{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,3]],"date-time":"2026-10-03T05:37:55Z","timestamp":1791005875479,"version":"4.1.0"},"reference-count":127,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2018,11,27]],"date-time":"2018-11-27T00:00:00Z","timestamp":1543276800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Ministry of Education Malaysia","award":["FRGS: 600-RMI\/ST\/FRGS\/5\/3\/FST (47\/2011) and RAGS:600-RMI\/RAGS 5\/3 (92\/2012)."],"award-info":[{"award-number":["FRGS: 600-RMI\/ST\/FRGS\/5\/3\/FST (47\/2011) and RAGS:600-RMI\/RAGS 5\/3 (92\/2012)."]}]},{"name":"Ministry of Education Malaysia","award":["FRGS: 600-RMI\/ST\/FRGS\/5\/3\/FST (47\/2011) and RAGS:600-RMI\/RAGS 5\/3 (92\/2012)."],"award-info":[{"award-number":["FRGS: 600-RMI\/ST\/FRGS\/5\/3\/FST (47\/2011) and RAGS:600-RMI\/RAGS 5\/3 (92\/2012)."]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>Bile acids (BA) are classically known as an important agent in lipid absorption and cholesterol metabolism. Nowadays, their role in glucose regulation and energy homeostasis are widely reported. BAs are involved in various cellular signaling pathways, such as protein kinase cascades, cyclic AMP (cAMP) synthesis, and calcium mobilization. They are ligands for several nuclear hormone receptors, including farnesoid X-receptor (FXR). Recently, BAs have been shown to bind to muscarinic receptor and Takeda G-protein-coupled receptor 5 (TGR5), both G-protein-coupled receptor (GPCR), independent of the nuclear hormone receptors. Moreover, BA signals have also been elucidated in other nonclassical BA pathways, such as sphingosine-1-posphate and BK (large conductance calcium- and voltage activated potassium) channels. Hydrophobic BAs have been proven to affect heart rate and its contraction. Elevated BAs are associated with arrhythmias in adults and fetal heart, and altered ratios of primary and secondary bile acid are reported in chronic heart failure patients. Meanwhile, in patients with liver cirrhosis, cardiac dysfunction has been strongly linked to the increase in serum bile acid concentrations. In contrast, the most hydrophilic BA, known as ursodeoxycholic acid (UDCA), has been found to be beneficial in improving peripheral blood flow in chronic heart failure patients and in protecting the heart against reperfusion injury. This review provides an overview of BA signaling, with the main emphasis on past and present perspectives on UDCA signals in the heart.<\/jats:p>","DOI":"10.3390\/biom8040159","type":"journal-article","created":{"date-parts":[[2018,11,27]],"date-time":"2018-11-27T12:17:35Z","timestamp":1543321055000},"page":"159","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":126,"title":["Overview of Bile Acids Signaling and Perspective on the Signal of Ursodeoxycholic Acid, the Most Hydrophilic Bile Acid, in the Heart"],"prefix":"10.3390","volume":"8","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4540-3367","authenticated-orcid":false,"given":"Noorul Izzati","family":"Hanafi","sequence":"first","affiliation":[{"name":"Institute of Medical Molecular Biotechnology, Faculty of Medicine, Universiti Teknologi MARA, Sungai Buloh 47000, Selangor, Malaysia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anis Syamimi","family":"Mohamed","sequence":"additional","affiliation":[{"name":"Institute of Medical Molecular Biotechnology, Faculty of Medicine, Universiti Teknologi MARA, Sungai Buloh 47000, Selangor, Malaysia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1671-4839","authenticated-orcid":false,"given":"Siti Hamimah","family":"Sheikh Abdul Kadir","sequence":"additional","affiliation":[{"name":"Institute of Medical Molecular Biotechnology, Faculty of Medicine, Universiti Teknologi MARA, Sungai Buloh 47000, Selangor, Malaysia"},{"name":"Department of Biochemistry and Molecular Medicine, Faculty of Medicine, Universiti Teknologi MARA, Sungai Buloh 47000, Selangor, Malaysia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohd Hafiz Dzarfan","family":"Othman","sequence":"additional","affiliation":[{"name":"Advanced Membrane Technology Research Centre (AMTEC), Universiti Teknologi Malaysia, Johor Bharu 81310, Johor, Malaysia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2018,11,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"614","DOI":"10.1016\/S0022-2275(20)37966-9","article-title":"The enterohepatic circulation of bile acids during continuous liquid formula perfusion of the duodenum","volume":"24","author":"Rutgeerts","year":"1983","journal-title":"J. Lipid Res."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"S237","DOI":"10.2337\/dc09-S355","article-title":"Bile acids and metabolic regulation: Mechanisms and clinical responses to bile acid sequestration","volume":"32","author":"Staels","year":"2009","journal-title":"Diabetes Care"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1194\/jlr.R500013-JLR200","article-title":"Bile salt biotransformations by human intestinal bacteria","volume":"47","author":"Ridlon","year":"2006","journal-title":"J. Lipid Res."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Lefebvre, P., Cariou, B., Lien, F., Kuipers, F., and Staels, B. (2009). Role of Bile Acids and Bile Acid Receptors in Metabolic Regulation. Physiol. Rev., 147\u2013191.","DOI":"10.1152\/physrev.00010.2008"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"929","DOI":"10.1152\/ajpgi.00315.2013","article-title":"Colonic inflammation and secondary bile acids in alcoholic cirrhosis","volume":"306","author":"Kakiyama","year":"2014","journal-title":"Am. J. Physiol. Gastrointest. Liver Physiol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1148","DOI":"10.1016\/S0022-2275(20)33519-7","article-title":"Highly simplified method for gas-liquid chromatographic quantitation of bile acids and sterols in human stool","volume":"40","author":"Batta","year":"1999","journal-title":"J. Lipid Res."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"2647","DOI":"10.1001\/archinte.159.22.2647","article-title":"The continuing importance of bile acids in liver and intestinal disease","volume":"159","author":"Hofmann","year":"1999","journal-title":"Arch. Intern. Med."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"754067","DOI":"10.1155\/2012\/754067","article-title":"Bile Acid signaling in liver metabolism and diseases","volume":"2012","author":"Li","year":"2012","journal-title":"J. Lipids"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"2180","DOI":"10.1016\/j.cellsig.2008.06.014","article-title":"Bile acids and signal transduction: Role in glucose homeostasis","volume":"20","author":"Nguyen","year":"2008","journal-title":"Cell. Signal."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1429","DOI":"10.3892\/or.2012.1918","article-title":"Pro-apoptotic role of the MEK\/ERK pathway in ursodeoxycholic acid-induced apoptosis in SNU601 gastric cancer cells","volume":"28","author":"Lim","year":"2012","journal-title":"Oncol. Rep."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"564","DOI":"10.1016\/j.molmed.2011.05.010","article-title":"Bile acids and colon cancer: Solving the puzzle with nuclear receptors","volume":"17","author":"Degirolamo","year":"2011","journal-title":"Trends Mol. Med."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1016\/j.apsb.2015.01.004","article-title":"Bile acid nuclear receptor FXR and digestive system diseases","volume":"5","author":"Ding","year":"2015","journal-title":"Acta Pharm. Sin. B"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"302","DOI":"10.1016\/j.dld.2013.10.021","article-title":"The bile acid TGR5 membrane receptor: From basic research to clinical application","volume":"46","author":"Duboc","year":"2014","journal-title":"Dig. Liver Dis."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"S25","DOI":"10.1016\/j.jhep.2015.02.023","article-title":"New paradigms in the treatment of hepatic cholestasis: From UDCA to FXR, PXR and beyond","volume":"62","author":"Beuers","year":"2015","journal-title":"J. Hepatol."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Miyazaki-Anzai, S., Masuda, M., Levi, M., Keenan, A.L., and Miyazaki, M. (2014). Dual activation of the bile acid nuclear receptor FXR and G-Protein-Coupled receptor TGR5 protects mice against atherosclerosis. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0108270"},{"key":"ref_16","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_17","doi-asserted-by":"crossref","first-page":"1956","DOI":"10.1194\/jlr.M300182-JLR200","article-title":"FXR-mediated down-regulation of CYP7A1 dominates LXR\u03b1 in long-term cholesterol-fed NZW rabbits","volume":"44","author":"Xu","year":"2003","journal-title":"J. Lipid Res."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1216","DOI":"10.1002\/hep.27592","article-title":"Conjugated bile acid-activated S1P receptor 2 is a key regulator of sphingosine kinase 2 and hepatic gene expression","volume":"61","author":"Nagahashi","year":"2015","journal-title":"Hepatology"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"3375","DOI":"10.1073\/pnas.051014398","article-title":"An essential role for nuclear receptors SXR\/PXR in detoxification of cholestatic bile acids","volume":"98","author":"Xie","year":"2001","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"571","DOI":"10.1016\/S0959-437X(98)80013-0","article-title":"The LXRs: A new class of oxysterol receptors","volume":"8","author":"Peet","year":"1998","journal-title":"Curr. Opin. Genet. Dev."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1016\/j.mce.2012.05.004","article-title":"FXR signaling in the enterohepatic system","volume":"368","author":"Matsubara","year":"2013","journal-title":"Mol. Cell. Endocrinol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1451","DOI":"10.1002\/hep.26463","article-title":"The receptor TGR5 protects the liver from bile acid overload during liver regeneration in mice","volume":"58","author":"Doignon","year":"2013","journal-title":"Hepatology"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1111\/j.1365-2567.2012.03554.x","article-title":"Bile acids induce monocyte differentiation toward interleukin-12 hypo-producing dendritic cells via a TGR5-dependent pathway","volume":"136","author":"Ichikawa","year":"2012","journal-title":"Immunology"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1016\/S0014-2999(02)02690-0","article-title":"Selective interaction of bile acids with muscarinic receptors: A case of molecular mimicry","volume":"457","author":"Raufman","year":"2002","journal-title":"Eur. J. Pharmacol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"427","DOI":"10.1007\/s10571-009-9467-2","article-title":"Pilocarpine protects cobalt chloride-induced apoptosis of RGC-5 cells: Involvement of muscarinic receptors and HIF-1\u03b1 pathway","volume":"30","author":"Zhu","year":"2010","journal-title":"Cell. Mol. Neurobiol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"2005","DOI":"10.1096\/fj.06-6889com","article-title":"The sphingosine 1-phosphate receptor S1P2 triggers hepatic wound healing","volume":"21","author":"Li","year":"2007","journal-title":"FASEB J."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1002\/hep.24681","article-title":"Conjugated bile acids activate the sphingosine-1-phosphate receptor 2 in primary rodent hepatocytes","volume":"55","author":"Studer","year":"2012","journal-title":"Hepatology (Balt. Md.)"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"30988","DOI":"10.1074\/jbc.M115.668277","article-title":"Taurocholate Induces Cyclooxygenase-2 Expression via the Sphingosine 1-phosphate Receptor 2 in a Human Cholangiocarcinoma Cell Line","volume":"290","author":"Liu","year":"2015","journal-title":"J. Biol. Chem."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1093\/cvr\/cvp086","article-title":"Sphingosine-1-phosphate receptor signaling in the heart","volume":"82","author":"Means","year":"2009","journal-title":"Cardiovasc. Res."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Schmidt, A., Lenzig, P., Oslender-Bujotzek, A., Kusch, J., Lucas, S.D., Gr\u00fcnder, S., and Wiemuth, D. (2014). The Bile Acid-Sensitive Ion Channel (BASIC) Is activated by alterations of its membrane environment. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0111549"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"662","DOI":"10.4254\/wjh.v7.i4.662","article-title":"Arrhythmia risk in liver cirrhosis","volume":"7","author":"Mozos","year":"2015","journal-title":"World J. Hepatol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1016\/j.gdata.2015.07.026","article-title":"Genome-wide profiling to analyze the effects of FXR activation on mouse renal proximal tubular cells","volume":"6","author":"Gui","year":"2015","journal-title":"Genom. Data"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"3668","DOI":"10.1073\/pnas.0400046101","article-title":"Expression and activation of the farnesoid X receptor in the vasculature","volume":"101","author":"Walsh","year":"2004","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"31441","DOI":"10.1074\/jbc.M200474200","article-title":"Lithocholic acid decreases expression of bile salt 139 export pump through farnesoid X receptor antagonist activity","volume":"277","author":"Yu","year":"2002","journal-title":"J. Biol. Chem."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1016\/S1050-1738(00)00043-8","article-title":"FXR, a Bile Acid Receptor and Biological Sensor","volume":"10","author":"Tu","year":"2000","journal-title":"Trends Cardiovasc. Med."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"570","DOI":"10.1016\/j.tips.2009.08.001","article-title":"Bile-acid-activated receptors: Targeting TGR5 and farnesoid-X-receptor in lipid and glucose disorders","volume":"30","author":"Fiorucci","year":"2009","journal-title":"Trends Pharmacol. Sci."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1016\/j.bbalip.2014.04.008","article-title":"Bile acid signaling in lipid metabolism: Metabolomic and lipidomic analysis of lipid and bile acid markers linked to anti-obesity and anti-diabetes in mice","volume":"1851","author":"Qi","year":"2015","journal-title":"Biochim. Biophys. Acta (BBA)"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1186\/1756-8722-4-41","article-title":"Impact of bile acids on the growth of human cholangiocarcinoma via FXR","volume":"4","author":"Dai","year":"2011","journal-title":"J. Hematol. Oncol."},{"key":"ref_39","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_40","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1016\/j.jsbmb.2011.06.012","article-title":"FXR and PXR: Potential therapeutic targets in cholestasis","volume":"130","author":"Jonker","year":"2012","journal-title":"J. Steroid Biochem. Mol. Biol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"367","DOI":"10.1038\/sj.bjp.0707235","article-title":"Hepatoprotective role of PXR activation and MRP3 in cholic acid-induced cholestasis","volume":"151","author":"Teng","year":"2007","journal-title":"Br. J. Pharmacol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"19081","DOI":"10.1074\/jbc.M600116200","article-title":"Pregnane X receptor is a target of farnesoid X receptor","volume":"281","author":"Jung","year":"2006","journal-title":"J. Biol. Chem."},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Ma, Y., and Liu, D. (2012). Activation of pregnane X receptor by pregnenolone 16 alpha-carbonitrile prevents high-fat diet-induced obesity in AKR\/J mice. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0038734"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1151","DOI":"10.1210\/me.2009-0482","article-title":"A Novel Bile Acid-Activated Vitamin D Receptor Signaling in Human Hepatocytes","volume":"24","author":"Han","year":"2010","journal-title":"Mol. Endocrinol."},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Ishizwa, M., Akagi, D., and Makishima, M. (2018). Lithocholic acid is a vitamin D receptor ligand that acts preferentially in the ileum. Int. J. Mol. Sci., 19.","DOI":"10.3390\/ijms19071975"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"726","DOI":"10.1210\/er.2008-0004","article-title":"Vitamin D and human health: Lessons from vitamin D receptor null mice","volume":"29","author":"Bouillon","year":"2008","journal-title":"Endocr. Rev."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1194\/jlr.M400294-JLR200","article-title":"Selective activation of vitamin D receptor by lithocholic acid acetate, a bile acid derivative","volume":"46","author":"Adachi","year":"2005","journal-title":"J. Lipid Res."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1","DOI":"10.3389\/fphys.2014.00145","article-title":"The role of vitamin D in skeletal and cardiac muscle function","volume":"5","author":"Polly","year":"2014","journal-title":"Front. Physiol."},{"key":"ref_49","first-page":"109275","article-title":"Links between Vitamin D Deficiency and Cardiovascular Diseases","volume":"2015","author":"Mozos","year":"2005","journal-title":"Biomed. Res. Int."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"8784971","DOI":"10.1155\/2017\/8784971","article-title":"Crosstalk between Vitamins A, B12, D, K, C, and E Status and Arterial Stiffness","volume":"2017","author":"Mozos","year":"2017","journal-title":"Dis. Markers"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"423","DOI":"10.1016\/S0039-128X(00)00127-6","article-title":"Selective activation of liver X receptor \u03b1 by 6\u03b1-hydroxy bile acids and analogs","volume":"65","author":"Song","year":"2000","journal-title":"Steroids"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"996","DOI":"10.1002\/hep.24107","article-title":"Overexpression of cholesterol 7\u03b1-hydroxylase promotes hepatic bile acid synthesis and secretion and maintains cholesterol homeostasis","volume":"53","author":"Li","year":"2011","journal-title":"Hepatology"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"9435","DOI":"10.1074\/jbc.M209706200","article-title":"A G protein-coupled receptor responsive to bile acids","volume":"278","author":"Kawamata","year":"2003","journal-title":"J. Biol. Chem."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1016\/j.cmet.2009.08.001","article-title":"TGR5-mediated bile acid sensing controls glucose homeostasis","volume":"10","author":"Thomas","year":"2009","journal-title":"Cell Metab."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"78","DOI":"10.1016\/j.bbrc.2008.04.171","article-title":"Expression and function of the bile acid receptor TGR5 in Kupffer cells","volume":"372","author":"Keitel","year":"2008","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"5424","DOI":"10.1172\/JCI76289","article-title":"TGR5 reduces macrophage migration through mTOR-induced C\/EBP\u03b2 differential translation","volume":"124","author":"Perino","year":"2014","journal-title":"J. Clin. Investig."},{"key":"ref_57","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_58","first-page":"1","article-title":"Molecular Biology, Pharmacology, and Brain Distribution of Subtypes the Muscarinic Receptor","volume":"64","author":"Ehlert","year":"1950","journal-title":"Distribution"},{"key":"ref_59","doi-asserted-by":"crossref","unstructured":"Fryer, D.A., Christopoulos, A., and Nathanson, M.N. (2012). Muscarinic Receptors, Springer.","DOI":"10.1007\/978-3-642-23274-9"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1006\/phrs.2001.0835","article-title":"Muscarinic receptors in the mammalian heart","volume":"44","author":"Dhein","year":"2001","journal-title":"Pharmacol. Res."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1124\/jpet.102.036376","article-title":"Lithocholylcholine, a bile acid\/acetylcholine hybrid, is a muscarinic receptor antagonist","volume":"303","author":"Cheng","year":"2002","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_62","doi-asserted-by":"crossref","unstructured":"Sheikh Abdul Kadir, S.H., Miragoli, M., Abu-Hayyeh, S., Moshkov, A.V., Xie, Q., Keitel, V., Nikolaev, V.O., Williamson, C., and Gorelik, J. (2010). Bile acid-induced arrhythmia is mediated by muscarinic M2 receptors in neonatal rat cardiomyocytes. PLoS ONE, 5.","DOI":"10.1371\/journal.pone.0009689"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"7110","DOI":"10.1038\/s41598-018-25569-4","article-title":"Bile acids and their respective conjugates elicit different responses in neonatal cardiomyocytes: Role of Gi protein, muscarinic receptors and TGR5","volume":"8","author":"Ibrahim","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1016\/j.apsb.2014.12.009","article-title":"Bile acids and sphingosine-1-phosphate receptor 2 in hepatic lipid metabolism","volume":"5","author":"Kwong","year":"2015","journal-title":"Acta Pharm. Sin. B"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"2441","DOI":"10.1194\/jlr.M800286-JLR200","article-title":"Structural determinants of monohydroxylated bile acids to activate beta 1 subunit-containing BK channels","volume":"49","author":"Bukiya","year":"2008","journal-title":"J. Lipid Res."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"35314","DOI":"10.1074\/jbc.M114.577825","article-title":"Activation of calcium- and voltage-gated potassium channels of large conductance by leukotriene B4","volume":"289","author":"Bukiya","year":"2014","journal-title":"J. Biol. Chem."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"160","DOI":"10.1007\/BF00177718","article-title":"Effects of bile acids on ventricular muscle contraction and electrophysiological properties: Studies in rat papillary muscle and isolated ventricular myocytes","volume":"335","author":"Binah","year":"1987","journal-title":"Naunyn Schmiedebergs. Arch. Pharmacol."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1080\/jmf.10.2.131.135","article-title":"Ursodeoxycholic acid for the treatment of intrahepatic cholestasis of pregnancy","volume":"10","author":"Laifer","year":"2001","journal-title":"J. Matern.-Fetal Med."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"141","DOI":"10.3109\/01480545.2012.658919","article-title":"The effect of ursodeoxycholic acid on oxidative stress level and DNase activity in rat liver after bile duct ligation","volume":"36","author":"Sokolovic","year":"2012","journal-title":"Drug Chem. Toxicol."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"779","DOI":"10.1053\/jhep.2002.32533","article-title":"Inhibition of the MAPK and PI3K pathways enhances UDCA-induced apoptosis in primary rodent hepatocytes","volume":"35","author":"Qiao","year":"2002","journal-title":"Hepatology (Balt. MD)"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"483","DOI":"10.1093\/jn\/134.2.483","article-title":"UDCA can inhibit DCA-induced apoptosis via modulation of EGFR\/Raf-1\/ERK signaling in human colon cancer cells","volume":"134","author":"Im","year":"2004","journal-title":"J. Nutr."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"846","DOI":"10.1093\/jnci\/dji144","article-title":"Phase III trial of ursodeoxycholic acid to prevent colorectal adenoma recurrence","volume":"97","author":"Alberts","year":"2005","journal-title":"J. Natl. Cancer Inst."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"1419","DOI":"10.1038\/labinvest.2014.117","article-title":"Tauroursodeoxycholic acid inhibits experimental colitis by preventing early intestinal epithelial cell death","volume":"94","author":"Laukens","year":"2014","journal-title":"Lab. Investig."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"610","DOI":"10.1016\/j.bbrc.2011.05.043","article-title":"Structure-function analysis of the tertiary bile acid TUDCA for the resolution of endoplasmic reticulum stress in intestinal epithelial cells","volume":"409","author":"Berger","year":"2011","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_75","doi-asserted-by":"crossref","unstructured":"Fekaj, E., Gjata, A., and Maxhuni, M. (2013). The effect of ursodeoxycholic acid in liver functional restoration of patients with obstructive jaundice after endoscopic treatment: A prospective, randomized, and controlled study. BMC Surg., 13.","DOI":"10.1186\/1471-2482-13-38"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"1","DOI":"10.3748\/wjg.15.2049","article-title":"Intrahepatic cholestasis of pregnancy","volume":"15","author":"Geenes","year":"2009","journal-title":"World J. Gastroenterol."},{"key":"ref_77","first-page":"318","article-title":"Drug insight: Mechanisms and sites of action of ursodeoxycholic acid in cholestasis. Nature Clinical Practice","volume":"3","author":"Beuers","year":"2006","journal-title":"Gastroenterol. Hepatol."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1007\/BF01311711","article-title":"Differing effects of ursodeoxycholic or chenodeoxycholic acid on biliary cholesterol saturation and bile acid metabolism in man. A dose-response study","volume":"27","author":"Thistle","year":"1982","journal-title":"Dig. Dis. Sci."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"4336","DOI":"10.3748\/wjg.v13.i32.4336","article-title":"Effects of long-term hydrophilic bile acid therapy on in vitro containing of gallbladder muscle strips in patients with cholesterol gallstones","volume":"13","author":"Mas","year":"2007","journal-title":"World J. Gastroenterol."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"2790","DOI":"10.1172\/JCI1325","article-title":"A novel role for ursodeoxycholic acid in inhibiting apoptosis by modulating mitochondrial membrane perturbation","volume":"101","author":"Rodrigues","year":"1998","journal-title":"J. Clin. Investig."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"1721","DOI":"10.1194\/jlr.R900011-JLR200","article-title":"Bile acids: Regulation of apoptosis by ursodeoxycholic acid","volume":"50","author":"Amaral","year":"2009","journal-title":"J. Lipid Res."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1016\/j.jhep.2012.08.002","article-title":"Bile acid transporters and regulatory nuclear receptors in the liver and beyond","volume":"58","author":"Halilbasic","year":"2013","journal-title":"J. Hepatol."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"1","DOI":"10.3389\/fnins.2015.00080","article-title":"Hydrophilic bile acids protect human blood-brain barrier endothelial cells from disruption by unconjugated bilirubin: An in vitro study","volume":"9","author":"Palmela","year":"2015","journal-title":"Front. Neurosci."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1007\/s12177-009-9030-x","article-title":"Bile acids in treatment of ocular disease","volume":"2","author":"Boatright","year":"2009","journal-title":"J. Ocul. Biol. Dis. Inf."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1186\/2193-1801-2-20","article-title":"Incretin secretion stimulated by ursodeoxycholic acid in healthy subjects","volume":"2","author":"Murakami","year":"2013","journal-title":"SpringerPlus"},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"1740","DOI":"10.1136\/gut.2008.160333","article-title":"Decreased number of activated macrophages in gallbladder muscle layer of cholesterol gallstone patients following ursodeoxycholic acid","volume":"57","author":"Guarino","year":"2008","journal-title":"Gut"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"3038","DOI":"10.1093\/brain\/awt224","article-title":"Ursocholanic acid rescues mitochondrial function in common forms of familial Parkinson\u2019s disease","volume":"136","author":"Mortiboys","year":"2013","journal-title":"Brain"},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"1206","DOI":"10.1111\/eci.12355","article-title":"Ursodeoxycholic acid decreases bilirubin-induced osteoblast apoptosis","volume":"44","author":"Dubreuil","year":"2014","journal-title":"Eur. J. Clin. Investig."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"363","DOI":"10.1042\/cs1000363","article-title":"The bile acid taurocholate impairs rat cardiomyocyte function: A proposed mechanism for intra-uterine fetal death in obstetric cholestasis","volume":"100","author":"Williamson","year":"2001","journal-title":"Clin. Sci. (Lond. Engl.)"},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1042\/cs1030191","article-title":"Taurocholate induces changes in rat cardiomyocyte contraction and calcium dynamics","volume":"200","author":"Gorelik","year":"2002","journal-title":"Clin. Sci. (Lond.)"},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"1282","DOI":"10.1002\/hep.24492","article-title":"A protective antiarrhythmic role of ursodeoxycholic acid in an in vitro rat model of the cholestatic fetal heart","volume":"54","author":"Miragoli","year":"2011","journal-title":"Hepatology (Balt. MD)"},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"3730","DOI":"10.1111\/j.1582-4934.2009.00741.x","article-title":"The use of embryonic stem cell-derived cardiomyocytes as a model to study fetal arrhythmia related to maternal disease","volume":"13","author":"Ali","year":"2009","journal-title":"J. Cell. Mol. Med."},{"key":"ref_93","doi-asserted-by":"crossref","unstructured":"Mohamed, A.S., Hanafi, N.I., Siran, R., Md Nor, J., Abdul Hamid Hasani, N., Ab Rahim, S., and Sheikh Abdul Kadir, S.H. (2017). Ursodeoxycholic acid protects cardiomyocytes against cobalt chloride induced hypoxia by regulating transcriptional mediator of cells stress hypoxia inducible factor 1\u03b1 and p53 protein. Cell Biochem. Funct., 1\u201311.","DOI":"10.1002\/cbf.3303"},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"424","DOI":"10.1046\/j.1471-0528.2003.02273.x","article-title":"Dexamethasone and ursodeoxycholic acid protect against the arrhythmogenic effect of taurocholate in an in vitro study of rat cardiomyocytes","volume":"110","author":"Gorelik","year":"2003","journal-title":"BJOG Int. J. Obstet. Gynaecol."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"887","DOI":"10.1002\/hep.1840080430","article-title":"Hepatotoxic bile acids increase cytosolic Ca++ activity of isolated rat hepatocytes","volume":"8","author":"Anwer","year":"1988","journal-title":"Hepatology"},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"3553","DOI":"10.3748\/wjg.v12.i22.3553","article-title":"Bile Acid Interactions with Cholangiocytes","volume":"12","author":"Xia","year":"2006","journal-title":"World J. Gastroenterol."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1016\/S0021-9258(17)31237-1","article-title":"Characteristics of bile acid-mediated Ca release from permeabilized liver cells and liver microsomes","volume":"264","author":"Combettes","year":"1989","journal-title":"J. Biol. Chem."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"10322","DOI":"10.1074\/jbc.RA118.002733","article-title":"The Exercise-Inducible Bile Acid Receptor Tgr5 Improves Skeletal Muscle Function in Mice","volume":"293","author":"Takashi","year":"2018","journal-title":"J. Biol. Chem."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1042\/bj2730153","article-title":"Effects of taurolithocholate, a Ca2(+)-mobilizing agent, on cell Ca2(+) in rat hepatocytes, human platelets and neuroblastoma NG108-15 cell line","volume":"273","author":"Coquil","year":"1991","journal-title":"Biochem. J."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"2337","DOI":"10.1172\/JCI31909","article-title":"Ligand activation of LXR\u03b2 reverses atherosclerosis and cellular cholesterol overload in mice lacking LXR\u03b1 and apoE","volume":"117","author":"Bradley","year":"2007","journal-title":"J. Clin. Investig."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"479","DOI":"10.1007\/BF02979156","article-title":"Effect of Ursodeoxycholic Acid Injury in Isolated Rat Heart Ischemia\/Reperfusion","volume":"22","author":"Lee","year":"1999","journal-title":"Arch. Pharm. Res."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"766","DOI":"10.1016\/j.yjmcc.2005.07.014","article-title":"Hydrophilic bile salt ursodeoxycholic acid protects myocardium against reperfusion injury in a PI3K\/Akt dependent pathway","volume":"39","author":"Rajesh","year":"2005","journal-title":"J. Mol. Cell. Cardiol."},{"key":"ref_103","doi-asserted-by":"crossref","unstructured":"Mahmoud, A., and Elshazly, S.M. (2014). Ursodeoxycholic Acid ameliorates fructose-induced metabolic syndrome in rats. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0106993"},{"key":"ref_104","doi-asserted-by":"crossref","unstructured":"Hanafi, N.I., Mohamed, A.S., Md Noor, J., Abdul Hamid Hasani, N., Siran, R., Osman, N.J., Ab Rahim, S., and Sheikh Abdul Kadir, S.H. (2016). Ursodeoxycholic acid upregulates ERK and Akt in the protection of cardiomyocytes against CoCl2. Genet. Mol. Res. GMR, 15.","DOI":"10.4238\/gmr.15028150"},{"key":"ref_105","first-page":"1","article-title":"Ursodeoxycholic Acid Regulates Caspase-9 and ROS Production in Protecting Cardiomyocytes Against Hypoxia","volume":"79","author":"Hanafi","year":"2017","journal-title":"J. Teknol. (Sci. Eng.) UTM"},{"key":"ref_106","doi-asserted-by":"crossref","unstructured":"Chung, J., An, S.H., Kang, S.W., and Kwon, K. (2016). Ursodeoxycholic Acid (UDCA) Exerts Anti-Atherogenic Effects by Inhibiting RAGE Signaling in Diabetic Atherosclerosis. PLoS ONE, 11.","DOI":"10.1371\/journal.pone.0147839"},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"661","DOI":"10.1046\/j.1365-2125.1999.00940.x","article-title":"Ursodeoxycholic acid and endothelial-dependent, nitric oxide-independent vasodilatation of forearm resistance arteries in patients with coronary heart disease","volume":"47","author":"Sinisalo","year":"1999","journal-title":"Br. J. Clin. Pharmacol."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"585","DOI":"10.1016\/j.jacc.2011.10.880","article-title":"Ursodeoxycholic acid in patients with chronic heart failure: A double-blind, randomized, placebo-controlled, crossover trial","volume":"59","author":"Schefold","year":"2012","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_109","first-page":"592","article-title":"Adjuvant treatment with ursodeoxycholic acid may reduce the incidence of acute cardiac allograft rejection","volume":"17","author":"Stiehl","year":"1998","journal-title":"J. Heart Lung Transplant."},{"key":"ref_110","first-page":"619207","article-title":"Regulation of DDAH1 as a Potential Therapeutic Target for Treating Cardiovascular Diseases","volume":"2013","author":"Liu","year":"2013","journal-title":"\u00c9vid.-Based Complement. Altern. Med. ECAM"},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"1345","DOI":"10.1016\/j.bbadis.2017.12.039","article-title":"Heart and bile acids\u2013Clinical consequences of altered bile acid metabolism","volume":"1864","author":"Vasavan","year":"2018","journal-title":"Biochim. Biophys. Acta Mol. Basis Dis."},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"392","DOI":"10.1097\/MEG.0000000000001043","article-title":"Total bile acid levels are associated with left atrial volume and cardiac output in patients with cirrhosis","volume":"30","author":"Voiosu","year":"2018","journal-title":"Eur. J. Gastroenterol. Hepatol."},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"2333","DOI":"10.1089\/ars.2009.2469","article-title":"Macrophage Apoptosis in Atherosclerosis: Consequences on Plaque Progression and the Role of Endoplasmic Reticulum","volume":"11","author":"Tabas","year":"2009","journal-title":"Antioxid Redox Signal"},{"key":"ref_114","doi-asserted-by":"crossref","unstructured":"Granados, D.P., Tanguay, P.-L., Hardy, M.-P., de Verteuil, D., Meloche, S., and Perreault, C. (2009). ER stress processing of MHC class I-associated peptides. BMC Immunology, 10.","DOI":"10.1186\/1471-2172-10-10"},{"key":"ref_115","first-page":"1","article-title":"Ursodeoxycholic Acid and Its Taurine- or Colitogenic Dysbiosis and Equally Suppress Experimental Colitis in Mice","volume":"83","author":"Hindryckx","year":"2017","journal-title":"Appl. Environ. Microbiol."},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"e220","DOI":"10.1038\/cddis.2011.101","article-title":"Caspase deficiency alters the murine gut microbiome","volume":"2","author":"Brinkman","year":"2011","journal-title":"Cell Death Dis."},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"fiv008","DOI":"10.1093\/femsec\/fiv008","article-title":"Polyphenol-rich sorghum brans alter colon microbiota and impact species diversity and species richness after multiple bouts of dextran sodium sulfate-induced colitis","volume":"91","author":"Ritchie","year":"2015","journal-title":"FEMS Microbiol. Ecol."},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"174","DOI":"10.18869\/acadpub.ibj.21.3.174","article-title":"The effect of oral consumption of probiotics in prevention of heart injury in a rat myocardial infarction model: A. histopathological, hemodynamic and biochemical evaluation","volume":"21","author":"Sadeghzadeh","year":"2017","journal-title":"Iran. Biomed. J."},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"491","DOI":"10.1161\/CIRCHEARTFAILURE.113.000978","article-title":"Probiotic administration attenuates myocardial hypertrophy and heart failure after myocardial infarction in the rat","volume":"7","author":"Gan","year":"2014","journal-title":"Circ. Heart Fail."},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"348","DOI":"10.1016\/j.ijcard.2014.11.034","article-title":"Probiotic therapy with Saccharomyces boulardii for heart failure patients: A. randomized, double-blind, placebo-controlled pilot trial","volume":"179","author":"Costanza","year":"2015","journal-title":"Int. J. Cardiol."},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1016\/j.canlet.2005.04.016","article-title":"Ursodeoxycholic acid differentially affects three types of sphingomyelinase in human colon cancer Caco 2 cells","volume":"235","author":"Liu","year":"2006","journal-title":"Cancer Lett."},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"519","DOI":"10.1002\/ejhf.73","article-title":"Diaphragm dysfunction in heart failure is accompanied by increases in neutral sphingomyelinase activity and ceramide content","volume":"16","author":"Empinado","year":"2014","journal-title":"Eur. J. Heart Fail."},{"key":"ref_123","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1093\/cvr\/cvp030","article-title":"Sphingomyelinases: Their regulation and roles in cardiovascular pathophysiology","volume":"82","author":"Pavoine","year":"2009","journal-title":"Cardiovasc. Res."},{"key":"ref_124","doi-asserted-by":"crossref","first-page":"198","DOI":"10.1161\/01.RES.86.2.198","article-title":"Rapid Activation of Neutral Sphingomyelinase by Hypoxia-Reoxygenation of Cardiac Myocytes","volume":"86","author":"Hernandez","year":"2000","journal-title":"Circ. Res."},{"key":"ref_125","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1136\/heartjnl-2012-302920j.52","article-title":"Relationship Between Sphingomyelinase, Ceramide and Clinical Presentation, Extent and Severity of Atherosclerotic Coronary Artery Disease","volume":"98","author":"Yu","year":"2012","journal-title":"Heart"},{"key":"ref_126","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1016\/j.yjmcc.2016.02.019","article-title":"Targeting acid sphingomyelinase reduces cardiac ceramide accumulation in the post-ischemic heart","volume":"93","author":"Klevstig","year":"2016","journal-title":"J. Mol. Cell. Cardiol."},{"key":"ref_127","doi-asserted-by":"crossref","first-page":"2944","DOI":"10.1152\/ajpheart.01331.2006","article-title":"Sphingosine 1-phosphate S1P2 and S1P3 receptor-mediated Akt activation protects against in vivo myocardial ischemia-reperfusion injury","volume":"292","author":"Means","year":"2007","journal-title":"Am. J. Physiol. Heart Circ. Physiol."}],"container-title":["Biomolecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2218-273X\/8\/4\/159\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T15:32:47Z","timestamp":1760196767000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2218-273X\/8\/4\/159"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,11,27]]},"references-count":127,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2018,12]]}},"alternative-id":["biom8040159"],"URL":"https:\/\/doi.org\/10.3390\/biom8040159","relation":{"has-preprint":[{"id-type":"doi","id":"10.20944\/preprints201810.0235.v1","asserted-by":"object"}]},"ISSN":["2218-273X"],"issn-type":[{"value":"2218-273X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2018,11,27]]}}}