Bile Acid Sequestration via Colesevelam Reduces Bile Acid Hydrophobicity and Improves Liver Pathology in <i>Cyp2c70</i><sup>−/−</sup> Mice with a Human-like Bile Acid Composition
Bile acids (BAs) and their signaling pathways have been identified as therapeutic targets for liver and metabolic diseases. We generated <i>Cyp2c70</i><sup>−/−</sup> (KO) mice that were not able to convert chenodeoxycholic acid into rodent-specific muricholic acids (MCAs) and...
| Main Authors: | , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2023-09-01
|
| Series: | Biomedicines |
| Subjects: | |
| Online Access: | https://www.mdpi.com/2227-9059/11/9/2495 |
| _version_ | 1797581168232628224 |
|---|---|
| author | Anna Palmiotti Hilde D. de Vries Milaine V. Hovingh Martijn Koehorst Niels L. Mulder Esther Verkade Melany K. Veentjer Theo H. van Dijk Vincent W. Bloks Rick Havinga Henkjan J. Verkade Jan Freark de Boer Folkert Kuipers |
| author_facet | Anna Palmiotti Hilde D. de Vries Milaine V. Hovingh Martijn Koehorst Niels L. Mulder Esther Verkade Melany K. Veentjer Theo H. van Dijk Vincent W. Bloks Rick Havinga Henkjan J. Verkade Jan Freark de Boer Folkert Kuipers |
| author_sort | Anna Palmiotti |
| collection | DOAJ |
| description | Bile acids (BAs) and their signaling pathways have been identified as therapeutic targets for liver and metabolic diseases. We generated <i>Cyp2c70</i><sup>−/−</sup> (KO) mice that were not able to convert chenodeoxycholic acid into rodent-specific muricholic acids (MCAs) and, hence, possessed a more hydrophobic, human-like BA pool. Recently, we have shown that KO mice display cholangiopathic features with the 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% <i>w</i>/<i>w</i>) of male <i>Cyp2c70</i><sup>+/+</sup> (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 <i>Cyp2c70</i><sup>−/−</sup> mice with a human-like bile acid composition without affecting insulin sensitivity. |
| first_indexed | 2024-03-10T23:00:23Z |
| format | Article |
| id | doaj.art-6f2bbd3a48534fe2b250f2e7649963fb |
| institution | Directory Open Access Journal |
| issn | 2227-9059 |
| language | English |
| last_indexed | 2024-03-10T23:00:23Z |
| publishDate | 2023-09-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Biomedicines |
| spelling | doaj.art-6f2bbd3a48534fe2b250f2e7649963fb2023-11-19T09:42:08ZengMDPI AGBiomedicines2227-90592023-09-01119249510.3390/biomedicines11092495Bile Acid Sequestration via Colesevelam Reduces Bile Acid Hydrophobicity and Improves Liver Pathology in <i>Cyp2c70</i><sup>−/−</sup> Mice with a Human-like Bile Acid CompositionAnna Palmiotti0Hilde D. de Vries1Milaine V. Hovingh2Martijn Koehorst3Niels L. Mulder4Esther Verkade5Melany K. Veentjer6Theo H. van Dijk7Vincent W. Bloks8Rick Havinga9Henkjan J. Verkade10Jan Freark de Boer11Folkert Kuipers12Department of Pediatrics, University of Groningen, University Medical Center Groningen, 9713 GZ Groningen, The NetherlandsDepartment of Laboratory Medicine, University of Groningen, University Medical Center Groningen, 9713 GZ Groningen, The NetherlandsDepartment of Pediatrics, University of Groningen, University Medical Center Groningen, 9713 GZ Groningen, The NetherlandsDepartment of Laboratory Medicine, University of Groningen, University Medical Center Groningen, 9713 GZ Groningen, The NetherlandsDepartment of Pediatrics, University of Groningen, University Medical Center Groningen, 9713 GZ Groningen, The NetherlandsDepartment of Pediatrics, University of Groningen, University Medical Center Groningen, 9713 GZ Groningen, The NetherlandsDepartment of Pediatrics, University of Groningen, University Medical Center Groningen, 9713 GZ Groningen, The NetherlandsDepartment of Laboratory Medicine, University of Groningen, University Medical Center Groningen, 9713 GZ Groningen, The NetherlandsDepartment of Pediatrics, University of Groningen, University Medical Center Groningen, 9713 GZ Groningen, The NetherlandsDepartment of Pediatrics, University of Groningen, University Medical Center Groningen, 9713 GZ Groningen, The NetherlandsDepartment of Pediatrics, University of Groningen, University Medical Center Groningen, 9713 GZ Groningen, The NetherlandsDepartment of Pediatrics, University of Groningen, University Medical Center Groningen, 9713 GZ Groningen, The NetherlandsDepartment of Pediatrics, University of Groningen, University Medical Center Groningen, 9713 GZ Groningen, The NetherlandsBile acids (BAs) and their signaling pathways have been identified as therapeutic targets for liver and metabolic diseases. We generated <i>Cyp2c70</i><sup>−/−</sup> (KO) mice that were not able to convert chenodeoxycholic acid into rodent-specific muricholic acids (MCAs) and, hence, possessed a more hydrophobic, human-like BA pool. Recently, we have shown that KO mice display cholangiopathic features with the 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% <i>w</i>/<i>w</i>) of male <i>Cyp2c70</i><sup>+/+</sup> (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 <i>Cyp2c70</i><sup>−/−</sup> mice with a human-like bile acid composition without affecting insulin sensitivity.https://www.mdpi.com/2227-9059/11/9/2495bile acidscolesevelamenterohepatic circulationliverhumanized mouse model |
| spellingShingle | Anna Palmiotti Hilde D. de Vries Milaine V. Hovingh Martijn Koehorst Niels L. Mulder Esther Verkade Melany K. Veentjer Theo H. van Dijk Vincent W. Bloks Rick Havinga Henkjan J. Verkade Jan Freark de Boer Folkert Kuipers Bile Acid Sequestration via Colesevelam Reduces Bile Acid Hydrophobicity and Improves Liver Pathology in <i>Cyp2c70</i><sup>−/−</sup> Mice with a Human-like Bile Acid Composition Biomedicines bile acids colesevelam enterohepatic circulation liver humanized mouse model |
| title | Bile Acid Sequestration via Colesevelam Reduces Bile Acid Hydrophobicity and Improves Liver Pathology in <i>Cyp2c70</i><sup>−/−</sup> Mice with a Human-like Bile Acid Composition |
| title_full | Bile Acid Sequestration via Colesevelam Reduces Bile Acid Hydrophobicity and Improves Liver Pathology in <i>Cyp2c70</i><sup>−/−</sup> Mice with a Human-like Bile Acid Composition |
| title_fullStr | Bile Acid Sequestration via Colesevelam Reduces Bile Acid Hydrophobicity and Improves Liver Pathology in <i>Cyp2c70</i><sup>−/−</sup> Mice with a Human-like Bile Acid Composition |
| title_full_unstemmed | Bile Acid Sequestration via Colesevelam Reduces Bile Acid Hydrophobicity and Improves Liver Pathology in <i>Cyp2c70</i><sup>−/−</sup> Mice with a Human-like Bile Acid Composition |
| title_short | Bile Acid Sequestration via Colesevelam Reduces Bile Acid Hydrophobicity and Improves Liver Pathology in <i>Cyp2c70</i><sup>−/−</sup> Mice with a Human-like Bile Acid Composition |
| title_sort | bile acid sequestration via colesevelam reduces bile acid hydrophobicity and improves liver pathology in i cyp2c70 i sup sup mice with a human like bile acid composition |
| topic | bile acids colesevelam enterohepatic circulation liver humanized mouse model |
| url | https://www.mdpi.com/2227-9059/11/9/2495 |
| work_keys_str_mv | AT annapalmiotti bileacidsequestrationviacolesevelamreducesbileacidhydrophobicityandimprovesliverpathologyinicyp2c70isupsupmicewithahumanlikebileacidcomposition AT hildeddevries bileacidsequestrationviacolesevelamreducesbileacidhydrophobicityandimprovesliverpathologyinicyp2c70isupsupmicewithahumanlikebileacidcomposition AT milainevhovingh bileacidsequestrationviacolesevelamreducesbileacidhydrophobicityandimprovesliverpathologyinicyp2c70isupsupmicewithahumanlikebileacidcomposition AT martijnkoehorst bileacidsequestrationviacolesevelamreducesbileacidhydrophobicityandimprovesliverpathologyinicyp2c70isupsupmicewithahumanlikebileacidcomposition AT nielslmulder bileacidsequestrationviacolesevelamreducesbileacidhydrophobicityandimprovesliverpathologyinicyp2c70isupsupmicewithahumanlikebileacidcomposition AT estherverkade bileacidsequestrationviacolesevelamreducesbileacidhydrophobicityandimprovesliverpathologyinicyp2c70isupsupmicewithahumanlikebileacidcomposition AT melanykveentjer bileacidsequestrationviacolesevelamreducesbileacidhydrophobicityandimprovesliverpathologyinicyp2c70isupsupmicewithahumanlikebileacidcomposition AT theohvandijk bileacidsequestrationviacolesevelamreducesbileacidhydrophobicityandimprovesliverpathologyinicyp2c70isupsupmicewithahumanlikebileacidcomposition AT vincentwbloks bileacidsequestrationviacolesevelamreducesbileacidhydrophobicityandimprovesliverpathologyinicyp2c70isupsupmicewithahumanlikebileacidcomposition AT rickhavinga bileacidsequestrationviacolesevelamreducesbileacidhydrophobicityandimprovesliverpathologyinicyp2c70isupsupmicewithahumanlikebileacidcomposition AT henkjanjverkade bileacidsequestrationviacolesevelamreducesbileacidhydrophobicityandimprovesliverpathologyinicyp2c70isupsupmicewithahumanlikebileacidcomposition AT janfrearkdeboer bileacidsequestrationviacolesevelamreducesbileacidhydrophobicityandimprovesliverpathologyinicyp2c70isupsupmicewithahumanlikebileacidcomposition AT folkertkuipers bileacidsequestrationviacolesevelamreducesbileacidhydrophobicityandimprovesliverpathologyinicyp2c70isupsupmicewithahumanlikebileacidcomposition |