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Heme Exporter FLVCR1a Regulates Heme Synthesis and Degradation and Controls Activity of Cytochromes P450

BACKGROUND & AIMS: The liver has one of the highest rates of heme synthesis of any organ. More than 50% of the heme synthesized in the liver is used for synthesis of P450 enzymes, which metabolize exogenous and endogenous compounds that include natural products, hormones, drugs, and carcinogens....

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Autores principales: Vinchi, Francesca, Ingoglia, Giada, Chiabrando, Deborah, Mercurio, Sonia, Turco, Emilia, Silengo, Lorenzo, Altruda, Fiorella, Tolosano, Emanuela
Formato: Online Artículo Texto
Lenguaje:English
Publicado: W.B. Saunders 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4000440/
https://www.ncbi.nlm.nih.gov/pubmed/24486949
http://dx.doi.org/10.1053/j.gastro.2014.01.053
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author Vinchi, Francesca
Ingoglia, Giada
Chiabrando, Deborah
Mercurio, Sonia
Turco, Emilia
Silengo, Lorenzo
Altruda, Fiorella
Tolosano, Emanuela
author_facet Vinchi, Francesca
Ingoglia, Giada
Chiabrando, Deborah
Mercurio, Sonia
Turco, Emilia
Silengo, Lorenzo
Altruda, Fiorella
Tolosano, Emanuela
author_sort Vinchi, Francesca
collection PubMed
description BACKGROUND & AIMS: The liver has one of the highest rates of heme synthesis of any organ. More than 50% of the heme synthesized in the liver is used for synthesis of P450 enzymes, which metabolize exogenous and endogenous compounds that include natural products, hormones, drugs, and carcinogens. Feline leukemia virus subgroup C cellular receptor 1a (FLVCR1a) is plasma membrane heme exporter that is ubiquitously expressed and controls intracellular heme content in hematopoietic lineages. We investigated the role of Flvcr1a in liver function in mice. METHODS: We created mice with conditional disruption of Mfsd7b, which encodes Flvcr1a, in hepatocytes (Flvcr1a(fl/fl);alb-cre mice). Mice were analyzed under basal conditions, after phenylhydrazine-induced hemolysis, and after induction of cytochromes P450 synthesis. Livers were collected and analyzed by histologic, quantitative real-time polymerase chain reaction, and immunoblot analyses. Hepatic P450 enzymatic activities were measured. RESULTS: Flvcr1a(fl/fl);alb-cre mice accumulated heme and iron in liver despite up-regulation of heme oxygenase 1, ferroportin, and ferritins. Hepatic heme export activity of Flvcr1a was closely associated with heme biosynthesis, which is required to sustain cytochrome induction. Upon cytochromes P450 stimulation, Flvcr1a(fl/fl);alb-cre mice had reduced cytochrome activity, associated with accumulation of heme in hepatocytes. The expansion of the cytosolic heme pool in these mice was likely responsible for the early inhibition of heme synthesis and increased degradation of heme, which reduced expression and activity of cytochromes P450. CONCLUSIONS: In livers of mice, Flvcr1a maintains a free heme pool that regulates heme synthesis and degradation as well as cytochromes P450 expression and activity. These findings have important implications for drug metabolism.
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spelling pubmed-40004402014-05-01 Heme Exporter FLVCR1a Regulates Heme Synthesis and Degradation and Controls Activity of Cytochromes P450 Vinchi, Francesca Ingoglia, Giada Chiabrando, Deborah Mercurio, Sonia Turco, Emilia Silengo, Lorenzo Altruda, Fiorella Tolosano, Emanuela Gastroenterology Original Research BACKGROUND & AIMS: The liver has one of the highest rates of heme synthesis of any organ. More than 50% of the heme synthesized in the liver is used for synthesis of P450 enzymes, which metabolize exogenous and endogenous compounds that include natural products, hormones, drugs, and carcinogens. Feline leukemia virus subgroup C cellular receptor 1a (FLVCR1a) is plasma membrane heme exporter that is ubiquitously expressed and controls intracellular heme content in hematopoietic lineages. We investigated the role of Flvcr1a in liver function in mice. METHODS: We created mice with conditional disruption of Mfsd7b, which encodes Flvcr1a, in hepatocytes (Flvcr1a(fl/fl);alb-cre mice). Mice were analyzed under basal conditions, after phenylhydrazine-induced hemolysis, and after induction of cytochromes P450 synthesis. Livers were collected and analyzed by histologic, quantitative real-time polymerase chain reaction, and immunoblot analyses. Hepatic P450 enzymatic activities were measured. RESULTS: Flvcr1a(fl/fl);alb-cre mice accumulated heme and iron in liver despite up-regulation of heme oxygenase 1, ferroportin, and ferritins. Hepatic heme export activity of Flvcr1a was closely associated with heme biosynthesis, which is required to sustain cytochrome induction. Upon cytochromes P450 stimulation, Flvcr1a(fl/fl);alb-cre mice had reduced cytochrome activity, associated with accumulation of heme in hepatocytes. The expansion of the cytosolic heme pool in these mice was likely responsible for the early inhibition of heme synthesis and increased degradation of heme, which reduced expression and activity of cytochromes P450. CONCLUSIONS: In livers of mice, Flvcr1a maintains a free heme pool that regulates heme synthesis and degradation as well as cytochromes P450 expression and activity. These findings have important implications for drug metabolism. W.B. Saunders 2014-05 /pmc/articles/PMC4000440/ /pubmed/24486949 http://dx.doi.org/10.1053/j.gastro.2014.01.053 Text en © 2014 AGA Institute. Published by Elsevier Inc. All rights reserved. https://creativecommons.org/licenses/by-nc-nd/4.0/This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (https://creativecommons.org/licenses/by-nc-nd/4.0/) , which allows reusers to copy and distribute the material in any medium or format in unadapted form only, for noncommercial purposes only, and only so long as attribution is given to the creator.
spellingShingle Original Research
Vinchi, Francesca
Ingoglia, Giada
Chiabrando, Deborah
Mercurio, Sonia
Turco, Emilia
Silengo, Lorenzo
Altruda, Fiorella
Tolosano, Emanuela
Heme Exporter FLVCR1a Regulates Heme Synthesis and Degradation and Controls Activity of Cytochromes P450
title Heme Exporter FLVCR1a Regulates Heme Synthesis and Degradation and Controls Activity of Cytochromes P450
title_full Heme Exporter FLVCR1a Regulates Heme Synthesis and Degradation and Controls Activity of Cytochromes P450
title_fullStr Heme Exporter FLVCR1a Regulates Heme Synthesis and Degradation and Controls Activity of Cytochromes P450
title_full_unstemmed Heme Exporter FLVCR1a Regulates Heme Synthesis and Degradation and Controls Activity of Cytochromes P450
title_short Heme Exporter FLVCR1a Regulates Heme Synthesis and Degradation and Controls Activity of Cytochromes P450
title_sort heme exporter flvcr1a regulates heme synthesis and degradation and controls activity of cytochromes p450
topic Original Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4000440/
https://www.ncbi.nlm.nih.gov/pubmed/24486949
http://dx.doi.org/10.1053/j.gastro.2014.01.053
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