Ileal bile acid transporter inhibition in Cyp2c70 KO mice ameliorates cholestatic liver injury.

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., Bennett AL; Department of Pediatrics, Division of Pediatric Gastroenterology, Hepatology and Nutrition, Emory University School of Medicine, Children's Healthcare of Atlanta, Atlanta, Georgia, USA., Klindt C; Department of Pediatrics, Division of Pediatric Gastroenterology, Hepatology and Nutrition, Emory University School of Medicine, Children's Healthcare of Atlanta, Atlanta, Georgia, USA., Donepudi AC; Department of Pediatrics, Division of Pediatric Gastroenterology, Hepatology and Nutrition, Emory University School of Medicine, Children's Healthcare of Atlanta, Atlanta, Georgia, USA., Malla SR; Department of Pediatrics, Division of Pediatric Gastroenterology, Hepatology and Nutrition, Emory University School of Medicine, Children's Healthcare of Atlanta, Atlanta, Georgia, USA., Pachura KJ; Department of Pediatrics, Division of Pediatric Gastroenterology, Hepatology and Nutrition, Emory University School of Medicine, Children's Healthcare of Atlanta, Atlanta, Georgia, USA., Zaufel A; Division of Gastroenterology and Hepatology, Department of Internal Medicine, Medical University of Graz, Graz, Austria., Moustafa T; Division of Gastroenterology and Hepatology, Department of Internal Medicine, Medical University of Graz, Graz, 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. Electronic address: paul.dawson@emory.edu., 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. Electronic address: saul.karpen@emory.edu.
Jazyk:	angličtina
Zdroj:	Journal of lipid research [J Lipid Res] 2022 Sep; Vol. 63 (9), pp. 100261. Date of Electronic Publication: 2022 Aug 05.
DOI:	10.1016/j.jlr.2022.100261
Abstrakt:	Cyp2c70 is the liver enzyme in rodents responsible for synthesis of the primary 6-hydroxylated muricholate bile acid (BA) species. Cyp2c70 KO mice are devoid of protective, hydrophilic muricholic acids, leading to a more human-like BA composition and subsequent cholestatic liver injury. Pharmacological inhibition of the ileal BA transporter (IBAT) has been shown to be therapeutic in cholestatic models. Here, we aimed to determine if IBAT inhibition with SC-435 is protective in Cyp2c70 KO mice. As compared to WT mice, we found male and female Cyp2c70 KO mice exhibited increased levels of serum liver injury markers, and our evaluation of liver histology revealed increased hepatic inflammation, macrophage infiltration, and biliary cell proliferation. We demonstrate serum and histologic markers of liver damage were markedly reduced with SC-435 treatment. Additionally, we show hepatic gene expression in pathways related to immune cell activation and inflammation were significantly upregulated in Cyp2c70 KO mice and reduced to levels indistinguishable from WT with IBAT inhibition. In Cyp2c70 KO mice, the liver BA content was significantly increased, enriched in chenodeoxycholic acid, and more hydrophobic, exhibiting a hydrophobicity index value and red blood cell lysis properties similar to human liver BAs. Furthermore, we determined IBAT inhibition reduced the total hepatic BA levels but did not affect overall hydrophobicity of the liver BAs. These findings suggest that there may be a threshold in the liver for pathological accretion of hydrophobic BAs and reducing hepatic BA accumulation can be sufficient to alleviate liver injury, independent of BA pool hydrophobicity. Competing Interests: Conflict of interest One or more of the authors has an actual or perceived conflict of interest with the contents of this article. Paul A. Dawson received Research Funding from Albireo Pharma. Saul J. Karpen received Consulting fees from Albireo Pharma, Intercept Pharmaceutical, and Mirum Pharma. (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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