{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T01:10:22Z","timestamp":1792458622745,"version":"4.5.0"},"reference-count":111,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2024,5,14]],"date-time":"2024-05-14T00:00:00Z","timestamp":1715644800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Fondazione Cassa di Risparmio di Bologna","award":["22010-COD SME 2022.0071"],"award-info":[{"award-number":["22010-COD SME 2022.0071"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Diseases"],"abstract":"<jats:p>Bile acids (BAs) and bilirubin, primarily known for their role in lipid metabolism and as heme catabolite, respectively, have been found to have diverse effects on various physiological processes, including oxidative stress and inflammation. Indeed, accumulating evidence showed that the interplay between BAs and bilirubin in these processes involves intricate regulatory mechanisms mediated by specific receptors and signaling pathways under certain conditions and in specific contexts. Oxidative stress plays a significant role in the development and progression of cardiovascular diseases (CVDs) due to its role in inflammation, endothelial dysfunction, hypertension, and other risk factors. In the cardiovascular (CV) system, recent studies have suggested that BAs and bilirubin have some opposite effects related to oxidative and inflammatory mechanisms, but this area of research is still under investigation. This review aims to introduce BAs and bilirubin from a biochemical and physiological point of view, emphasizing their potential protective or detrimental effects on CVDs. Moreover, clinical studies that have assessed the association between BAs\/bilirubin and CVD were examined in depth to better interpret the possible link between them.<\/jats:p>","DOI":"10.3390\/diseases12050103","type":"journal-article","created":{"date-parts":[[2024,5,14]],"date-time":"2024-05-14T10:26:36Z","timestamp":1715682396000},"page":"103","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":34,"title":["Bile Acids and Bilirubin Role in Oxidative Stress and Inflammation in Cardiovascular Diseases"],"prefix":"10.3390","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3026-6830","authenticated-orcid":false,"given":"Angela","family":"Punzo","sequence":"first","affiliation":[{"name":"Department of Biomedical and Neuromotor Sciences, Alma Mater Studiorum, University of Bologna, 40126 Bologna, Italy"},{"name":"Biostructures and Biosystems National Institute (INBB), 00136 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessia","family":"Silla","sequence":"additional","affiliation":[{"name":"Department for Life Quality Studies, Alma Mater Studiorum, University of Bologna, 47921 Rimini, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7853-0042","authenticated-orcid":false,"given":"Federica","family":"Fogacci","sequence":"additional","affiliation":[{"name":"Hypertension and Cardiovascular Risk Research Center, Medical and Surgery Sciences Dept., Alma Mater Studiorum, University of Bologna, 40138 Bologna, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8778-6258","authenticated-orcid":false,"given":"Matteo","family":"Perillo","sequence":"additional","affiliation":[{"name":"Department of Biomedical and Neuromotor Sciences, Alma Mater Studiorum, University of Bologna, 40126 Bologna, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4367-3884","authenticated-orcid":false,"given":"Arrigo F. G.","family":"Cicero","sequence":"additional","affiliation":[{"name":"Hypertension and Cardiovascular Risk Research Center, Medical and Surgery Sciences Dept., Alma Mater Studiorum, University of Bologna, 40138 Bologna, Italy"},{"name":"Cardiovascular Medicine Unit, IRCCS AOU di Bologna, 40138 Bologna, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6740-5331","authenticated-orcid":false,"given":"Cristiana","family":"Caliceti","sequence":"additional","affiliation":[{"name":"Department of Biomedical and Neuromotor Sciences, Alma Mater Studiorum, University of Bologna, 40126 Bologna, Italy"},{"name":"Biostructures and Biosystems National Institute (INBB), 00136 Rome, Italy"},{"name":"Interdepartmental Centre for Industrial Agrofood Research\u2014CIRI Agrofood, University of Bologna, 47521 Cesena, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,5,14]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"237","DOI":"10.2147\/VHRM.S379874","article-title":"A Heart-Healthy Diet for Cardiovascular Disease Prevention: Where Are We Now?","volume":"19","author":"Diab","year":"2023","journal-title":"Vasc. Health Risk Manag."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1302","DOI":"10.1161\/CIRCRESAHA.117.310782","article-title":"Emerging Role of Precision Medicine in Cardiovascular Disease","volume":"122","author":"Leopold","year":"2018","journal-title":"Circ. Res."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"713","DOI":"10.5603\/KP.a2018.0071","article-title":"Oxidative Stress and Cardiovascular Disease: New Insights","volume":"76","author":"Pignatelli","year":"2018","journal-title":"Kardiol. Pol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"180","DOI":"10.1016\/j.redox.2015.01.002","article-title":"Oxidative Stress: A Concept in Redox Biology and Medicine","volume":"4","author":"Sies","year":"2015","journal-title":"Redox Biol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"107879","DOI":"10.1016\/j.pharmthera.2021.107879","article-title":"Resolution of Inflammation: An Organizing Principle in Biology and Medicine","volume":"227","author":"Panigrahy","year":"2021","journal-title":"Pharmacol. Ther."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"723093","DOI":"10.1155\/2015\/723093","article-title":"Potential Benefits of Berberine in the Management of Perimenopausal Syndrome","volume":"2015","author":"Caliceti","year":"2015","journal-title":"Oxid. Med. Cell Longev."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1345","DOI":"10.1016\/j.bbadis.2017.12.039","article-title":"Heart and Bile Acids\u2014Clinical Consequences of Altered Bile Acid Metabolism","volume":"1864","author":"Vasavan","year":"2018","journal-title":"Biochim. Biophys. Acta (BBA)-Mol. Basis Dis."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"063","DOI":"10.1385\/CT:5:1:063","article-title":"Bile Acids Are Toxic for Isolated Cardiac Mitochondria: A Possible Cause for Hepatic-Derived Cardiomyopathies?","volume":"5","author":"Ferreira","year":"2005","journal-title":"Cardiovasc. Toxicol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"29240","DOI":"10.1038\/srep29240","article-title":"Bilirubin Is an Endogenous Antioxidant in Human Vascular Endothelial Cells","volume":"6","author":"Ziberna","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"H429","DOI":"10.1152\/ajpheart.00417.2017","article-title":"Bilirubin Acts as a Multipotent Guardian of Cardiovascular Integrity: More than Just a Radical Idea","volume":"315","author":"Bulmer","year":"2018","journal-title":"Am. J. Physiol.-Heart Circ. Physiol."},{"key":"ref_11","unstructured":"ASReview LAB Developers (2024, April 01). ASReview LAB\u2014A Tool for AI-Assisted Systematic Reviews Zenodo v1.5. Available online: https:\/\/zenodo.org\/records\/10464713."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1038\/s42256-020-00287-7","article-title":"An Open Source Machine Learning Framework for Efficient and Transparent Systematic Reviews","volume":"3","author":"Schram","year":"2021","journal-title":"Nat. Mach. Intell."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Perillo, M., Silla, A., Punzo, A., Caliceti, C., Kriete, A., Sell, C., and Lorenzini, A. (2023). Peto\u2019s Paradox: Nature Has Used Multiple Strategies to Keep Cancer at Bay While Evolving Long Lifespans and Large Body Masses. A Systematic Mini-Review. Biomed. J., 47.","DOI":"10.1016\/j.bj.2023.100654"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"308","DOI":"10.12998\/wjcc.v9.i2.308","article-title":"Overview of Bile Acid Signaling in the Cardiovascular System","volume":"9","author":"Zhang","year":"2021","journal-title":"World J. Clin. Cases"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"108238","DOI":"10.1016\/j.pharmthera.2022.108238","article-title":"Bile Acid Metabolism and Signaling, the Microbiota, and Metabolic Disease","volume":"237","author":"Cai","year":"2022","journal-title":"Pharmacol. Ther."},{"key":"ref_16","unstructured":"Chiang, J.Y.L. (2013). Comprehensive Physiology, Wiley."},{"key":"ref_17","unstructured":"Chen, I., and Cassaro, S. (2023). Physiology, Bile Acids, StatPearls Publishing LLC."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1083","DOI":"10.1016\/j.jhep.2017.11.025","article-title":"Role of Bile Acids in the Gut-Liver Axis","volume":"68","author":"Schneider","year":"2018","journal-title":"J. Hepatol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1152\/physiologyonline.1999.14.1.24","article-title":"Bile Acids: The Good, the Bad, and the Ugly","volume":"14","author":"Hofmann","year":"1999","journal-title":"Physiology"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"804","DOI":"10.3748\/wjg.15.804","article-title":"Bile Acids: Chemistry, Physiology, and Pathophysiology","volume":"15","author":"Monte","year":"2009","journal-title":"World J. Gastroenterol."},{"key":"ref_21","unstructured":"Ticho, A.L., Malhotra, P., Dudeja, P.K., Gill, R.K., and Alrefai, W.A. (2019). Comprehensive Physiology, Wiley."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1146\/annurev.biochem.72.121801.161712","article-title":"The Enzymes, Regulation, and Genetics of Bile Acid Synthesis","volume":"72","author":"Russell","year":"2003","journal-title":"Annu. Rev. Biochem."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"802","DOI":"10.1111\/apt.13333","article-title":"Systematic Review: Bile Acids and Intestinal Inflammation-luminal Aggressors or Regulators of Mucosal Defence?","volume":"42","author":"Pavlidis","year":"2015","journal-title":"Aliment. Pharmacol. Ther."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Bourgin, M., Kriaa, A., Mkaouar, H., Mariaule, V., Jablaoui, A., Maguin, E., and Rhimi, M. (2021). Bile Salt Hydrolases: At the Crossroads of Microbiota and Human Health. Microorganisms, 9.","DOI":"10.3390\/microorganisms9061122"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1038\/nrgastro.2017.119","article-title":"Bile Acid\u2013Microbiota Crosstalk in Gastrointestinal Inflammation and Carcinogenesis","volume":"15","author":"Jia","year":"2018","journal-title":"Nat. Rev. Gastroenterol. Hepatol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1420","DOI":"10.1111\/liv.13394","article-title":"Bile Acids and Cardiovascular Function in Cirrhosis","volume":"37","author":"Voiosu","year":"2017","journal-title":"Liver Int."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"108757","DOI":"10.1016\/j.steroids.2020.108757","article-title":"Enterohepatic Circulation of Bile Acids and Their Emerging Roles on Glucolipid Metabolism","volume":"165","author":"Chen","year":"2021","journal-title":"Steroids"},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Caliceti, C., Punzo, A., Silla, A., Simoni, P., Roda, G., and Hrelia, S. (2022). New Insights into Bile Acids Related Signaling Pathways in the Onset of Colorectal Cancer. Nutrients, 14.","DOI":"10.3390\/nu14142964"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"543","DOI":"10.1016\/S1097-2765(00)80348-2","article-title":"Endogenous Bile Acids Are Ligands for the Nuclear Receptor FXR\/BAR","volume":"3","author":"Wang","year":"1999","journal-title":"Mol. Cell"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"714","DOI":"10.1016\/S0006-291X(02)02550-0","article-title":"Identification of Membrane-Type Receptor for Bile Acids (M-BAR)","volume":"298","author":"Maruyama","year":"2002","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"478","DOI":"10.1124\/dmd.121.000415","article-title":"Pregnane X Receptor and the Gut-Liver Axis: A Recent Update","volume":"50","author":"Dutta","year":"2022","journal-title":"Drug Metab. Dispos."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1002","DOI":"10.1124\/dmd.121.000482","article-title":"Searching for Constitutive Androstane Receptor Modulators","volume":"50","author":"Honkakoski","year":"2022","journal-title":"Drug Metab. Dispos."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1313","DOI":"10.1126\/science.1070477","article-title":"Vitamin D Receptor As an Intestinal Bile Acid Sensor","volume":"296","author":"Makishima","year":"2002","journal-title":"Science"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1636","DOI":"10.1194\/jlr.R069286","article-title":"The Roles of Bile Acids and Sphingosine-1-Phosphate Signaling in the Hepatobiliary Diseases","volume":"57","author":"Nagahashi","year":"2016","journal-title":"J. Lipid Res."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"101094","DOI":"10.1016\/j.plipres.2021.101094","article-title":"Bile Acids and Their Receptors in Metabolic Disorders","volume":"82","author":"Fiorucci","year":"2021","journal-title":"Prog. Lipid Res."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1247","DOI":"10.3389\/fphar.2020.01247","article-title":"Farnesoid X Receptor Agonists as Therapeutic Target for Cardiometabolic Diseases","volume":"11","author":"Li","year":"2020","journal-title":"Front. Pharmacol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"224","DOI":"10.1016\/S2213-8587(16)30155-3","article-title":"Clinical Relevance of the Bile Acid Receptor TGR5 in Metabolism","volume":"5","author":"Scheltema","year":"2017","journal-title":"Lancet Diabetes Endocrinol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"646","DOI":"10.3389\/fphys.2016.00646","article-title":"TGR5, Not Only a Metabolic Regulator","volume":"7","author":"Guo","year":"2016","journal-title":"Front. Physiol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"E191","DOI":"10.1152\/ajpendo.00405.2020","article-title":"Bilirubin as a Metabolic Hormone: The Physiological Relevance of Low Levels","volume":"320","author":"Creeden","year":"2021","journal-title":"Am. J. Physiol.-Endocrinol. Metab."},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Repsold, L., and Joubert, A.M. (2018). Eryptosis: An Erythrocyte\u2019s Suicidal Type of Cell Death. Biomed. Res. Int., 2018.","DOI":"10.1155\/2018\/9405617"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"140","DOI":"10.1016\/j.tem.2018.01.002","article-title":"Bilirubin in the Liver\u2013Gut Signaling Axis","volume":"29","author":"Hamoud","year":"2018","journal-title":"Trends Endocrinol. Metab."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1016\/0304-4165(72)90119-5","article-title":"The Reduction of Bile Pigments by Faecal and Intestinal Bacteria","volume":"264","author":"Fahmy","year":"1972","journal-title":"Biochim. Biophys. Acta (BBA)-Gen. Subj."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"238","DOI":"10.1016\/j.jhep.2004.10.012","article-title":"The Impact of Intestinal Microflora on Serum Bilirubin Levels","volume":"42","author":"Zelenka","year":"2005","journal-title":"J. Hepatol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1016\/j.molmed.2023.01.007","article-title":"The Physiology of Bilirubin: Health and Disease Equilibrium","volume":"29","author":"Vitek","year":"2023","journal-title":"Trends Mol. Med."},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Hall, B., Levy, S., Dufault-Thompson, K., Ndjite, G.M., Weiss, A., Braccia, D., Jenkins, C., Yang, Y., Arp, G., and Abeysinghe, S. (2023). Discovery of the Gut Microbial Enzyme Responsible for Bilirubin Reduction to Urobilinogen. bioRxiv.","DOI":"10.1101\/2023.02.07.527579"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"2120","DOI":"10.1016\/j.freeradbiomed.2012.03.002","article-title":"Reduced Circulating Oxidized LDL Is Associated with Hypocholesterolemia and Enhanced Thiol Status in Gilbert Syndrome","volume":"52","author":"Boon","year":"2012","journal-title":"Free Radic. Biol. Med."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"569","DOI":"10.1249\/MSS.0b013e3182357dd4","article-title":"Effect of Different Doses of Aerobic Exercise Training on Total Bilirubin Levels","volume":"44","author":"Swift","year":"2012","journal-title":"Med. Sci. Sports Exerc."},{"key":"ref_48","first-page":"E18","article-title":"Soto Conti Bilirubin: The Toxic Mechanisms of an Antioxidant Molecule","volume":"119","author":"Constanza","year":"2021","journal-title":"Arch. Argent. Pediatr."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"13224","DOI":"10.1038\/s41598-021-92442-2","article-title":"Association of Serum Bilirubin Levels with Risk of Cancer Development and Total Death","volume":"11","author":"Inoguchi","year":"2021","journal-title":"Sci. Rep."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s12967-021-03207-4","article-title":"Bilirubin Ameliorates Murine Atherosclerosis through Inhibiting Cholesterol Synthesis and Reshaping the Immune System","volume":"20","author":"Wen","year":"2022","journal-title":"J. Transl. Med."},{"key":"ref_51","doi-asserted-by":"crossref","unstructured":"Tsai, M.-T., and Tarng, D.-C. (2018). Beyond a Measure of Liver Function-Bilirubin Acts as a Potential Cardiovascular Protector in Chronic Kidney Disease Patients. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20010117"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"e007792","DOI":"10.1161\/JAHA.117.007792","article-title":"Bilirubin Is Inversely Associated with Cardiovascular Disease Among HIV-Positive and HIV-Negative Individuals in VACS (Veterans Aging Cohort Study)","volume":"7","author":"Marconi","year":"2018","journal-title":"J. Am. Heart Assoc."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"4847941","DOI":"10.1155\/2021\/4847941","article-title":"Redox-Dependent Effects in the Physiopathological Role of Bile Acids","volume":"2021","author":"Simon","year":"2021","journal-title":"Oxid. Med. Cell. Longev."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1016\/0003-9861(90)90004-I","article-title":"Bile Acids: Antioxidants or Enhancers of Peroxidation Depending on Lipid Concentration","volume":"276","author":"DeLange","year":"1990","journal-title":"Arch. Biochem. Biophys."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"327","DOI":"10.1002\/(SICI)1099-1271(199811\/12)13:6<327::AID-BIO500>3.0.CO;2-O","article-title":"Antioxidant Properties of Bile Salt Micelles Evaluated with Different Chemiluminescent Assays: A Possible Physiological Role","volume":"13","author":"Roda","year":"1998","journal-title":"J. Biolumin. Chemilumin."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1002\/hep.28890","article-title":"Bile Acid Excess Induces Cardiomyopathy and Metabolic Dysfunctions in the Heart","volume":"65","author":"Desai","year":"2017","journal-title":"Hepatology"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"1382","DOI":"10.1038\/s42255-023-00844-5","article-title":"CRAT Links Cholesterol Metabolism to Innate Immune Responses in the Heart","volume":"5","author":"Mao","year":"2023","journal-title":"Nat. Metab."},{"key":"ref_58","first-page":"549","article-title":"Bile Acids, Oxidative Stress, and Renal Function in Biliary Obstruction","volume":"17","author":"Bomzon","year":"1997","journal-title":"Semin. Nephrol."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1016\/j.celrep.2014.02.032","article-title":"Microbiota Modification with Probiotics Induces Hepatic Bile Acid Synthesis via Downregulation of the Fxr-Fgf15 Axis in Mice","volume":"7","author":"Degirolamo","year":"2014","journal-title":"Cell Rep."},{"key":"ref_60","first-page":"261","article-title":"The Role of Bile Acids in Cardiovascular Diseases: From Mechanisms to Clinical Implications","volume":"14","author":"Zhang","year":"2022","journal-title":"Aging Dis."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"9270","DOI":"10.3892\/mmr.2017.7698","article-title":"Farnesoid X Receptor Deletion Improves Cardiac Function, Structure and Remodeling Following Myocardial Infarction in Mice","volume":"16","author":"Gao","year":"2017","journal-title":"Mol. Med. Rep."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"1834","DOI":"10.1093\/eurheartj\/ehs011","article-title":"Cardiomyocyte-Expressed Farnesoid-X-Receptor Is a Novel Apoptosis Mediator and Contributes to Myocardial Ischaemia\/Reperfusion Injury","volume":"34","author":"Pu","year":"2013","journal-title":"Eur. Heart J."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"159","DOI":"10.4103\/2470-7511.305419","article-title":"Bile Acid and Cholesterol Metabolism in Atherosclerotic Cardiovascular Disease and Therapy","volume":"5","author":"Chiang","year":"2020","journal-title":"Cardiol. Plus"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"558","DOI":"10.1210\/en.2007-0805","article-title":"Functional Vitamin D Receptor (VDR) in the T-Tubules of Cardiac Myocytes: VDR Knockout Cardiomyocyte Contractility","volume":"149","author":"Tishkoff","year":"2008","journal-title":"Endocrinology"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"1663","DOI":"10.1161\/ATVBAHA.113.301565","article-title":"Bile Acid Receptor TGR5 Agonism Induces NO Production and Reduces Monocyte Adhesion in Vascular Endothelial Cells","volume":"33","author":"Kida","year":"2013","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"2097","DOI":"10.1002\/hep.23585","article-title":"Hypertrophic Cardiomyopathy and Dysregulation of Cardiac Energetics in a Mouse Model of Biliary Fibrosis","volume":"51","author":"Desai","year":"2010","journal-title":"Hepatology"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1016\/j.jphs.2016.05.010","article-title":"Cellular Function and Signaling Pathways of Vascular Smooth Muscle Cells Modulated by Sphingosine 1-Phosphate","volume":"132","author":"Machida","year":"2016","journal-title":"J. Pharmacol. Sci."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"1485","DOI":"10.1016\/j.jhep.2021.06.010","article-title":"Bilirubin: The Yellow Hormone?","volume":"75","author":"Tiribelli","year":"2021","journal-title":"J. Hepatol."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"812","DOI":"10.1161\/CIRCRESAHA.122.322418","article-title":"Destabilization of Atherosclerotic Plaque by Bilirubin Deficiency","volume":"132","author":"Chen","year":"2023","journal-title":"Circ. Res."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"338","DOI":"10.1016\/j.bbrc.2009.06.029","article-title":"Bilirubin Inhibits the TNF\u03b1-Related Induction of Three Endothelial Adhesion Molecules","volume":"386","author":"Mazzone","year":"2009","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"C422","DOI":"10.1152\/ajpcell.00381.2008","article-title":"Nox4 NADPH Oxidase Mediates Oxidative Stress and Apoptosis Caused by TNF-\u03b1 in Cerebral Vascular Endothelial Cells","volume":"296","author":"Basuroy","year":"2009","journal-title":"Am. J. Physiol.-Cell Physiol."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"636","DOI":"10.1161\/HYPERTENSIONAHA.107.092296","article-title":"Induction of Heme Oxygenase-1 In Vivo Suppresses NADPH Oxidase\u2013Derived Oxidative Stress","volume":"50","author":"Datla","year":"2007","journal-title":"Hypertension"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"106520","DOI":"10.1016\/j.intimp.2020.106520","article-title":"Physiological Concentrations of Bilirubin Control Inflammatory Response by Inhibiting NF-\u039aB and Inflammasome Activation","volume":"84","author":"Li","year":"2020","journal-title":"Int. Immunopharmacol."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"R738","DOI":"10.1152\/ajpregu.90889.2008","article-title":"Inhibition of Bilirubin Metabolism Induces Moderate Hyperbilirubinemia and Attenuates ANG II-Dependent Hypertension in Mice","volume":"297","author":"Vera","year":"2009","journal-title":"Am. J. Physiol.-Regul. Integr. Comp. Physiol."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"918","DOI":"10.1093\/ajh\/hpt038","article-title":"Antihypertensive Actions of Moderate Hyperbilirubinemia: Role of Superoxide Inhibition","volume":"26","author":"Stec","year":"2013","journal-title":"Am. J. Hypertens."},{"key":"ref_76","doi-asserted-by":"crossref","unstructured":"Kumar, R., and Jain, R. (2016). Studies on Serum Nitric Oxide Levels in Subjects with High Bilirubin Value in Comparison of Normal Healthy Control Subjects. Int. J. Bioassays, 5.","DOI":"10.21746\/ijbio.2016.03.004"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"e000914","DOI":"10.1136\/openhrt-2018-000914","article-title":"Antioxidant Bilirubin Works in Multiple Ways to Reduce Risk for Obesity and Its Health Complications","volume":"5","author":"DiNicolantonio","year":"2018","journal-title":"Open Heart"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"274","DOI":"10.1152\/japplphysiol.00909.2013","article-title":"Time Course-Dependent Changes in the Transcriptome of Human Skeletal Muscle during Recovery from Endurance Exercise: From Inflammation to Adaptive Remodeling","volume":"116","author":"Neubauer","year":"2014","journal-title":"J. Appl. Physiol."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"244","DOI":"10.1097\/MOL.0000000000000597","article-title":"Bile Acid Alterations in Nonalcoholic Fatty Liver Disease, Obesity, Insulin Resistance and Type 2 Diabetes: What Do the Human Studies Tell?","volume":"30","author":"Haas","year":"2019","journal-title":"Curr. Opin. Lipidol."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1016\/j.atherosclerosis.2019.12.010","article-title":"Reduced Bile Acid Excretion Is an Independent Risk Factor for Stroke and Mortality: A Prospective Follow-up Study","volume":"293","author":"Charach","year":"2020","journal-title":"Atherosclerosis"},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1186\/s12944-021-01620-8","article-title":"Increased Admission Serum Total Bile Acids Can Be Associated with Decreased 3-Month Mortality in Patients with Acute Ischemic Stroke","volume":"21","author":"Huang","year":"2022","journal-title":"Lipids Health Dis."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1053\/j.ajkd.2017.06.017","article-title":"Deoxycholic Acid, a Metabolite of Circulating Bile Acids, and Coronary Artery Vascular Calcification in CKD","volume":"71","author":"Jovanovich","year":"2018","journal-title":"Am. J. Kidney Dis."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"e0109","DOI":"10.1097\/HC9.0000000000000109","article-title":"Elevated Bile Acids Are Associated with Left Ventricular Structural Changes in Biliary Atresia","volume":"7","author":"Virk","year":"2023","journal-title":"Hepatol. Commun."},{"key":"ref_84","doi-asserted-by":"crossref","unstructured":"Reshetnyak, V.I., and Maev, I.V. (2022). Features of Lipid Metabolism Disorders in Primary Biliary Cholangitis. Biomedicines, 10.","DOI":"10.3390\/biomedicines10123046"},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"370","DOI":"10.1111\/liv.15463","article-title":"High Prevalence of Lower Limb Atherosclerosis Is Linked with the Gut\u2013Liver Axis in Patients with Primary Biliary Cholangitis","volume":"43","author":"Ponziani","year":"2023","journal-title":"Liver Int."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"88","DOI":"10.1186\/s12944-019-1041-4","article-title":"Impact of Ursodeoxycholic Acid on Circulating Lipid Concentrations: A Systematic Review and Meta-Analysis of Randomized Placebo-Controlled Trials","volume":"18","author":"Banach","year":"2019","journal-title":"Lipids Health Dis."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1093\/bmb\/ldaa006","article-title":"Obeticholic Acid a New Therapy in PBC and NASH","volume":"133","author":"Chapman","year":"2020","journal-title":"Br. Med. Bull."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"1723","DOI":"10.1093\/clinchem\/46.11.1723","article-title":"Association of Serum Bilirubin Concentration with Risk of Coronary Artery Disease","volume":"46","author":"Mayer","year":"2000","journal-title":"Clin. Chem."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1016\/j.plipres.2012.11.001","article-title":"Bilirubin and beyond: A Review of Lipid Status in Gilbert\u2019s Syndrome and Its Relevance to Cardiovascular Disease Protection","volume":"52","author":"Bulmer","year":"2013","journal-title":"Prog. Lipid Res."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"oead059","DOI":"10.1093\/ehjopen\/oead059","article-title":"Exploring the Link between Gilbert\u2019s Syndrome and Atherosclerotic Cardiovascular Disease: Insights from a Subpopulation-Based Analysis of over One Million Individuals","volume":"3","author":"Kartoun","year":"2023","journal-title":"Eur. Heart J. Open"},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"e000467","DOI":"10.1136\/bmjmed-2022-000467","article-title":"Effect of Bilirubin and Gilbert Syndrome on Health: Cohort Analysis of Observational, Genetic, and Mendelian Randomisation Associations","volume":"2","author":"Hamilton","year":"2023","journal-title":"BMJ Med."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"911","DOI":"10.1177\/00033197211059693","article-title":"Dose-Response Association Between Bilirubin and Cardiovascular Disease: A Systematic Review and Meta-Analysis","volume":"73","author":"Zuo","year":"2022","journal-title":"Angiology"},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"1016","DOI":"10.1016\/j.numecd.2021.01.002","article-title":"Physiologically Increased Total Bilirubin Is Associated with Reduced Risk of First Myocardial Infarction: A Meta-Analysis and Dose-Response Analysis","volume":"31","author":"Yao","year":"2021","journal-title":"Nutr. Metab. Cardiovasc. Dis."},{"key":"ref_94","doi-asserted-by":"crossref","unstructured":"Li, X., Zhao, C., Pan, C., Jiang, G., and Zhang, B. (2022). Role of Bilirubin in the Prognosis of Coronary Artery Disease and Its Relationship with Cardiovascular Risk Factors: A Meta-Analysis. BMC Cardiovasc. Disord., 22.","DOI":"10.1186\/s12872-022-02899-w"},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"944","DOI":"10.1097\/GME.0000000000001999","article-title":"Serum Total Bilirubin and New-Onset Hypertension in Perimenopausal Women: A Cross-Sectional Study","volume":"29","author":"He","year":"2022","journal-title":"Menopause"},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"136","DOI":"10.1161\/ATVBAHA.122.318086","article-title":"Association Between Serum Bilirubin, Lipid Levels, and Prevalence of Femoral and Carotid Atherosclerosis: A Population-Based Cross-Sectional Study","volume":"43","author":"Su","year":"2023","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"e3413","DOI":"10.1002\/dmrr.3413","article-title":"Effects of Sodium-glucose Co-transporter 2 Inhibitors on Liver Parameters and Steatosis: A Meta-analysis of Randomized Clinical Trials","volume":"37","author":"Coelho","year":"2021","journal-title":"Diabetes Metab. Res. Rev."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"64","DOI":"10.2174\/1871530321999210128201259","article-title":"Association Between Total Bilirubin Levels and Cardio-Metabolic Risk Factors Related to Obesity","volume":"22","author":"Mahsoub","year":"2022","journal-title":"Endocr. Metab. Immune Disord. Drug Targets"},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"1109","DOI":"10.1016\/j.metabol.2009.04.003","article-title":"Acute Effect of Weight Loss on Levels of Total Bilirubin in Obese, Cardiovascular High-Risk Patients: An Analysis from the Lead-in Period of the Sibutramine Cardiovascular Outcome Trial","volume":"58","author":"Andersson","year":"2009","journal-title":"Metabolism"},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"3000605211004226","DOI":"10.1177\/03000605211004226","article-title":"Relationship between Serum Bilirubin Concentration and Sarcopenia in Patients with Type 2 Diabetes: A Cross-Sectional Study","volume":"49","author":"Wang","year":"2021","journal-title":"J. Int. Med. Res."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"84","DOI":"10.1186\/s40798-022-00463-6","article-title":"Serum Bilirubin Concentrations and the Prevalence of Gilbert Syndrome in Elite Athletes","volume":"8","author":"Bolek","year":"2022","journal-title":"Sports Med. Open"},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"286","DOI":"10.1177\/0003319714537111","article-title":"Association Between Flavonoid-Rich Fruit and Vegetable Consumption and Total Serum Bilirubin","volume":"66","author":"Loprinzi","year":"2015","journal-title":"Angiology"},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"701422","DOI":"10.3389\/fnut.2021.701422","article-title":"Higher Serum Bilirubin Levels in Response to Higher Carbohydrate Intake During Early Pregnancy and Lower Gestational Diabetes Mellitus Occurrence in Overweight and Obese Gravidae","volume":"8","author":"He","year":"2021","journal-title":"Front. Nutr."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"2609","DOI":"10.1016\/j.clnu.2021.04.008","article-title":"Gender and Gut Microbiota Composition Determine Hepatic Bile Acid, Metabolic and Inflammatory Response to a Single Fast-Food Meal in Healthy Adults","volume":"40","author":"Figge","year":"2021","journal-title":"Clin. Nutr."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"1106","DOI":"10.1038\/ijo.2017.70","article-title":"Untangling the Relationship between Diet and Visceral Fat Mass through Blood Metabolomics and Gut Microbiome Profiling","volume":"41","author":"Pallister","year":"2017","journal-title":"Int. J. Obes."},{"key":"ref_106","doi-asserted-by":"crossref","unstructured":"Adin, C.A. (2021). Bilirubin as a Therapeutic Molecule: Challenges and Opportunities. Antioxidants, 10.","DOI":"10.3390\/antiox10101536"},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"268","DOI":"10.1111\/bcp.13458","article-title":"Parenteral Bilirubin in Healthy Volunteers: A Reintroduction in Translational Research","volume":"84","author":"Dekker","year":"2018","journal-title":"Br. J. Clin. Pharmacol."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"108507","DOI":"10.1016\/j.pharmthera.2023.108507","article-title":"Beyond Statins: New Pharmacological Targets to Decrease LDL-Cholesterol and Cardiovascular Events","volume":"250","author":"Raschi","year":"2023","journal-title":"Pharmacol. Ther."},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"1373","DOI":"10.1080\/14656566.2021.1915290","article-title":"Improving Adherence with Treatment-Resistant Hypertension","volume":"22","author":"Borghi","year":"2021","journal-title":"Expert Opin. Pharmacother."},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1007\/s11883-020-00883-3","article-title":"Targeting Inflammation to Reduce Residual Cardiovascular Risk","volume":"22","author":"Ajala","year":"2020","journal-title":"Curr. Atheroscler. Rep."},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"108","DOI":"10.1097\/MOL.0000000000000672","article-title":"Reducing Residual Cardiovascular Risk with Novel Therapies","volume":"31","author":"Davidson","year":"2020","journal-title":"Curr. Opin. 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