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      Thermodynamic interference with bile acid demicelleization reduces systemic entry and injury during cholestasis

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          Abstract

          Bile acids (BA), with their large hydrophobic steroid nucleus and polar groups are amphipathic molecules. 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 in vivo. Sodium taurocholate (STC) belongs to a major class of bile salts. STC has a CMC in the 5–8 mM 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 in vivo environment (pH 7.4, Na 0.15 M), ITC showed STC to have a U shaped reduction in micellar breakdown between 37 °C and 15 °C with a nadir at 25 °C approaching ≈90% 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 ≈75% reduction in micellar breakdown at 25 °C compared to 37 °C. In vivo pancreatic cooling to 25 °C reduced the increase in circulating BAs after infusion of 120 mM (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.

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          Most cited references 61

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          A constrained regularization method for inverting data represented by linear algebraic or integral equations

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            Bile acid receptors as targets for drug development.

            The intracellular nuclear receptor farnesoid X receptor and the transmembrane G protein-coupled receptor TGR5 respond to bile acids by activating transcriptional networks and/or signalling cascades. These cascades affect the expression of a great number of target genes relevant for bile acid, cholesterol, lipid and carbohydrate metabolism, as well as genes involved in inflammation, fibrosis and carcinogenesis. Pregnane X receptor, vitamin D receptor and constitutive androstane receptor are additional nuclear receptors that respond to bile acids, albeit to a more restricted set of species of bile acids. Recognition of dedicated bile acid receptors prompted the development of semi-synthetic bile acid analogues and nonsteroidal compounds that target these receptors. These agents hold promise to become a new class of drugs for the treatment of chronic liver disease, hepatocellular cancer and extrahepatic inflammatory and metabolic diseases. This Review discusses the relevant bile acid receptors, the new drugs that target bile acid signalling and their possible applications.
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              Models of acute and chronic pancreatitis.

              Animal models of acute and chronic pancreatitis have been created to examine mechanisms of pathogenesis, test therapeutic interventions, and study the influence of inflammation on the development of pancreatic cancer. In vitro models can be used to study early stage, short-term processes that involve acinar cell responses. Rodent models reproducibly develop mild or severe disease. One of the most commonly used pancreatitis models is created by administration of supraphysiologic concentrations of caerulein, an ortholog of cholecystokinin. Induction of chronic pancreatitis with factors thought to have a role in human disease, such as combinations of lipopolysaccharide and chronic ethanol feeding, might be relevant to human disease. Models of autoimmune chronic pancreatitis have also been developed. Most models, particularly of chronic pancreatitis, require further characterization to determine which features of human disease they include. Copyright © 2013 AGA Institute. Published by Elsevier Inc. All rights reserved.
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                Author and article information

                Contributors
                singh.vijay@mayo.edu
                Journal
                Sci Rep
                Sci Rep
                Scientific Reports
                Nature Publishing Group UK (London )
                2045-2322
                21 May 2020
                21 May 2020
                2020
                : 10
                Affiliations
                [1 ]ISNI 0000 0000 8875 6339, GRID grid.417468.8, Department of Medicine, , Mayo Clinic, ; Scottsdale, AZ USA
                [2 ]ISNI 0000 0004 1936 9000, GRID grid.21925.3d, Department of Medicine, , University of Pittsburgh, ; Pittsburgh, PA USA
                [3 ]ISNI 0000 0004 1936 9000, GRID grid.21925.3d, Department of Pathology, , University of Pittsburgh, ; Pittsburgh, PA USA
                [4 ]ISNI 0000 0001 2151 2636, GRID grid.215654.1, Department of Chemical Engineering, School for Engineering of Matter, Transport and Energy, , Arizona State University, ; Tempe, AZ USA
                [5 ]ISNI 0000 0000 8875 6339, GRID grid.417468.8, Department of Cardiovascular Medicine, Mayo Clinic Arizona, ; Scottsdale, USA
                [6 ]ISNI 0000 0001 2151 2636, GRID grid.215654.1, School of Molecular Sciences, , Arizona State University, ; Tempe, AZ USA
                [7 ]ISNI 0000 0000 8875 6339, GRID grid.417468.8, Department of Biochemistry and Molecular Biology, , Mayo Clinic Arizona, ; Scottsdale, USA
                Article
                65451
                10.1038/s41598-020-65451-w
                7242474
                32439972
                © The Author(s) 2020

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

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                blood flow, biophysical chemistry

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