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Thermodynamic interference with bile acid demicelleization reduces systemic entry and injury during cholestasis
- Source :
- Scientific Reports, Vol 10, Iss 1, Pp 1-14 (2020), Scientific Reports
- Publication Year :
- 2020
- Publisher :
- Nature Publishing Group, 2020.
-
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.
- Subjects :
- Male
0301 basic medicine
medicine.drug_class
Phospholipid
lcsh:Medicine
Lung injury
Micelle
Article
Bile Acids and Salts
Mice
03 medical and health sciences
chemistry.chemical_compound
0302 clinical medicine
Cholestasis
Biophysical chemistry
Phosphatidylcholine
medicine
Animals
Humans
lcsh:Science
Micelles
Inflammation
Pancreatic duct
Multidisciplinary
Bile acid
lcsh:R
Temperature
technology, industry, and agriculture
Shock
Isothermal titration calorimetry
Lung Injury
Blood flow
medicine.disease
Myocardial Contusions
030104 developmental biology
medicine.anatomical_structure
chemistry
Biophysics
Thermodynamics
030211 gastroenterology & hepatology
lcsh:Q
Subjects
Details
- Language :
- English
- ISSN :
- 20452322
- Volume :
- 10
- Issue :
- 1
- Database :
- OpenAIRE
- Journal :
- Scientific Reports
- Accession number :
- edsair.doi.dedup.....1fc7016f7a49cfb00b1724d074939331