Preprint Article Version 1 Preserved in Portico This version is not peer-reviewed

Bile Acid Sequestration by Colesevelam Reduces Bile Acid Hydrophobicity and Improves Liver Pathology in Cyp2c70-/- Mice with a Human-Like Bile Acid Composition

Anna Palmiotti
ORCID logo ,
Hilde D. De Vries
,
Milaine V. Hovingh
,
Martijn Koehorst
,
Niels L. Mulder
,
Esther Verkade
,
Melany K. Veentjer
,
Theo H. Van Dijk
,
Vincent W. Bloks
ORCID logo ,
Rick Havinga
,
Henkjan J. Verkade
,
Jan Freark De Boer
* ORCID logo ,
Folkert Kuipers
* ORCID logo
Version 1 : Received: 8 August 2023 / Approved: 9 August 2023 / Online: 10 August 2023 (04:16:37 CEST)

A peer-reviewed article of this Preprint also exists.

Palmiotti, A.; de Vries, H.D.; Hovingh, M.V.; Koehorst, M.; Mulder, N.L.; Verkade, E.; Veentjer, M.K.; van Dijk, T.H.; Bloks, V.W.; Havinga, R.; Verkade, H.J.; de Boer, J.F.; Kuipers, F. Bile Acid Sequestration via Colesevelam Reduces Bile Acid Hydrophobicity and Improves Liver Pathology in Cyp2c70−/− Mice with a Human-like Bile Acid Composition. Biomedicines 2023, 11, 2495. Palmiotti, A.; de Vries, H.D.; Hovingh, M.V.; Koehorst, M.; Mulder, N.L.; Verkade, E.; Veentjer, M.K.; van Dijk, T.H.; Bloks, V.W.; Havinga, R.; Verkade, H.J.; de Boer, J.F.; Kuipers, F. Bile Acid Sequestration via Colesevelam Reduces Bile Acid Hydrophobicity and Improves Liver Pathology in Cyp2c70−/− Mice with a Human-like Bile Acid Composition. Biomedicines 2023, 11, 2495.

Abstract

Bile acids (BAs) and their signalling pathways have been identified as therapeutic targets for liver and metabolic diseases. We generated Cyp2c70-/- (KO) mice that are not able to convert chenodeoxycholic acid into rodent-specific muricholic acids (MCAs) and, hence, possess a more hydrophobic, human-like BA pool. Recently, we have shown that KO mice display cholangiopathic features with development of liver fibrosis. The aim of this study was to determine whether BA sequestration modulates liver pathology in Western type-diet (WTD)-fed KO mice. The BA sequestrant colesevelam was mixed into the WTD (2% w/w) of male Cyp2c70+/+ (WT) and KO mice and the effects were evaluated after 3 weeks of treatment. Colesevelam increased fecal BA excretion in WT and KO mice and reduced the hydrophobicity of biliary BAs in KO mice. Colesevelam ameliorated diet-induced hepatic steatosis in WT mice, whereas KO mice were resistant to diet-induced steatosis and BA sequestration had no additional effects on liver fat content. Total cholesterol concentrations in livers of colesevelam-treated WT and KO mice were significantly lower than those of untreated controls. Of particular note, colesevelam treatment normalized plasma levels of liver damage markers in KO mice and markedly decreased hepatic mRNA levels of fibrogenesis-related genes in KO mice. Lastly, colesevelam did not affect glucose excursions and insulin sensitivity in WT or KO mice. Our data show that BA sequestration ameliorates liver pathology in Cyp2c70-/- mice with a human-like bile acid composition without affecting insulin sensitivity.

Keywords

bile acids; colesevelam; enterohepatic circulation; liver; humanized mouse model

Subject

Biology and Life Sciences, Endocrinology and Metabolism

Copyright: This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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