006, Vol. 54, pp. 1233-1245.Frauwirth K.A., Riley J.L., Harris M.H., Parry R.V., Rathmell J.C., Plas D.R., Elstrom R.L., June C.H., Thompson C.B. The CD28 signaling pathway regulates glucose metabolism. Immunity, 2002, Vol. 16, pp. 769-777.Frauwirth K.A., Riley J.L., Harris M.H., Parry R.V., Rathmell J.C., Plas D.R., Elstrom R.L., June C.H., Thompson C.B. The CD28 signaling pathway regulates glucose metabolism. Immunity, 2002, Vol. 16, pp. 769-777.Fuentes E., Guzman-Jofre L., Moore-Carrasco R., Palomo I. Role of PPARs in inflammatory processes associated with metabolic syndrome. Mol. Med. Rep., 2013, Vol. 8, pp. 1611-1616.Fuentes E., Guzman-Jofre L., Moore-Carrasco R., Palomo I. Role of PPARs in inflammatory processes associated with metabolic syndrome. Mol. Med. Rep., 2013, Vol. 8, pp. 1611-1616.Fulbp T., Dupuis G., Witkowski J.M., Larbi A. The role of immunosenescence in the development of agerelated diseases. Rev. Invest. Clin., 2016, Vol. 68, no. 2, pp. 84-91.Fulbp T., Dupuis G., Witkowski J.M., Larbi A. The role of immunosenescence in the development of agerelated diseases. Rev. Invest. Clin., 2016, Vol. 68, no. 2, pp. 84-91.Gervois P, Mansouri R.M. PPARa as a therapeutic target in inflammation-associated diseases. Expert Opin. Ther. Targets., 2012, Vol. 16, pp. 1113-1125.Gervois P, Mansouri R.M. PPARa as a therapeutic target in inflammation-associated diseases. Expert Opin. Ther. Targets., 2012, Vol. 16, pp. 1113-1125.Grygiel-Gorniak B. Peroxisome proliferator-activated receptors and their ligands: nutritional and clinical implications - a review. Nutr. J., 2014, Vol. 13, 17. doi: 10.1186/1475-2891-13-17.Grygiel-Gorniak B. Peroxisome proliferator-activated receptors and their ligands: nutritional and clinical implications - a review. Nutr. J., 2014, Vol. 13, 17. doi: 10.1186/1475-2891-13-17.Guri A.J., Mohapatra S.K., Horne W.T., Hontecillas R., Bassaganya-Riera J. The role of T cell PPAR у in mice with experimental inflammatory bowel disease. BMC Gastroenterol., 2010, Vol. 10, 60. doi: 10.1186/1471-230X-10-60.Guri A.J., Mohapatra S.K., Horne W.T., Hontecillas R., Bassaganya-Riera J. The role of T cell PPAR у in mice with experimental inflammatory bowel disease. BMC Gastroenterol., 2010, Vol. 10, 60. doi: 10.1186/1471-230X-10-60.Heffernan K.S., Ranadive S.M., Jae S.Y. Exercise as medicine for COVID-19: On PPAR with emerging pharmacotherapy. Med. Hypotheses, 2020, Vol. 143, 110197. doi: 10.1016/j.mehy.2020.110197.Heffernan K.S., Ranadive S.M., Jae S.Y. Exercise as medicine for COVID-19: On PPAR with emerging pharmacotherapy. Med. Hypotheses, 2020, Vol. 143, 110197. doi: 10.1016/j.mehy.2020.110197.Hontecillas R., Bassaganya-Riera J. Peroxisome proliferator-activated receptor у is required for regulatory CD4+ T cell-mediated protection against colitis. J. Immunol., 2007, Vol. 178, pp. 2940-2949.Hontecillas R., Bassaganya-Riera J. Peroxisome proliferator-activated receptor у is required for regulatory CD4+ T cell-mediated protection against colitis. J. Immunol., 2007, Vol. 178, pp. 2940-2949.Huang S.C., Everts B., Ivanova Y., O’Sullivan D., Nascimento M., Smith A.M., Beatty W., Love-Gregory L., Lam W.Y., O’Neill C.M., Yan C., Du H., Abumrad N.A., Urban J.F. Jr, Artyomov M.N., Pearce E.L., Pearce E.J. Cell-intrinsic lysosomal lipolysis is essential for alternative activation of macrophages. Nat. Immunol., 2014, Vol. 15, pp. 846-855.Huang S.C., Everts B., Ivanova Y., O’Sullivan D., Nascimento M., Smith A.M., Beatty W., Love-Gregory L., Lam W.Y., O’Neill C.M., Yan C., Du H., Abumrad N.A., Urban J.F. Jr, Artyomov M.N., Pearce E.L., Pearce E.J. Cell-intrinsic lysosomal lipolysis is essential for alternative activation of macrophages. Nat. Immunol., 2014, Vol. 15, pp. 846-855.Jiao M., Ren F., Zhou L. Peroxisome proliferator-activated receptor a activation attenuates the inflammatory response to protect the liver from acute failure by promoting the autophagy pathway. Cell Death Dis., 2014, Vol. 5, e1397. doi: 10.1038/cddis.2014.361.Jiao M., Ren F., Zhou L. Peroxisome proliferator-activated receptor a activation attenuates the inflammatory response to protect the liver from acute failure by promoting the autophagy pathway. Cell Death Dis., 2014, Vol. 5, e1397. doi: 10.1038/cddis.2014.361.Jun M., Foote C., Lv J., Neal B., Patel A., Nicholls S.J., Grobbee D.E., Cass A., Chalmers J., Perkovic V Effects of fibrates on cardiovascular outcomes: a systematic review and meta-analysis. Lancet, 2010, Vol. 375, no. 9729, pp. 1875-1884.Jun M., Foote C., Lv J., Neal B., Patel A., Nicholls S.J., Grobbee D.E., Cass A., Chalmers J., Perkovic V Effects of fibrates on cardiovascular outcomes: a systematic review and meta-analysis. Lancet, 2010, Vol. 375, no. 9729, pp. 1875-1884.Keech A., Simes R.J., Barter P, Best J., Scott R., Taskinen M.R., Forder P, Pillai A., Davis T., Glasziou P, Drury P, Kesaniemi Y.A., Sullivan D., Hunt D., Colman P, d’Emden M., Whiting M., Ehnholm C., Laakso M. FIELD Study Investigators. Effects of long-term fenofibrate therapy on cardiovascular events in 9795 people with type 2 diabetes mellitus (the FIELD study): randomized controlled trial. Lancet, 2005, Vol. 366, no. 9500, pp. 1849-1861.Keech A., Simes R.J., Barter P, Best J., Scott R., Taskinen M.R., Forder P, Pillai A., Davis T., Glasziou P, Drury P, Kesaniemi Y.A., Sullivan D., Hunt D., Colman P, d’Emden M., Whiting M., Ehnholm C., Laakso M. FIELD Study Investigators. Effects of long-term fenofibrate therapy on cardiovascular events in 9795 people with type 2 diabetes mellitus (the FIELD study): randomized controlled trial. Lancet, 2005, Vol. 366, no. 9500, pp. 1849-1861.Kholodenko B.N., Bruggeman F.J., Sauro H.M. Mechanistic and modular approaches to modeling and inference of cellular regulatory networks. Systems Biology: definitions and perspectives. Springer-Verlag., 2005, pp. 143-159.Kholodenko B.N., Bruggeman F.J., Sauro H.M. Mechanistic and modular approaches to modeling and inference of cellular regulatory networks. Systems Biology: definitions and perspectives. Springer-Verlag., 2005, pp. 143-159.Klotz L., Burgdorf S., Dani I., Saijo K., Flossdorf J., Hucke S., Alferink J., Nowak N., Beyer M., Mayer G. The nuclear receptor PPAR у selectively inhibits Th17 differentiation in a T cell-intrinsic fashion and suppresses CNS autoimmunity. J. Exp. Med., 2009, Vol. 206, pp. 2079-2089.Klotz L., Burgdorf S., Dani I., Saijo K., Flossdorf J., Hucke S., Alferink J., Nowak N., Beyer M., Mayer G. The nuclear receptor PPAR у selectively inhibits Th17 differentiation in a T cell-intrinsic fashion and suppresses CNS autoimmunity. J. Exp. Med., 2009, Vol. 206, pp. 2079-2089.Korbecki J., Bobinski R., Dutka M. Self-regulation of the inflammatory response by peroxisome proliferator-activated receptors. Inflamm. Res., 2019, Vol. 68, pp. 443-458.Korbecki J., Bobinski R., Dutka M. Self-regulation of the inflammatory response by peroxisome proliferator-activated receptors. Inflamm. Res., 2019, Vol. 68, pp. 443-458.Kytikova O.Y., Perelman J.M., Novgorodtseva T.P., Denisenko Y.K., Kolosov V.P., Antonyuk M.V., Gvozdenko T.A. Peroxisome proliferator-activated receptors as a therapeutic target in asthma. PPAR Res., 2020, Vol. 2020, 8906968. doi: 10.1155/2020/8906968.Kytikova O.Y., Perelman J.M., Novgorodtseva T.P., Denisenko Y.K., Kolosov V.P., Antonyuk M.V., Gvozdenko T.A. Peroxisome proliferator-activated receptors as a therapeutic target in asthma. PPAR Res., 2020, Vol. 2020, 8906968. doi: 10.1155/2020/8906968.Lane T.A., Lamkin G.E. A reassessment of the energy requirements for neutrophil migration: adenosine triphosphate depletion enhances chemotaxis. Blood, 1984, Vol. 64, pp. 986-993.Lane T.A., Lamkin G.E. A reassessment of the energy requirements for neutrophil migration: adenosine triphosphate depletion enhances chemotaxis. Blood, 1984, Vol. 64, pp. 986-993.Le A., Lane A.N., Hamaker M., Bose S., Gouw A., Barbi J., Tsukamoto T., Rojas C.J., Slusher B.S., Zhang H. Glucose-independent glutamine metabolism via TCA cycling for proliferation and survival in B cells. Cell Metab., 2012, Vol. 15, pp. 110-121.Le A., Lane A.N., Hamaker M., Bose S., Gouw A., Barbi J., Tsukamoto T., Rojas C.J., Slusher B.S., Zhang H. Glucose-independent glutamine metabolism via TCA cycling for proliferation and survival in B cells. Cell Metab., 2012, Vol. 15, pp. 110-121.le Menn G., Neels J.G. Regulation of immune cell function by PPARs and the connection with metabolic and neurodegenerative diseases. Int. J. Mol. Sci., 2018, Vol. 19, no. 6, pp. 1575. doi: 10.3390/ijms19061575.le Menn G., Neels J.G. Regulation of immune cell function by PPARs and the connection with metabolic and neurodegenerative diseases. Int. J. Mol. Sci., 2018, Vol. 19, no. 6, pp. 1575. doi: 10.3390/ijms19061575.Lee M., Savera L., Towfighic A., Chow J., Ovbiagele B. Efficacy of fibrates for cardiovascular risk reduction in persons with atherogenic dyslipidemia: a meta-analysis. Atherosclerosis, 2011, Vol. 217, no. 2, pp. 492-498.Lee M., Savera L., Towfighic A., Chow J., Ovbiagele B. Efficacy of fibrates for cardiovascular risk reduction in persons with atherogenic dyslipidemia: a meta-analysis. Atherosclerosis, 2011, Vol. 217, no. 2, pp. 492-498.Lee W., Bajwa P.J., Carson M.J. Fenofibrate represses interleukin-17 and interferon-gamma expression and improves colitis in interleukin-10-deficient mice. Gastroenterology, 2007, Vol. 133, no. 1, pp. 108-123.Lee W., Bajwa P.J., Carson M.J. Fenofibrate represses interleukin-17 and interferon-gamma expression and improves colitis in interleukin-10-deficient mice. Gastroenterology, 2007, Vol. 133, no. 1, pp. 108-123.Liao D., Tan H., Hui R., Li Z., Jiang X., Gaubatz J., Yang F., Durante W, Chan L., Schafer A.I., Pownall H.J., Yang X., Wang H. Hyperhomocysteinemia decreases circulating high-density lipoprotein by inhibiting apolipoprotein A-I protein synthesis and enhancing HDL cholesterol clearance. Circ. Res., 2006, Vol. 99, no. 6, pp. 598-606.Liao D., Tan H., Hui R., Li Z., Jiang X., Gaubatz J., Yang F., Durante W, Chan L., Schafer A.I., Pownall H.J., Yang X., Wang H. Hyperhomocysteinemia decreases circulating high-density lipoprotein by inhibiting apolipoprotein A-I protein synthesis and enhancing HDL cholesterol clearance. Circ. Res., 2006, Vol. 99, no. 6, pp. 598-606.Lima E., Lima M.M.D., Marques C.D., Duarte A.L.B., Pita I., Pita M.G. Peroxisome proliferator-activated receptor agonists (PPARs): a promising prospect in the treatment of psoriasis and psoriatic arthritis. An. Bras. Dermatol., 2013, Vol. 88, no. 6, pp. 1029-1035.Lima E., Lima M.M.D., Marques C.D., Duarte A.L.B., Pita I., Pita M.G. Peroxisome proliferator-activated receptor agonists (PPARs): a promising prospect in the treatment of psoriasis and psoriatic arthritis. An. Bras. Dermatol., 2013, Vol. 88, no. 6, pp. 1029-1035.Macintyre A.N., Gerriets V.A., Nichols A.G., Michalek R.D., Rudolph M.C., Deoliveira D., Anderson S.M., Abel E.D., Chen B.J., Jeffrey C., Rathmell J.C. The glucose transporter Glut1 is selectively essential for CD4 T cell activation and effector function. Cell Metab., 2014, Vol. 20, pp. 61-72.Macintyre A.N., Gerriets V.A., Nichols A.G., Michalek R.D., Rudolph M.C., Deoliveira D., Anderson S.M., Abel E.D., Chen B.J., Jeffrey C., Rathmell J.C. The glucose transporter Glut1 is selectively essential for CD4 T cell activation and effector function. Cell Metab., 2014, Vol. 20, pp. 61-72.Madej A., Okopien B., Kowalski J., Zielinski M., Wysocki J., Szygula B., Kalina Z., Herman Z.S. Effects of fenofibrate on plasma cytokine concentrations in patients with atherosclerosis and hyperlipoproteinemia IIb. Int. J. Clin. Pharmacol. Ther., 1998, Vol. 36, no. 6, pp. 345-349.Madej A., Okopien B., Kowalski J., Zielinski M., Wysocki J., Szygula B., Kalina Z., Herman Z.S. Effects of fenofibrate on plasma cytokine concentrations in patients with atherosclerosis and hyperlipoproteinemia IIb. Int. J. Clin. Pharmacol. Ther., 1998, Vol. 36, no. 6, pp. 345-349.Marx N., Sukhova G.K., Collins T., Libby P, Plutzky J. PPARalpha activators inhibit cytokine-induced vascular cell adhesion molecule-1 expression in human endothelial cells. Circulation, 1999, Vol. 99, no. 24, pp. 3125-3131.Marx N., Sukhova G.K., Collins T., Libby P, Plutzky J. PPARalpha activators inhibit cytokine-induced vascular cell adhesion molecule-1 expression in human endothelial cells. Circulation, 1999, Vol. 99, no. 24, pp. 3125-3131.Michalek R.D., Gerriets V.A., Jacobs S.R., Macintyre A.N., MacIver N.J., Mason E.F., Sullivan S.A., Nichols A.G., Rathmell J.C. Cutting edge: distinct glycolytic and lipid oxidative metabolic programs are essential for effector and regulatory CD4+ T cell subsets. J. Immunol., 2011, Vol. 186, pp. 3299-3303.Michalek R.D., Gerriets V.A., Jacobs S.R., Macintyre A.N., MacIver N.J., Mason E.F., Sullivan S.A., Nichols A.G., Rathmell J.C. Cutting edge: distinct glycolytic and lipid oxidative metabolic programs are essential for effector and regulatory CD4+ T cell subsets. J. Immunol., 2011, Vol. 186, pp. 3299-3303.Michalik L., Auwerx J., Berger J.P., Chatterjee V.K., Glass C.K., Gonzalez F.J., Grimaldi P.A., Kadowaki T., Lazar M.A., O’Rahilly S., Palmer C.N.A., Plutzky J., Reddy J.K., Spiegelman B.M., Staels B., Wahli W. International union of pharmacology. LXI. Peroxisome proliferator-activated receptors. Pharmacol. Rev., 2006, Vol. 58, no. 4, pp. 726-741.Michalik L., Auwerx J., Berger J.P., Chatterjee V.K., Glass C.K., Gonzalez F.J., Grimaldi P.A., Kadowaki T., Lazar M.A., O’Rahilly S., Palmer C.N.A., Plutzky J., Reddy J.K., Spiegelman B.M., Staels B., Wahli W. International union of pharmacology. LXI. Peroxisome proliferator-activated receptors. Pharmacol. Rev., 2006, Vol. 58, no. 4, pp. 726-741.Moraes L.A., Piqueras L., Bishop-Bailey D. Peroxisome proliferator-activated receptors and inflammation. Pharmacol. Ther., 2006, Vol. 110, pp. 371-385.Moraes L.A., Piqueras L., Bishop-Bailey D. Peroxisome proliferator-activated receptors and inflammation. Pharmacol. Ther., 2006, Vol. 110, pp. 371-385.Namgaladze D., Lips S., Leiker T.J., Murphy R.C., Ekroos K., Ferreiros N., Geisslinger G., Brune B. Inhibition of macrophage fatty acid P-oxidation exacerbates palmitate-induced inflammatory and endoplasmic reticulum stress responses. Diabetologia, 2014, Vol. 57, pp. 1067-1077.Namgaladze D., Lips S., Leiker T.J., Murphy R.C., Ekroos K., Ferreiros N., Geisslinger G., Brune B. Inhibition of macrophage fatty acid P-oxidation exacerbates palmitate-induced inflammatory and endoplasmic reticulum stress responses. Diabetologia, 2014, Vol. 57, pp. 1067-1077.Necela B.M., Su W, Thompson E.A. Toll-like receptor 4 mediates cross-talk between peroxisome proliferator-activated receptor gamma and nuclear factor-kappaB in macrophages. Immunology, 2008, Vol. 125, no. 3, pp. 344-358.Necela B.M., Su W, Thompson E.A. Toll-like receptor 4 mediates cross-talk between peroxisome proliferator-activated receptor gamma and nuclear factor-kappaB in macrophages. Immunology, 2008, Vol. 125, no. 3, pp. 344-358.Nogueira-Recalde U., Lorenzo-Gomez I., Blanco F.J., Loza M.I., Grassi D., Shirinsky V., Shirinsky I., Lotz M., Robbins P.D., Dominguez E., Carames B. Fibrates as drugs with senolytic andautophagic activity for osteoarthritis therapy. EBioMedicine, 2019, Vol. 45, pp. 588-605.Nogueira-Recalde U., Lorenzo-Gomez I., Blanco F.J., Loza M.I., Grassi D., Shirinsky V., Shirinsky I., Lotz M., Robbins P.D., Dominguez E., Carames B. Fibrates as drugs with senolytic andautophagic activity for osteoarthritis therapy. EBioMedicine, 2019, Vol. 45, pp. 588-605.Nuclear Receptors Nomenclature Committee. A unified nomenclature system for the nuclear receptor superfamily. Cell, 1999, Vol. 97, pp. 161-163.Nuclear Receptors Nomenclature Committee. A unified nomenclature system for the nuclear receptor superfamily. Cell, 1999, Vol. 97, pp. 161-163.Okamoto H., Iwamoto T., Kotake S., Momohara S., Yamanaka H., Kamatani N. Inhibition of NF-kappaB signaling by fenofibrate, a peroxisome proliferator-activated receptor-alpha ligand, presents a therapeutic strategy for rheumatoid arthritis. Clin. Exp. Rheumatol., 2005, Vol. 23, pp. 323-330.Okamoto H., Iwamoto T., Kotake S., Momohara S., Yamanaka H., Kamatani N. Inhibition of NF-kappaB signaling by fenofibrate, a peroxisome proliferator-activated receptor-alpha ligand, presents a therapeutic strategy for rheumatoid arthritis. Clin. Exp. Rheumatol., 2005, Vol. 23, pp. 323-330.Park H.J., Kim D.H., Choi J.Y., Kim W.J., Kim J.Y., Senejani A.G., Hwang S.S., Kim L.K., Tobiasova Z., Lee G.R., Craft J., Bothwell A.L., Choi J.M. PPARy negatively regulates T cell activation to prevent follicular helper T cells and germinal center formation. PLoS One, 2014, Vol. 9, e99127. doi: 10.1371/journal.pone.0099127.Park H.J., Kim D.H., Choi J.Y., Kim W.J., Kim J.Y., Senejani A.G., Hwang S.S., Kim L.K., Tobiasova Z., Lee G.R., Craft J., Bothwell A.L., Choi J.M. PPARy negatively regulates T cell activation to prevent follicular helper T cells and germinal center formation. PLoS One, 2014, Vol. 9, e99127. doi: 10.1371/journal.pone.0099127.Park H.J., Park H.S., Lee J.U., Bothwell A.L., Choi J.M. Gender-specific differences in PPARy regulation of follicular helper T cell responses with estrogen. Sci. Rep., 2016, Vol. 6, 28495. doi: 10.1038/srep28495.Park H.J., Park H.S., Lee J.U., Bothwell A.L., Choi J.M. Gender-specific differences in PPARy regulation of follicular helper T cell responses with estrogen. Sci. Rep., 2016, Vol. 6, 28495. doi: 10.1038/srep28495.Park H.J., Park H.S., Lee J.U., Bothwell A.L., Choi J.M. Sex-based selectivity of PPARy regulation in Th1, Th2, and Th17 differentiation. Int. J. Mol. Sci., 2016, Vol. 17, 1347. doi: 10.3390/ijms17081347.Park H.J., Park H.S., Lee J.U., Bothwell A.L., Choi J.M. Sex-based selectivity of PPARy regulation in Th1, Th2, and Th17 differentiation. Int. J. Mol. Sci., 2016, Vol. 17, 1347. doi: 10.3390/ijms17081347.Penas F., Mirkin G.A., Vera M., Cevey A., Gonzalez C.D., Gomez M.I., Sales M.E., Goren N.B. Treatment in vitro with PPARa and PPARy ligands drives M1-to-M2 polarization of macrophages from T. cruzi - infected mice. Biochim. Biophys. Acta., 2015, Vol. 1852, pp. 893-904.Penas F., Mirkin G.A., Vera M., Cevey A., Gonzalez C.D., Gomez M.I., Sales M.E., Goren N.B. Treatment in vitro with PPARa and PPARy ligands drives M1-to-M2 polarization of macrophages from T. cruzi - infected mice. Biochim. Biophys. Acta., 2015, Vol. 1852, pp. 893-904.Phong B., Avery L., Menk A.V., Delgoffe G.M., Kane L.P Cutting edge: murine mast cells rapidly modulate metabolic pathways essential for distinct effector functions. J. Immunol., 2017, Vol. 198, pp. 640-644.Phong B., Avery L., Menk A.V., Delgoffe G.M., Kane L.P Cutting edge: murine mast cells rapidly modulate metabolic pathways essential for distinct effector functions. J. Immunol., 2017, Vol. 198, pp. 640-644.Pyper S.R., Viswakarma N., Yu S., Reddy J.K. PPAR alpha: energy combustion, hypolipidemia, inflammation and cancer. Nucl. Recept. Signal., 2010, Vol. 8, e002. doi: 10.1621/nrs.08002.Pyper S.R., Viswakarma N., Yu S., Reddy J.K. PPAR alpha: energy combustion, hypolipidemia, inflammation and cancer. Nucl. Recept. Signal., 2010, Vol. 8, e002. doi: 10.1621/nrs.08002.Rajamani K., Colman P.G., Li L.P., Best J.D., Voysey M., D’Emden M.C., Laakso M., Baker J.R., Keech A.C. FIELD Study Investigators. Effect of fenofibrate on amputation events in people with type 2 diabetes mellitus (FIELD study): a prespecified analysis of a randomised controlled trial. Lancet, 2009, Vol. 373, pp. 1780-1788.Rajamani K., Colman P.G., Li L.P., Best J.D., Voysey M., D’Emden M.C., Laakso M., Baker J.R., Keech A.C. FIELD Study Investigators. Effect of fenofibrate on amputation events in people with type 2 diabetes mellitus (FIELD study): a prespecified analysis of a randomised controlled trial. Lancet, 2009, Vol. 373, pp. 1780-1788.Riccardi L., Mazzon E., Bruscoli S., Esposito E., Crisafulli C., di Paola R., Caminiti R., Riccardi C., Cuzzocrea S. Peroxisome proliferator-activated receptor-alpha modulates the anti-inflammatory effect of glucocorticoids in a model of inflammatory bowel disease in mice. Shock, 2009, Vol. 31, no. 3, pp. 308-316.Riccardi L., Mazzon E., Bruscoli S., Esposito E., Crisafulli C., di Paola R., Caminiti R., Riccardi C., Cuzzocrea S. Peroxisome proliferator-activated receptor-alpha modulates the anti-inflammatory effect of glucocorticoids in a model of inflammatory bowel disease in mice. Shock, 2009, Vol. 31, no. 3, pp. 308-316.Ricote M., Glass C.K. PPARs and molecular mechanisms of transrepression. Biochim. Biophys. Acta., 2007, Vol. 1771, pp. 926-935.Ricote M., Glass C.K. PPARs and molecular mechanisms of transrepression. Biochim. Biophys. Acta., 2007, Vol. 1771, pp. 926-935.Rival Y., Puech L., Taillandier T. PPAR activators and COX inhibitors selectively block cytokine-induced COX-2 expression and activity in human aortic smooth muscle cells. Eur. J. Pharmacol., 2009, Vol. 606, no. 1-3, pp. 121-129.Rival Y., Puech L., Taillandier T. PPAR activators and COX inhibitors selectively block cytokine-induced COX-2 expression and activity in human aortic smooth muscle cells. Eur. J. Pharmacol., 2009, Vol. 606, no. 1-3, pp. 121-129.Rodriguez-Espinosa O., Rojas-Espinosa O., Moreno-Altamirano M.M., Lopez-Villegas E.O., Sanchez-Garcia FJ. Metabolic requirements for neutrophil extracellular traps formation. Immunology, 2015, Vol. 145, pp. 213-224.Rodriguez-Espinosa O., Rojas-Espinosa O., Moreno-Altamirano M.M., Lopez-Villegas E.O., Sanchez-Garcia FJ. Metabolic requirements for neutrophil extracellular traps formation. Immunology, 2015, Vol. 145, pp. 213-224.Rotman N., Wahli W. Fatty acid synthesis and PPARalpha hand in hand. Chem. Biol., 2009, Vol. 16, no. 8, pp. 801-802.Rotman N., Wahli W. Fatty acid synthesis and PPARalpha hand in hand. Chem. Biol., 2009, Vol. 16, no. 8, pp. 801-802.Shah A., Rader D.J., Millar J.S. The effect of PPAR-alpha agonism on apolipoprotein metabolism in humans. Atherosclerosis, 2010, Vol. 210, no. 1, pp. 35-40.Shah A., Rader D.J., Millar J.S. The effect of PPAR-alpha agonism on apolipoprotein metabolism in humans. Atherosclerosis, 2010, Vol. 210, no. 1, pp. 35-40.Shi L.Z., Wang R., Huang G., Vogel P, Neale G., Green D.R., Chi H. HIFla-dependent glycolytic pathway orchestrates a metabolic checkpoint for the differentiation of TH17 and Treg cells. J. Exp. Med., 2011, Vol. 208, pp. 1367-1376.Shi L.Z., Wang R., Huang G., Vogel P, Neale G., Green D.R., Chi H. HIFla-dependent glycolytic pathway orchestrates a metabolic checkpoint for the differentiation of TH17 and Treg cells. J. Exp. Med., 2011, Vol. 208, pp. 1367-1376.Shirinsky I., Polovnikova O., Kalinovskaya N., Shirinsky V The effects of fenofibrate on inflammation and cardiovascular markers in patients with active rheumatoid arthritis: a pilot study. Rheumatol. Int., 2013. Vol. 33, no. 12, pp. 3045-3048.Shirinsky I., Polovnikova O., Kalinovskaya N., Shirinsky V The effects of fenofibrate on inflammation and cardiovascular markers in patients with active rheumatoid arthritis: a pilot study. Rheumatol. Int., 2013. Vol. 33, no. 12, pp. 3045-3048.Shirinsky I.V., Shirinsky V.S. Targeting nuclear hormone receptors: PPAR alpha agonists as potential disease -modifing drugs for rheumatoid arthritis. Int. J. Rhematol., 2011, Vol. 2011, 937843. doi: 10.1155/2011/937843.Shirinsky I.V., Shirinsky V.S. Targeting nuclear hormone receptors: PPAR alpha agonists as potential disease -modifing drugs for rheumatoid arthritis. Int. J. Rhematol., 2011, Vol. 2011, 937843. doi: 10.1155/2011/937843.Shirinsky I.V., Shirinsky V.S. Treatment of erosive osteoarthritis with peroxisome proliferator-activated receptor alpha agonist fenofibrate: a pilot study. Rheumatol. Int., 2014, Vol. 34, no. 5, pp. 613-616.Shirinsky I.V., Shirinsky V.S. Treatment of erosive osteoarthritis with peroxisome proliferator-activated receptor alpha agonist fenofibrate: a pilot study. Rheumatol. Int., 2014, Vol. 34, no. 5, pp. 613-616.Staels B., Koenig W., Habib A. Activation of human aortic smooth-muscle cells is inhibited by PPARalpha but not by PPARgamma activators. Nature, 1998, Vol. 393, no. 6687, pp. 790-793.Staels B., Koenig W., Habib A. Activation of human aortic smooth-muscle cells is inhibited by PPARalpha but not by PPARgamma activators. Nature, 1998, Vol. 393, no. 6687, pp. 790-793.Sumbayev V.V., Nicholas S.A., Streatfield C.L., Gibbs B.F. Involvement of hypoxia-inducible factor-1 HiF(1a) in IgE-mediated primary human basophil responses. Eur. J. Immunol., 2009, Vol. 39, pp. 3511-3519.Sumbayev V.V., Nicholas S.A., Streatfield C.L., Gibbs B.F. Involvement of hypoxia-inducible factor-1 HiF(1a) in IgE-mediated primary human basophil responses. Eur. J. Immunol., 2009, Vol. 39, pp. 3511-3519.Taskinen M.R., Sullivan D.R., Ehnholm C., Whiting M., Zannino D., Keech A.C. Relationships of HDL cholesterol, ApoA-I, and ApoA-II with homocysteine and creatinine in patients with type 2 diabetes treated with fenofibrate. Arterioscler. Thromb. Vasc. Biol., 2009, Vol. 29, no. 6, pp. 950-955.Taskinen M.R., Sullivan D.R., Ehnholm C., Whiting M., Zannino D., Keech A.C. Relationships of HDL cholesterol, ApoA-I, and ApoA-II with homocysteine and creatinine in patients with type 2 diabetes treated with fenofibrate. Arterioscler. Thromb. Vasc. Biol., 2009, Vol. 29, no. 6, pp. 950-955.van der Geest K.S., Abdulahad W.H., Tete S.M., Lorencetti P.G., Horst G., Bos N.A., Kroesen B.J., Brouwer E., Boots A.M. Aging disturbs the balance between effector and regulatory CD4+ T cells. Exp. Gerontol., 2014, Vol. 60, pp. 190-196.van der Geest K.S., Abdulahad W.H., Tete S.M., Lorencetti P.G., Horst G., Bos N.A., Kroesen B.J., Brouwer E., Boots A.M. Aging disturbs the balance between effector and regulatory CD4+ T cells. Exp. Gerontol., 2014, Vol. 60, pp. 190-196.van der Windt G.J., Everts B., Chang C.H., Curtis J.D., Freitas T.C., Amiel E., Pearce E.J., Pearce E.L. Mitochondrial respiratory capacity is a critical regulator of CD8+ T cell memory development. Immunity, 2012, Vol. 36, pp. 68-78.van der Windt G.J., Everts B., Chang C.H., Curtis J.D., Freitas T.C., Amiel E., Pearce E.J., Pearce E.L. Mitochondrial respiratory capacity is a critical regulator of CD8+ T cell memory development. Immunity, 2012, Vol. 36, pp. 68-78.van Eekeren I.C.M., Clockaerts S., Lubberts E., Verhaar J., van Osch G., Bierma-Zeinstra S.M. Fibrates as therapy for osteoarthritis and rheumatoid arthritis? A systematic review Ther. Adv. Musculoskelet. Dis., 2013, Vol. 5, no. 1, pp. 33-44.van Eekeren I.C.M., Clockaerts S., Lubberts E., Verhaar J., van Osch G., Bierma-Zeinstra S.M. Fibrates as therapy for osteoarthritis and rheumatoid arthritis? A systematic review Ther. Adv. Musculoskelet. Dis., 2013, Vol. 5, no. 1, pp. 33-44.Wahli W., Michalik L. PPARs at the crossroads of lipid signaling and inflammation. Trends Endocrinol. Metab., 2012, Vol. 23, pp. 351-363.Wahli W., Michalik L. PPARs at the crossroads of lipid signaling and inflammation. Trends Endocrinol. Metab., 2012, Vol. 23, pp. 351-363.Wang R., Dillon C.P., Shi L.Z., Milasta S., Carter R., Finkelstein D., McCormick L.L., Fitzgerald P, Chi H., Munger J. The transcription factor Myc controls metabolic reprogramming upon T lymphocyte activation. Immunity, 2011, Vol. 35, pp. 871-882.Wang R., Dillon C.P., Shi L.Z., Milasta S., Carter R., Finkelstein D., McCormick L.L., Fitzgerald P, Chi H., Munger J. The transcription factor Myc controls metabolic reprogramming upon T lymphocyte activation. Immunity, 2011, Vol. 35, pp. 871-882.Wohlfert E.A., Nichols F.C., Nevius E., Clark R.B. Peroxisome proliferator-activated receptor у (PPARy) and immunoregulation: enhancement of regulatory T cells through PPARy-dependent and -independent mechanisms. J. Immunol., 2007, Vol. 178, pp. 4129-4135.Wohlfert E.A., Nichols F.C., Nevius E., Clark R.B. Peroxisome proliferator-activated receptor у (PPARy) and immunoregulation: enhancement of regulatory T cells through PPARy-dependent and -independent mechanisms. J. Immunol., 2007, Vol. 178, pp. 4129-4135.Wojtowicz S., Strosznajder A.K., Jezyna M. The novel role of PPAR Alpha in the brain: promising target in therapy of alzheimer’s disease and other neurodegenerative disorders. Neurochem. Res., 2020, Vol. 45, pp. 972-988.Wojtowicz S., Strosznajder A.K., Jezyna M. The novel role of PPAR Alpha in the brain: promising target in therapy of alzheimer’s disease and other neurodegenerative disorders. Neurochem. Res., 2020, Vol. 45, pp. 972-988.Yang Y., Gocke A.R., Lovett-Racke A., Drew P.D., Racke M.K. PPAR Alpha regulation of the immune response and autoimmune encephalomyelitis. PPAR Res., 2008, Vol. 2008, 546753. doi: 10.1155/2008/546753.Yang Y., Gocke A.R., Lovett-Racke A., Drew P.D., Racke M.K. PPAR Alpha regulation of the immune response and autoimmune encephalomyelitis. PPAR Res., 2008, Vol. 2008, 546753. doi: 10.1155/2008/546753.Zhang M.A., Ahn J.J., Zhao F.L., Selvanantham T., Mallevaey T., Stock N., Correa L., Clark R., Spaner D., Dunn S.E. Antagonizing peroxisome proliferator-activated receptor a activity selectively enhances Th1 immunity in male mice. J. Immunol., 2015, Vol. 195, pp. 5189-5202.Zhang M.A., Ahn J.J., Zhao F.L., Selvanantham T., Mallevaey T., Stock N., Correa L., Clark R., Spaner D., Dunn S.E. Antagonizing peroxisome proliferator-activated receptor a activity selectively enhances Th1 immunity in male mice. J. Immunol., 2015, Vol. 195, pp. 5189-5202.Zhang M.A., Rego D., Moshkova M., Kebir H., Chruscinski A., Nguyen H., Akkermann R., Stanczyk F.Z., Prat A., Steinman L. Peroxisome proliferator-activated receptor (PPAR)a and -y regulate IFNy and IL-17A production by human T cells in a sex-specific way. Proc. Natl Acad. Sci. USA, 2012, Vol. 109, pp. 9505-9510.Zhang M.A., Rego D., Moshkova M., Kebir H., Chruscinski A., Nguyen H., Akkermann R., Stanczyk F.Z., Prat A., Steinman L. Peroxisome proliferator-activated receptor (PPAR)a and -y regulate IFNy and IL-17A production by human T cells in a sex-specific way. Proc. Natl Acad. Sci. USA, 2012, Vol. 109, pp. 9505-9510.Zhang T., Shao B., Liu G.A. Rosuvastatin promotes the differentiation of peripheral blood monocytes into M2 macrophages in patients with atherosclerosis by activating PPAR-y. Eur. Rev. Med. Pharmacol. Sci., 2017, Vol. 21, pp. 4464-4471.Zhang T., Shao B., Liu G.A. Rosuvastatin promotes the differentiation of peripheral blood monocytes into M2 macrophages in patients with atherosclerosis by activating PPAR-y. Eur. Rev. Med. Pharmacol. Sci., 2017, Vol. 21, pp. 4464-4471.Zhu L., Hayen A., Bell K.J.L. Legacy effect of fibrate add-on therapy in diabetic patients with dyslipidemia: a secondary analysis of the ACCORDION study. Cardiovasc. Diabetol., 2020, Vol. 19, no. 1, 28. doi: 10.1186/s12933-020-01002-x.Zhu L., Hayen A., Bell K.J.L. Legacy effect of fibrate add-on therapy in diabetic patients with dyslipidemia: a secondary analysis of the ACCORDION study. Cardiovasc. Diabetol., 2020, Vol. 19, no. 1, 28. doi: 10.1186/s12933-020-01002-x.

The authors declare that there are no conflicts of interest present.