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

• Type of Material: Article
• Authors: Jennifer K Truong, Emory University; Ashley L Bennett, Emory University; Caroline Klindt, Emory University; Ajay C Donepudi, Emory University; Sudarshan R Malla, Emory University; Kimberly J Pachura, Emory University; Alex Zaufel, Medical University of Graz; Tarek Moustafa, Medical University of Graz; Paul Dawson, Emory University; Saul Karpen, Emory University
• Language: English
• Date: 2022-09-01
• Publisher: ELSEVIER
• Publication Version: Final Published Version
• Copyright Statement: © 2022 The Authors
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1016/j.jlr.2022.100261
• Title of Journal or Parent Work: JOURNAL OF LIPID RESEARCH
• Volume: 63
• Issue: 9
• Start Page: 100261
• End Page: 100261
• Grant/Funding Information: J. K. T. was supported by T32-GM008367 and an NIH diversity supplement (DK047987-28S1).; This research was supported by the National Institute of Diabetes and Digestive and Kidney Diseases grants DK047987 (P. A. D.) and DK056239 (S. J. K.), the Meredith Brown Fund at Emory, and Mason Trust Fund (S. J. K.).; C. K. was supported by the Deutsche Forschungsgemeinschaft (DFG; German Research Foundation) (KL 3389/1-1). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.; T. M. is a recipient of the Andrew K. Burroughs Fellowship from the European Association for the Study of the Liver and supported by the Doctoral College “Metabolic and Cardiovascular Disease” (A. Z.) of the Austrian Science Fund (FWF, DK-MCD W1226).
• Keywords: Biochemistry & Molecular Biology; BIOLOGY; Science & Technology; detergency; BALANCE; CHEMISTRY; ABSORPTION; Life Sciences & Biomedicine; biliary cell proliferation; muricholic acids; SALTS; MOUSE; MECHANISMS; cholesterol 7?-hydroxylase; enterohepatic circulation; METABOLISM; chenodeoxycholic acid; hydrophobicity; MODELS; Supplementary key words Cytochrome P450; MEMBRANES; sterol 12?-hydroxylase
• Research Categories: Health Sciences, Nutrition; Health Sciences, Medicine and Surgery

Abstract

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 indistinguish-