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Control of biliary phospholipid secretion. Effect of continuous and discontinuous infusion of taurocholate on biliary phospholipid secretion.

ABSTRACT: A major determinant of biliary lipid secretion is bile-salt secretion. Taurocholate (TC), a micelle-forming bile salt, was infused continuously at different rates in both isolated perfused livers and biliary-fistula rats. In both of these systems, infusion of TC brought about an elevated secretion of phosphatidylcholine for the duration of the TC infusion period. Initial phospholipid/bile-salt ratios in the bile were higher in the whole-animal model than in isolated livers, but at the higher infusion rates both secreted approx. 6 mol of phospholipid for every 100 mol of bile salt. The secretion of phospholipid, which was maintained even at high rates of bile-salt infusion, suggest a continuous and regulated phospholipid supply and secretion mechanism. In contrast, however, multiple short pulses of TC to the perfused liver, which brought about relatively equal biliary bile-salt output pulses, did not bring about equal phospholipid outputs, since the phospholipid peak size declined with each bile-salt pulse. These experiments taken together suggest either that a threshold (intracellular) bile-salt concentration may be required to 'switch-on' the phospholipid supply and that it may need to be maintained for continuous biliary phospholipid supply to the canalicular membrane.

SUBMITTER: Rahman K

PROVIDER: S-EPMC1146581 | biostudies-other | 1986 Mar

REPOSITORIES: biostudies-other

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Project description:Active secretion of bile salts into the canalicular lumen drives bile formation and promotes biliary cholesterol and phospholipid output. Disrupting hepatic bile salt uptake, by inhibition of sodium-taurocholate cotransporting polypetide (NTCP; Slc10a1) with Myrcludex B, is expected to limit bile salt flux through the liver and thereby to decrease biliary lipid excretion. Here, we show that Myrcludex B-mediated NTCP inhibition actually causes an increase in biliary cholesterol and phospholipid excretion whereas biliary bile salt output and bile salt composition remains unchanged. Increased lysosomal discharge into bile was excluded as a potential contributor to increased biliary lipid secretion. Induction of cholesterol secretion was not a consequence of increased ATP-binding cassette subfamily G member 5/8 activity given that NTCP inhibition still promoted cholesterol excretion in Abcg8-/- mice. Stimulatory effects of NTCP inhibition were maintained in Sr-b1-/- mice, eliminating the possibility that the increase in biliary lipids was derived from enhanced uptake of high-density lipoprotein-derived lipids. NTCP inhibition shifts bile salt uptake, which is generally more periportally restricted, toward pericentral hepatocytes, as was visualized using a fluorescently labeled conjugated bile salt. As a consequence, exposure of the canalicular membrane to bile salts was increased, allowing for more cholesterol and phospholipid molecules to be excreted per bile salt. Conclusion: NTCP inhibition increases biliary lipid secretion, which is independent of alterations in bile salt output, biliary bile salt hydrophobicity, or increased activity of dedicated cholesterol and phospholipid transporters. Instead, NTCP inhibition shifts hepatic bile salt uptake from mainly periportal hepatocytes toward pericentral hepatocytes, thereby increasing exposure of the canalicular membrane to bile salts linking to increased biliary cholesterol secretion. This process provides an additional level of control to biliary cholesterol and phospholipid secretion.

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Control of biliary phospholipid secretion. Effect of continuous and discontinuous infusion of taurocholate on biliary phospholipid secretion.

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