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.
Highlights
Bile acids (BA), with their large hydrophobic steroid nucleus and polar groups are amphipathic molecules
This is relevant to the way in which BAs may enter the circulation or signal, which is possible in 2 ways. (1) via receptors (e.g. FXR or gpBAR132) which are activated in the micromolar range, below the CMCs and likely by monomeric BAs, and 2) via membrane damage[33] occurring above their critical micellar concentrations such as during hemolysis[33], a bile leak, or reflux of bile into the pancreas[21,22]
Since BA levels in circulation are in the sub-micellar range[6,7], we hypothesized that breakdown of bile salt or mixed micelles following Sodium taurocholate (STC) pancreatitis would be essential for their entry into the circulation and mediating systemic effects
Summary
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). The conditions used were relevant to those of the infused STC and circulating bile acids (pH 7.4 and 0.15 mM Na), which helped identify the temperatures that interfere with micellar breakdown and could potentially be applied as local hypothermia during these diseases. We chose to test the effect of cooling in a severe pancreatitis model, by infusing STC into the pancreatic duct[21,22] followed by ligating the biliopancreatic duct[23] to allow passive reflux of bile and the phospholipids it contains into the pancreatic duct. This study describes the therapeutic relevance of preventing bile salt demicellization on disease severity
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