Active enterohepatic cycling is not required for the choleretic actions of 24-norUrsodeoxycholic acid in mice.

Autor:	Truong JK; Department of Pediatrics, Division of Pediatric Gastroenterology, Hepatology and Nutrition, Emory University School of Medicine, Children's Healthcare of Atlanta, Atlanta, Georgia, USA., Li J; Department of Pediatrics, Division of Pediatric Gastroenterology, Hepatology and Nutrition, Emory University School of Medicine, Children's Healthcare of Atlanta, Atlanta, Georgia, USA., Li Q; Department of Pediatrics, University of Pittsburgh Medical Center Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania, USA., Pachura K; Department of Pediatrics, Division of Pediatric Gastroenterology, Hepatology and Nutrition, Emory University School of Medicine, Children's Healthcare of Atlanta, Atlanta, Georgia, USA., Rao A; Department of Pediatrics, Division of Pediatric Gastroenterology, Hepatology and Nutrition, Emory University School of Medicine, Children's Healthcare of Atlanta, Atlanta, Georgia, USA., Gumber S; Division of Pathology and Laboratory Medicine, Yerkes National Research Center, Emory University School of Medicine, Atlanta, Georgia, USA., Fuchs CD; Hans Popper Laboratory of Molecular Hepatology, Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria., Feranchak AP; Department of Pediatrics, University of Pittsburgh Medical Center Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania, USA., Karpen SJ; Department of Pediatrics, Division of Pediatric Gastroenterology, Hepatology and Nutrition, Emory University School of Medicine, Children's Healthcare of Atlanta, Atlanta, Georgia, USA., Trauner M; Hans Popper Laboratory of Molecular Hepatology, Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria., Dawson PA; Department of Pediatrics, Division of Pediatric Gastroenterology, Hepatology and Nutrition, Emory University School of Medicine, Children's Healthcare of Atlanta, Atlanta, Georgia, USA.
Jazyk:	angličtina
Zdroj:	JCI insight [JCI Insight] 2023 Mar 22; Vol. 8 (6). Date of Electronic Publication: 2023 Mar 22.
DOI:	10.1172/jci.insight.149360
Abstrakt:	The pronounced choleretic properties of 24-norUrsodeoxycholic acid (norUDCA) to induce bicarbonate-rich bile secretion have been attributed to its ability to undergo cholehepatic shunting. The goal of this study was to identify the mechanisms underlying the choleretic actions of norUDCA and the role of the bile acid transporters. Here, we show that the apical sodium-dependent bile acid transporter (ASBT), organic solute transporter-α (OSTα), and organic anion transporting polypeptide 1a/1b (OATP1a/1b) transporters are dispensable for the norUDCA stimulation of bile flow and biliary bicarbonate secretion. Chloride channels in biliary epithelial cells provide the driving force for biliary secretion. In mouse large cholangiocytes, norUDCA potently stimulated chloride currents that were blocked by siRNA silencing and pharmacological inhibition of calcium-activated chloride channel transmembrane member 16A (TMEM16A) but unaffected by ASBT inhibition. In agreement, blocking intestinal bile acid reabsorption by coadministration of an ASBT inhibitor or bile acid sequestrant did not impact norUDCA stimulation of bile flow in WT mice. The results indicate that these major bile acid transporters are not directly involved in the absorption, cholehepatic shunting, or choleretic actions of norUDCA. Additionally, the findings support further investigation of the therapeutic synergy between norUDCA and ASBT inhibitors or bile acid sequestrants for cholestatic liver disease.
Databáze:	MEDLINE
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