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Altered vitamin A metabolism in human liver slices corresponds to fibrogenesis
ABSTRACT: All‐trans‐retinoic acid (atRA), the active metabolite of vitamin A, has antifibrogenic properties in vitro and in animal models. Liver vitamin A homeostasis is maintained by cell‐specific enzymatic activities including storage in hepatic stellate cells (HSCs), secretion into circulation fr...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8212748/ https://www.ncbi.nlm.nih.gov/pubmed/33382909 http://dx.doi.org/10.1111/cts.12962 |
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author | Czuba, Lindsay C. Wu, Xia Huang, Weize Hollingshead, Nicole Roberto, Jessica B. Kenerson, Heidi L. Yeung, Raymond S. Crispe, Ian N. Isoherranen, Nina |
author_facet | Czuba, Lindsay C. Wu, Xia Huang, Weize Hollingshead, Nicole Roberto, Jessica B. Kenerson, Heidi L. Yeung, Raymond S. Crispe, Ian N. Isoherranen, Nina |
author_sort | Czuba, Lindsay C. |
collection | PubMed |
description | ABSTRACT: All‐trans‐retinoic acid (atRA), the active metabolite of vitamin A, has antifibrogenic properties in vitro and in animal models. Liver vitamin A homeostasis is maintained by cell‐specific enzymatic activities including storage in hepatic stellate cells (HSCs), secretion into circulation from hepatocytes, and formation and clearance of atRA. During chronic liver injury, HSC activation is associated with a decrease in liver retinyl esters and retinol concentrations. atRA is synthesized through two enzymatic steps from retinol, but it is unknown if the loss of retinoid stores is associated with changes in atRA formation and which cell types contribute to the metabolic changes. The aim of this study was to determine if the vitamin A metabolic flux is perturbed in acute liver injury, and if changes in atRA concentrations are associated with HSC activation and collagen expression. At basal levels, HSC and Kupffer cells expressed key genes involved in vitamin A metabolism, whereas after acute liver injury, complex changes to the metabolic flux were observed in liver slices. These changes include a reproducible spike in atRA tissue concentrations, decreased retinyl ester and atRA formation rate, and time‐dependent changes to the expression of metabolizing enzymes. Kinetic simulations suggested that oxidoreductases are important in determining retinoid metabolic flux after liver injury. These early changes precede HSC activation and upregulation of profibrogenic gene expression, which were inversely correlated with atRA tissue concentrations, suggesting that HSC and Kupffer cells are key cells involved in changes to vitamin A metabolic flux and signaling after liver injury. STUDY HIGHLIGHTS: WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC? Vitamin A is metabolized in the liver for storage as retinyl esters in hepatic stellate cell (HSCs) or to all‐trans‐retinoic acid (at WHAT QUESTION DID THIS STUDY ADDRESS? Do changes in the expression of vitamin A metabolizing enzymes explain changes in at WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE? In healthy liver, both HSC and Kupffer cells may mediate vitamin A homeostasis. Following acute liver injury, complex changes in metabolizing enzyme expression/activity alter the metabolic flux of retinoids, resulting in a transient peak in atRA concentrations. The at HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE? Improved understanding of altered vitamin A metabolic flux in acute liver injury may provide insight into cell‐specific contributions to vitamin A loss and lead to novel interventions in liver fibrosis. |
format | Online Article Text |
id | pubmed-8212748 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-82127482021-06-25 Altered vitamin A metabolism in human liver slices corresponds to fibrogenesis Czuba, Lindsay C. Wu, Xia Huang, Weize Hollingshead, Nicole Roberto, Jessica B. Kenerson, Heidi L. Yeung, Raymond S. Crispe, Ian N. Isoherranen, Nina Clin Transl Sci Research ABSTRACT: All‐trans‐retinoic acid (atRA), the active metabolite of vitamin A, has antifibrogenic properties in vitro and in animal models. Liver vitamin A homeostasis is maintained by cell‐specific enzymatic activities including storage in hepatic stellate cells (HSCs), secretion into circulation from hepatocytes, and formation and clearance of atRA. During chronic liver injury, HSC activation is associated with a decrease in liver retinyl esters and retinol concentrations. atRA is synthesized through two enzymatic steps from retinol, but it is unknown if the loss of retinoid stores is associated with changes in atRA formation and which cell types contribute to the metabolic changes. The aim of this study was to determine if the vitamin A metabolic flux is perturbed in acute liver injury, and if changes in atRA concentrations are associated with HSC activation and collagen expression. At basal levels, HSC and Kupffer cells expressed key genes involved in vitamin A metabolism, whereas after acute liver injury, complex changes to the metabolic flux were observed in liver slices. These changes include a reproducible spike in atRA tissue concentrations, decreased retinyl ester and atRA formation rate, and time‐dependent changes to the expression of metabolizing enzymes. Kinetic simulations suggested that oxidoreductases are important in determining retinoid metabolic flux after liver injury. These early changes precede HSC activation and upregulation of profibrogenic gene expression, which were inversely correlated with atRA tissue concentrations, suggesting that HSC and Kupffer cells are key cells involved in changes to vitamin A metabolic flux and signaling after liver injury. STUDY HIGHLIGHTS: WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC? Vitamin A is metabolized in the liver for storage as retinyl esters in hepatic stellate cell (HSCs) or to all‐trans‐retinoic acid (at WHAT QUESTION DID THIS STUDY ADDRESS? Do changes in the expression of vitamin A metabolizing enzymes explain changes in at WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE? In healthy liver, both HSC and Kupffer cells may mediate vitamin A homeostasis. Following acute liver injury, complex changes in metabolizing enzyme expression/activity alter the metabolic flux of retinoids, resulting in a transient peak in atRA concentrations. The at HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE? Improved understanding of altered vitamin A metabolic flux in acute liver injury may provide insight into cell‐specific contributions to vitamin A loss and lead to novel interventions in liver fibrosis. John Wiley and Sons Inc. 2021-02-02 2021-05 /pmc/articles/PMC8212748/ /pubmed/33382909 http://dx.doi.org/10.1111/cts.12962 Text en © 2020 The Authors. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of the American Society for Clinical Pharmacology and Therapeutics. https://creativecommons.org/licenses/by-nc/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc/4.0/ (https://creativecommons.org/licenses/by-nc/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes. |
spellingShingle | Research Czuba, Lindsay C. Wu, Xia Huang, Weize Hollingshead, Nicole Roberto, Jessica B. Kenerson, Heidi L. Yeung, Raymond S. Crispe, Ian N. Isoherranen, Nina Altered vitamin A metabolism in human liver slices corresponds to fibrogenesis |
title | Altered vitamin A metabolism in human liver slices corresponds to fibrogenesis |
title_full | Altered vitamin A metabolism in human liver slices corresponds to fibrogenesis |
title_fullStr | Altered vitamin A metabolism in human liver slices corresponds to fibrogenesis |
title_full_unstemmed | Altered vitamin A metabolism in human liver slices corresponds to fibrogenesis |
title_short | Altered vitamin A metabolism in human liver slices corresponds to fibrogenesis |
title_sort | altered vitamin a metabolism in human liver slices corresponds to fibrogenesis |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8212748/ https://www.ncbi.nlm.nih.gov/pubmed/33382909 http://dx.doi.org/10.1111/cts.12962 |
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