{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,29]],"date-time":"2026-07-29T19:32:16Z","timestamp":1785353536794,"version":"3.55.0"},"reference-count":50,"publisher":"MDPI AG","issue":"14","license":[{"start":{"date-parts":[[2021,7,19]],"date-time":"2021-07-19T00:00:00Z","timestamp":1626652800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003243","name":"Ministerstvo Zdravotnictv\u00ed Cesk\u00e9 Republiky","doi-asserted-by":"publisher","award":["IN 00023001"],"award-info":[{"award-number":["IN 00023001"]}],"id":[{"id":"10.13039\/501100003243","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003243","name":"Ministerstvo Zdravotnictv\u00ed Cesk\u00e9 Republiky","doi-asserted-by":"publisher","award":["IGA_LF_2021_013"],"award-info":[{"award-number":["IGA_LF_2021_013"]}],"id":[{"id":"10.13039\/501100003243","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Metformin can reduce cardiovascular risk independent of glycemic control. The mechanisms behind its non-glycemic benefits, which include decreased energy intake, lower blood pressure and improved lipid and fatty acid metabolism, are not fully understood. In our study, metformin treatment reduced myocardial accumulation of neutral lipids\u2014triglycerides, cholesteryl esters and the lipotoxic intermediates\u2014diacylglycerols and lysophosphatidylcholines in a prediabetic rat model (p &lt; 0.001). We observed an association between decreased gene expression and SCD-1 activity (p &lt; 0.05). In addition, metformin markedly improved phospholipid fatty acid composition in the myocardium, represented by decreased SFA profiles and increased n3-PUFA profiles. Known for its cardioprotective and anti-inflammatory properties, metformin also had positive effects on arachidonic acid metabolism and CYP-derived arachidonic acid metabolites. We also found an association between increased gene expression of the cardiac isoform CYP2c with increased 14,15-EET (p &lt; 0.05) and markedly reduced 20-HETE (p &lt; 0.001) in the myocardium. Based on these results, we conclude that metformin treatment reduces the lipogenic enzyme SCD-1 and the accumulation of the lipotoxic intermediates diacylglycerols and lysophosphatidylcholine. Increased CYP2c gene expression and beneficial effects on CYP-derived arachidonic acid metabolites in the myocardium can also be involved in cardioprotective effect of metformin.<\/jats:p>","DOI":"10.3390\/ijms22147680","type":"journal-article","created":{"date-parts":[[2021,7,19]],"date-time":"2021-07-19T04:55:40Z","timestamp":1626670540000},"page":"7680","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":24,"title":["Metformin Affects Cardiac Arachidonic Acid Metabolism and Cardiac Lipid Metabolite Storage in a Prediabetic Rat Model"],"prefix":"10.3390","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8771-9338","authenticated-orcid":false,"given":"Denisa","family":"Miklankova","sequence":"first","affiliation":[{"name":"Centre for Experimental Medicine, Institute for Clinical and Experimental Medicine, 14021 Prague, Czech Republic"},{"name":"First Faculty of Medicine, Charles University, 12108 Prague, Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Irena","family":"Markova","sequence":"additional","affiliation":[{"name":"Centre for Experimental Medicine, Institute for Clinical and Experimental Medicine, 14021 Prague, Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martina","family":"H\u00fcttl","sequence":"additional","affiliation":[{"name":"Centre for Experimental Medicine, Institute for Clinical and Experimental Medicine, 14021 Prague, Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0869-8848","authenticated-orcid":false,"given":"Iveta","family":"Zapletalova","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Faculty of Medicine and Dentistry, Palacky University Olomouc, 77900 Olomouc, Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1252-4971","authenticated-orcid":false,"given":"Martin","family":"Poruba","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Faculty of Medicine and Dentistry, Palacky University Olomouc, 77900 Olomouc, Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hana","family":"Malinska","sequence":"additional","affiliation":[{"name":"Centre for Experimental Medicine, Institute for Clinical and Experimental Medicine, 14021 Prague, Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,7,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"364","DOI":"10.1016\/j.tcm.2015.10.004","article-title":"Metabolic syndrome update","volume":"26","author":"Grundy","year":"2016","journal-title":"Trends Cardiovasc. Med."},{"key":"ref_2","first-page":"1","article-title":"Metabolic syndrome and insulin resistance: Underlying causes and modification by exercise training","volume":"3","author":"Roberts","year":"2013","journal-title":"Compr. Physiol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"390","DOI":"10.2174\/157339912802083531","article-title":"Lipid composition of cell membranes and its relevance in type 2 diabetes mellitus","volume":"8","author":"Weijers","year":"2012","journal-title":"Curr. Diabetes Rev."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"831","DOI":"10.1016\/j.tem.2017.10.003","article-title":"Insights into Stearoyl-CoA Desaturase-1 Regulation of Systemic Metabolism","volume":"28","author":"AM","year":"2017","journal-title":"Trends Endocrinol. Metab."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"183","DOI":"10.18388\/pb.2018_130","article-title":"The role of stearoyl-CoA desaturase in the regulation of cardiac metabolism","volume":"64","author":"Tabaczar","year":"2018","journal-title":"Postepy. Biochem."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.plipres.2014.11.003","article-title":"Metabolic reprogramming of the heart through stearoyl-CoA desaturase","volume":"57","author":"Dobrzyn","year":"2015","journal-title":"Prog. Lipid. Res."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1016\/j.pharmthera.2017.05.005","article-title":"Cytochrome P450-derived eicosanoids and heart function","volume":"179","author":"Jamieson","year":"2017","journal-title":"Pharmacol. Ther."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1061","DOI":"10.2174\/1381612826666201222154616","article-title":"Metformin: Is it still the first line in type 2 diabetes management algorithm?","volume":"27","author":"Grammatiki","year":"2021","journal-title":"Curr. Pharm. Des."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1007\/s11892-017-0829-8","article-title":"Metformin: New Preparations and Nonglycemic Benefits","volume":"17","author":"Fujita","year":"2017","journal-title":"Curr. Diab. Rep."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"346","DOI":"10.1097\/MOL.0000000000000532","article-title":"Metformin, lipids and atherosclerosis prevention","volume":"29","author":"Jenkins","year":"2018","journal-title":"Curr. Opin. Lipidol."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Woo, S.L., Xu, H., Li, H., Zhao, Y., Hu, X., Zhao, J., Guo, X., Guo, T., Botchlett, R., and Qi, T. (2014). Metformin ameliorates hepatic steatosis and inflammation without altering adipose phenotype in diet-induced obesity. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0091111"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"893","DOI":"10.1016\/S0140-6736(01)06042-1","article-title":"Metformin in non-alcoholic steatohepatitis","volume":"358","author":"Marchesini","year":"2001","journal-title":"Lancet"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"880","DOI":"10.2337\/db13-0194","article-title":"Metformin lowers plasma triglycerides by promoting VLDL-triglyceride clearance by brown adipose tissue in mice","volume":"63","author":"Geerling","year":"2014","journal-title":"Diabetes"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"172","DOI":"10.1111\/j.1365-2036.2008.03869.x","article-title":"Clinical trial: Pilot study of metformin for the treatment of non-alcoholic steatohepatitis","volume":"29","author":"Loomba","year":"2009","journal-title":"Aliment. Pharmacol. Ther."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"657","DOI":"10.1016\/j.numecd.2017.04.009","article-title":"Metformin effects on the heart and the cardiovascular system: A review of experimental and clinical data","volume":"27","author":"Nesti","year":"2017","journal-title":"Nutr. Metab. Cardiovasc. Dis."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"181","DOI":"10.33549\/physiolres.933606","article-title":"Metformin attenuates myocardium dicarbonyl stress induced by chronic hypertriglyceridemia","volume":"67","author":"Malinska","year":"2018","journal-title":"Physiol. Res."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"80","DOI":"10.2174\/1381612826666200509232610","article-title":"Novel targets of metformin in cardioprotection: Beyond the effects mediated by AMPK","volume":"27","author":"Bolivar","year":"2021","journal-title":"Curr. Pharm. Des."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"953","DOI":"10.1016\/j.cmet.2014.09.018","article-title":"Metformin: From mechanisms of action to therapies","volume":"20","author":"Foretz","year":"2014","journal-title":"Cell. Metab."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"S49","DOI":"10.33549\/physiolres.930000.55.S1.49","article-title":"Hereditary hypertriglyceridemic rat: A suitable model of cardiovascular disease and metabolic syndrome?","volume":"55","author":"Zicha","year":"2006","journal-title":"Physiol. Res."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"8712979","DOI":"10.1155\/2019\/8712979","article-title":"The Effect of Lipotoxicity on Renal Dysfunction in a Nonobese Rat Model of Metabolic Syndrome: A Urinary Proteomic Approach","volume":"2019","author":"Markova","year":"2019","journal-title":"J. Diabetes. Res."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"805","DOI":"10.1016\/j.cmet.2012.04.006","article-title":"Lipid metabolism and toxicity in the heart","volume":"15","author":"Goldberg","year":"2012","journal-title":"Cell. Metab."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"122","DOI":"10.1186\/s12933-018-0762-4","article-title":"Association between insulin resistance and the development of cardiovascular disease","volume":"17","author":"Ormazabal","year":"2018","journal-title":"Cardiovasc. Diabetol."},{"key":"ref_23","first-page":"163","article-title":"Plasma ceramides as prognostic biomarkers and their arterial and myocardial tissue correlates in acute myocardial infarction","volume":"30","author":"Tan","year":"2018","journal-title":"JACC Basic. Transl. Sci."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1513","DOI":"10.1016\/j.bbalip.2016.02.016","article-title":"Lipid metabolism and signaling in cardiac lipotoxicity","volume":"1861","author":"Nzirorera","year":"2016","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Matsui, H., Yokoyama, T., Sekiguchi, K., Iijima, D., Sunaga, H., Maniwa, M., Ueno, M., Iso, T., Arai, M., and Kurabayashi, M. (2012). Stearoyl-CoA desaturase-1 (SCD1) augments saturated fatty acid-induced lipid accumulation and inhibits apoptosis in cardiac myocytes. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0033283"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1186\/1476-511X-9-7","article-title":"A rapid method for determining arachidonic:eicosapentaenoic acid ratios in whole blood lipids: Correlation with erythrocyte membrane ratios and validation in a large Italian population of various ages and pathologies","volume":"9","author":"Rizzo","year":"2010","journal-title":"Lipids. Health Dis."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"268","DOI":"10.1080\/00325481.2019.1607414","article-title":"The eicosapentaenoic acid:arachidonic acid ratio and its clinical utility in cardiovascular disease","volume":"131","author":"Nelson","year":"2019","journal-title":"Postgrad. Med."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1186\/s12944-015-0135-x","article-title":"The association of cardiovascular risk factors with saturated fatty acids and fatty acid desaturase indices in erythrocyte in middle-aged Korean adults","volume":"14","author":"Kim","year":"2015","journal-title":"Lipids Health Dis."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"102","DOI":"10.1186\/s12944-020-01282-y","article-title":"Fatty acid profile and estimated desaturase activities in whole blood are associated with metabolic health","volume":"19","author":"Svendsen","year":"2020","journal-title":"Lipids Health Dis."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1093\/ajcn\/88.1.203","article-title":"Markers of dietary fat quality and fatty acid desaturation as predictors of total and cardiovascular mortality: A population-based prospective study","volume":"88","author":"Warensjo","year":"2008","journal-title":"Am. J. Clin. Nutr."},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Drzewoski, J., and Hanefeld, M. (2021). The Current and Potential Therapeutic Use of Metformin-The Good Old Drug. Pharmaceuticals, 14.","DOI":"10.3390\/ph14020122"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"999","DOI":"10.4158\/EP151145.RA","article-title":"Metformin: Nonglycemic Effects and Potential Novel Indications","volume":"22","author":"Anabtawi","year":"2016","journal-title":"Endocr. Pract."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1011","DOI":"10.1001\/jama.1966.03100240145036","article-title":"In defense of the autopsy","volume":"196","author":"Wilson","year":"1966","journal-title":"JAMA"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"33904","DOI":"10.1074\/jbc.M304724200","article-title":"Identification and characterization of murine SCD4, a novel heart-specific stearoyl-CoA desaturase isoform regulated by leptin and dietary factors","volume":"278","author":"Miyazaki","year":"2003","journal-title":"J. Biol. Chem."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"E357","DOI":"10.1152\/ajpendo.00471.2007","article-title":"Loss of stearoyl-CoA desaturase 1 inhibits fatty acid oxidation and increases glucose utilization in the heart","volume":"294","author":"Dobrzyn","year":"2008","journal-title":"Am. J. Physiol. Endocrinol. Metab."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1425","DOI":"10.1016\/j.bbalip.2016.03.014","article-title":"Fuel availability and fate in cardiac metabolism: A tale of two substrates","volume":"1861","author":"Pascual","year":"2016","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"36312","DOI":"10.1074\/jbc.M109.049817","article-title":"DGAT1 expression increases heart triglyceride content but ameliorates lipotoxicity","volume":"284","author":"Liu","year":"2009","journal-title":"J. Biol. Chem."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1161\/01.RES.0000199348.10580.1d","article-title":"Cardiac myocyte apoptosis is associated with increased DNA damage and decreased survival in murine models of obesity","volume":"98","author":"Barouch","year":"2006","journal-title":"Circ. Res."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"382","DOI":"10.3389\/fphar.2019.00382","article-title":"Nrf2 as a potential mediator of cardiovascular risk in metabolic diseases","volume":"10","author":"DaCosta","year":"2019","journal-title":"Front. Pharmacol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"573","DOI":"10.1007\/s12265-020-10083-8","article-title":"NRF2 in Cardiovascular Diseases: A Ray of Hope!","volume":"14","author":"Vashi","year":"2020","journal-title":"J. Cardiovasc. Transl. Res."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"132","DOI":"10.1016\/j.mito.2011.05.007","article-title":"Increased availability of endogenous and dietary oleic acid contributes to the upregulation of cardiac fatty acid oxidation","volume":"12","author":"Dobrzyn","year":"2012","journal-title":"Mitochondrion"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1226","DOI":"10.1073\/pnas.0336724100","article-title":"A critical role for PPARalpha-mediated lipotoxicity in the pathogenesis of diabetic cardiomyopathy: Modulation by dietary fat content","volume":"100","author":"Finck","year":"2003","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"331","DOI":"10.1016\/j.yjmcc.2009.10.022","article-title":"Cytochrome P450 epoxygenases, soluble epoxide hydrolase, and the regulation of cardiovascular inflammation","volume":"48","author":"Deng","year":"2010","journal-title":"J. Mol. Cell. Cardiol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"173","DOI":"10.3109\/03602532.2012.754460","article-title":"Role of cytochrome P450-mediated arachidonic acid metabolites in the pathogenesis of cardiac hypertrophy","volume":"45","author":"Alsaad","year":"2013","journal-title":"Drug. Metab. Rev."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1016\/B978-0-12-416003-3.00013-5","article-title":"Health benefits of n-3 polyunsaturated fatty acids: Eicosapentaenoic acid and docosahexaenoic acid","volume":"65","author":"Siriwardhana","year":"2012","journal-title":"Adv. Food. Nutr. Res."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1505S","DOI":"10.1093\/ajcn\/83.6.1505S","article-title":"n-3 polyunsaturated fatty acids, inflammation, and inflammatory diseases","volume":"83","author":"Calder","year":"2006","journal-title":"Am. J. Clin. Nutr."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1045","DOI":"10.1016\/j.nut.2015.03.011","article-title":"Conjugated linoleic acid reduces visceral and ectopic lipid accumulation and insulin resistance in chronic severe hypertriacylglycerolemia","volume":"31","author":"Malinska","year":"2015","journal-title":"Nutrition"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1016\/0378-4347(95)00142-6","article-title":"Gas chromatographic analysis of fatty acid methyl esters","volume":"671","author":"Eder","year":"1995","journal-title":"J. Chromatogr. B Biomed. Appl."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1472","DOI":"10.1053\/meta.2001.27195","article-title":"Serum phospholipid fatty acid composition and insulin action in type 2 diabetic patients","volume":"50","author":"Pelikanova","year":"2001","journal-title":"Metabolism"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"448","DOI":"10.1080\/07315724.2014.976890","article-title":"Vegetarian Diets in the Prevention and Treatment of Type 2 Diabetes","volume":"34","author":"Kahleova","year":"2015","journal-title":"J. Am. Coll. Nutr."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/14\/7680\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T06:31:37Z","timestamp":1760164297000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/14\/7680"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,7,19]]},"references-count":50,"journal-issue":{"issue":"14","published-online":{"date-parts":[[2021,7]]}},"alternative-id":["ijms22147680"],"URL":"https:\/\/doi.org\/10.3390\/ijms22147680","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,7,19]]}}}