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• W4226200318 abstract "Bile flow is generated by the osmotic activity exerted by the secretion of bile acids and other solutes from hepatocytes into bile canaliculi. The bile duct system, lined by cholangiocytes, can subsequently alter the bile composition, but it has remained unclear whether bile acid transporters in cholangiocytes quantitatively contribute to the generation of bile flow in vivo. Classically, bile flow has been subclassified into a bile acid-dependent component, indicating the linear positive correlation between bile acid secretion and bile flow generation, and a bile acid-independent component, the Y-intercept of the bile acid secretion to bile flow correlation. The magnitude of bile acid-dependent bile flow (the slope of the linear correlation between bile flow and bile acid secretion rate, also termed “apparent choleretic activity”) depends on the physicochemical properties of different bile acid species, which determine their osmotic pressure. Unconjugated ursodeoxycholic acid (UDCA) and its C23 side chain-shortened analogue nor-UDCA can induce hypercholeresis, that is, much more bile flow than expected based on bile acid secretion rate. This characteristic is suggested to be beneficial in the treatment of cholestatic disorders. The proposed mechanism for hypercholeresis is the cholehepatic shunt, involving (passive) reuptake of these unconjugated bile acids by cholangiocytes, subsequent return to hepatocytes, and resecretion into canaliculi (Figure 1A).1Boyer J.L. Compr Physiol. 2013; 3: 1035-1078Crossref PubMed Scopus (425) Google Scholar,2Yoon Y.B. et al.Gastroenterology. 1986; 90: 837-852Abstract Full Text PDF PubMed Scopus (190) Google Scholar Conjugation of bile acids prevents their passive reabsorption across epithelia. Unconjugated bile acids, which have the potential to undergo cholehepatic shunting, are rarely found in bile, due to highly efficient hepatic conjugation of newly synthesized and of intestinally (re)absorbed bile acids. Because the apical sodium-dependent bile acid transporter (ASBT), the major bile acid transporter in the intestine, is expressed at the apical membrane of mouse and rat cholangiocytes, it has been hypothesized that ASBT in cholangiocytes is involved in the uptake of conjugated bile acids, thereby mediating their cholehepatic shunting, even under physiological conditions.3Alpini G. et al.Gastroenterology. 1997; 133: 1734-1740Abstract Full Text Full Text PDF Scopus (140) Google Scholar,4Lazaridis K.N. et al.J Clin Invest. 1997; 100: 2714-2721Crossref PubMed Scopus (223) Google Scholar This hypothesis is supported by experiments in bile duct-ligated rats, where secretin induced ASBT translocation to the cholangiocyte plasma membrane (which would increase the bile acid uptake capacity of cholangiocytes), increased bile flow, and prolonged biliary transit time of the administered conjugated bile acid.5Alpini G. et al.Hepatology. 2005; 41: 1037-1045Crossref PubMed Scopus (53) Google Scholar Pharmacological inhibition of ileal ASBT to interrupt the enterohepatic circulation of bile acids is being considered for the treatment of a number of liver and metabolic diseases, including cholestasis.6Li M. et al.Pharmacol Ther. 2020; 24: 107539Crossref Scopus (22) Google Scholar It has remained unclear, however, whether ASBT in cholangiocytes contributes to bile flow generation. Here, we investigated the contribution of cholangiocyte ASBT in the generation of bile flow in vivo (Figure 1A) by determining whether absence of ASBT decreases the choleretic capacity of tauro-UDCA (TUDCA), a conjugated bile acid with affinity for ASBT.7Lionarons D.A. et al.J Lipid Res. 2012; 53: 1535-1542Abstract Full Text Full Text PDF PubMed Scopus (22) Google Scholar To this end, we administered intravenous TUDCA to Asbt−/− and Asbt+/+ mice and quantified bile flow and bile acid secretion rate, both with and without secretin treatment (Supplementary Methods, mice characteristics in Table A1). Before TUDCA administration, bile flow and bile acid secretion rate were lower in Asbt−/− mice than those in Asbt+/+ mice, in line with previous studies8Van de Peppel I.P. et al.J Lipid Res. 2019; 60: 1562-1572Abstract Full Text Full Text PDF PubMed Scopus (12) Google Scholar (Figure A1A and B, 5.5 vs 7.6 μl/min/100-g BW, respectively, P = .003; and, 0.043 vs 0.195 μmol/min/100-g BW, respectively, P = .003). This observation can be explained by a smaller bile acid pool secondary to the reduced ileal bile acid reabsorption in Asbt−/− mice.8Van de Peppel I.P. et al.J Lipid Res. 2019; 60: 1562-1572Abstract Full Text Full Text PDF PubMed Scopus (12) Google Scholar To obtain similar bile acid secretion rates in the 2 genotypes, we infused TUDCA at stepwise increasing dosages. At a TUDCA infusion rate of 0.3 μmol/min, bile flow was similar in Asbt−/− and Asbt+/+ mice (Figure A1A and B). In both groups, bile flow and bile acid secretion rate increased with escalating TUDCA doses (Figure A1A and B), and bile flow correlated linearly and positively with bile acid secretion rate (Figure 1). The apparent choleretic activity of TUDCA (the slope of the regression line in Figure 1) was higher in Asbt−/− mice than in Asbt+/+ mice (Figure A1C, 7.2 vs 5.2 μl/μmol, P = .003), demonstrating that ASBT absence did not decrease the choleretic activity of TUDCA. Previous research showed that secretin induces ASBT translocation to the plasma membrane, which has been proposed to increase the bile acid reuptake capacity of cholangiocytes.5Alpini G. et al.Hepatology. 2005; 41: 1037-1045Crossref PubMed Scopus (53) Google Scholar To test whether the action of secretin on ASBT uptake capacity is required to induce hypercholeresis via cholehepatic shunting of TUDCA, we conducted an additional experiment with constant rate TUDCA infusion, followed by secretin treatment after reaching a stable biliary bile acid secretion rate (Supplementary Methods, mice characteristics in Table A2, Figure A2A). While secretin administration did not affect bile acid-dependent bile flow (Figure 2A, Figure A2A), it increased non–bile acid-dependent (probably ductal) bile flow (Figure 2B, Figure A2B), in accordance with previous literature.9Banales J.M. et al.World J Gastroenterol. 2006; 12: 3496-3511Crossref PubMed Scopus (98) Google Scholar This, however, was not different between Asbt−/− and Asbt+/+ mice (Figure 2B, Figure A2B, +3.3 vs +3.0 μl/min/100-g BW, P = .4), indicating that the increase in bile flow caused by secretin is independent of ASBT presence or activation. Although our study does not prove nor disprove the occurrence of cholehepatic shunting of conjugated bile acids, our results do not support a role for ASBT in mediating cholehepatic shunting of conjugated bile acids under physiological conditions, as absence of ASBT did not decrease the choleretic capacity of TUDCA, neither with nor without secretin. Instead, absence of ASBT slightly increased the choleretic capacity of TUDCA. We speculate that compensatory mechanisms, such as differences in the expression and function of proteins involved in the creation of bile flow arising as adaptations to the absence of ASBT, could potentially explain this observation. We cannot exclude that ASBT expressed by cholangiocytes lining the gallbladder in the WT mice does not mediate cholehepatic shunting, as the gallbladder was cannulated and thus unavailable for potential bile acid uptake in this study. Our conclusion that cholangiocyte ASBT does not mediate cholehepatic shunting thus applies to intrahepatic and extrahepatic, but not gallbladder, cholangiocytes. ASBT in cholangiocytes may have other functions that are not tested in our experiment, such as mediating bile acid-modulated nuclear receptor signaling.10Jones H. et al.Acta Pharm Sin B. 2015; 5: 123-128Crossref PubMed Scopus (56) Google Scholar Our in vivo results do not support the conclusions from bile duct-ligated rat experiments,5Alpini G. et al.Hepatology. 2005; 41: 1037-1045Crossref PubMed Scopus (53) Google Scholar which presented indications for cholehepatic shunting of conjugated bile acids. Because we performed our study only under physiological conditions, it is still possible that cholehepatic shunting of conjugated bile acids via ASBT occurs under pathological conditions, such as cholestasis.5Alpini G. et al.Hepatology. 2005; 41: 1037-1045Crossref PubMed Scopus (53) Google Scholar Further studies are required to investigate whether this is the case. Download .docx (.46 MB) Help with docx files Supplementary Methods, Figures A1, A2, Tables A1 and A2" @default.
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• W4226200318 title "The Apical Sodium-Dependent Bile Acid Transporter in Cholangiocytes Is Not Required for the Generation of Bile Flow in Mice" @default.
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