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In bile, these exist as micelles above their critical micellar concentration (CMC). In blood at low concentrations, these exist as monomers, initiating cellular signals. This micellar to monomer transition may involve complex thermodynamic interactions between bile salts alone or with phospholipids, i.e. mixed micelles and the aqueous environment. We therefore went on to test if therapeutically relevant changes in temperature could influence micellar behavior of bile salts, and in turn whether this affected the biological responses in cells, and <jats:italic>in vivo<\/jats:italic>. Sodium taurocholate (STC) belongs to a major class of bile salts. STC has a CMC in the 5\u20138\u2009mM range and its infusion into the pancreatic duct is commonly used to study pancreatitis. We thus studied micellar breakdown of STC using isothermal titration calorimetry (ITC), dynamic light scattering and cryogenic transmission electron microscopy. Under conditions relevant to the <jats:italic>in vivo<\/jats:italic> environment (pH 7.4, Na 0.15\u2009M), ITC showed STC to have a U shaped reduction in micellar breakdown between 37\u2009\u00b0C and 15\u2009\u00b0C with a nadir at 25\u2009\u00b0C approaching \u224890% inhibition. This temperature dependence paralleled pancreatic acinar injury induced by monomeric STC. Mixed micelles of STC and 1-palmitoyl, 2-oleyl phosphatidylcholine, a phospholipid present in high proportions in bile, behaved similarly, with \u224875% reduction in micellar breakdown at 25\u2009\u00b0C compared to 37\u2009\u00b0C. <jats:italic>In vivo<\/jats:italic> pancreatic cooling to 25\u2009\u00b0C reduced the increase in circulating BAs after infusion of 120\u2009mM (5%) STC into the pancreatic duct, and duct ligation. Lower BA levels were associated with improved cardiac function, reduced myocardial damage, shock, lung injury and improved survival independent of pancreatic injury. Thus micellar breakdown of bile salts is essential for their entry into the systemic circulation, and thermodynamic interference with this may reduce their systemic entry and consequent injury during cholestasis, such as from biliary pancreatitis.<\/jats:p>","DOI":"10.1038\/s41598-020-65451-w","type":"journal-article","created":{"date-parts":[[2020,5,21]],"date-time":"2020-05-21T10:02:26Z","timestamp":1590055346000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Thermodynamic interference with bile acid demicelleization reduces systemic entry and injury during cholestasis"],"prefix":"10.1038","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4652-1103","authenticated-orcid":false,"given":"Cristiane","family":"de Oliveira","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Biswajit","family":"Khatua","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bara","family":"El-Kurdi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Krutika","family":"Patel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vivek","family":"Mishra","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah","family":"Navina","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bradley J.","family":"Grim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5860-9658","authenticated-orcid":false,"given":"Srishti","family":"Gupta","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marek","family":"Belohlavek","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brian","family":"Cherry","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeffery","family":"Yarger","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5518-3412","authenticated-orcid":false,"given":"Matthew D.","family":"Green","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vijay P.","family":"Singh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2020,5,21]]},"reference":[{"key":"65451_CR1","doi-asserted-by":"publisher","first-page":"563","DOI":"10.1111\/j.1572-0241.2007.01095.x","volume":"102","author":"CC Lee","year":"2007","unstructured":"Lee, C. 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