Complex response to physiological and drug-induced hepatic heme demand in monoallelic ALAS1 mice

Regulation of 5-aminolevulinate synthase 1 (ALAS1) for nonerythroid heme is critical for respiration, cell signaling mechanisms and steroid/drug metabolism. ALAS1 is induced in some genetic disorders but unlike other genes in the heme pathway, a gene variant of ALAS1 associated with inherited diseas...

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Autores principales:	Viktoria Vagany, Susan Robinson, Tatyana Chernova, Andrew G. Smith
Formato:	article
Lenguaje:	EN
Publicado:	Elsevier 2021
Materias:	Aminolevulinic acid synthase 1 Semi null mice Hepatic response Compensation, complex regulation Medicine (General) R5-920 Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/03f78fad1f0040c5a05adcf272320377
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spelling	oai:doaj.org-article:03f78fad1f0040c5a05adcf2723203772021-11-14T04:32:59ZComplex response to physiological and drug-induced hepatic heme demand in monoallelic ALAS1 mice2214-426910.1016/j.ymgmr.2021.100818https://doaj.org/article/03f78fad1f0040c5a05adcf2723203772021-12-01T00:00:00Zhttp://www.sciencedirect.com/science/article/pii/S2214426921001130https://doaj.org/toc/2214-4269Regulation of 5-aminolevulinate synthase 1 (ALAS1) for nonerythroid heme is critical for respiration, cell signaling mechanisms and steroid/drug metabolism. ALAS1 is induced in some genetic disorders but unlike other genes in the heme pathway, a gene variant of ALAS1 associated with inherited disease has not been reported. BALB/c mice carrying a null ALAS1 allele caused by a βGEO insert were developed and used to determine the consequences of heme demand of a semi gene copy number. Homozygous disruption of ALAS1 (−/−) was lethal for embryo development post day 6.5 but expression in heterozygotes (+/−) was sufficient for the number of offspring and survival. In both wild type (WT +/+) and +/− mice expression of ALAS1 RNA was greatest in liver and harderian gland and much lower in kidney, lung, heart, brain and spleen. The effects of one WT ALAS1 allele in +/− mice on mRNA levels in liver and harderian gland were less marked compared to brain and other organs that were examined. Many other genes were up-regulated by heterozygosity in liver and brain but to a minimal extent. Hepatic heme oxygenase 1 (HMOX1) mRNA expression was significantly lower in +/− mice but not in brain. No elevated translation of WT allele ALAS1 mRNA was detected in +/− liver as a compensatory mechanism for the disabled allele. Fasting induced ALAS1 mRNA in both WT and +/− mice but only in +/− was this manifest as increased ALAS1 protein. The hepatic protoporphyria-inducing drug 4-ethyl-DDC caused induction of hepatic ALAS1 mRNA and protein levels in both WT and +/− mice but markedly less in the mice with only one intact allele. The findings illustrate the complex response of ALAS1 expression for heme demand but limited evidence that upregulation of a wild type allele can compensate for a null allele.Viktoria VaganySusan RobinsonTatyana ChernovaAndrew G. SmithElsevierarticleAminolevulinic acid synthase 1Semi null miceHepatic responseCompensation, complex regulationMedicine (General)R5-920Biology (General)QH301-705.5ENMolecular Genetics and Metabolism Reports, Vol 29, Iss , Pp 100818- (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Aminolevulinic acid synthase 1 Semi null mice Hepatic response Compensation, complex regulation Medicine (General) R5-920 Biology (General) QH301-705.5
spellingShingle	Aminolevulinic acid synthase 1 Semi null mice Hepatic response Compensation, complex regulation Medicine (General) R5-920 Biology (General) QH301-705.5 Viktoria Vagany Susan Robinson Tatyana Chernova Andrew G. Smith Complex response to physiological and drug-induced hepatic heme demand in monoallelic ALAS1 mice
description	Regulation of 5-aminolevulinate synthase 1 (ALAS1) for nonerythroid heme is critical for respiration, cell signaling mechanisms and steroid/drug metabolism. ALAS1 is induced in some genetic disorders but unlike other genes in the heme pathway, a gene variant of ALAS1 associated with inherited disease has not been reported. BALB/c mice carrying a null ALAS1 allele caused by a βGEO insert were developed and used to determine the consequences of heme demand of a semi gene copy number. Homozygous disruption of ALAS1 (−/−) was lethal for embryo development post day 6.5 but expression in heterozygotes (+/−) was sufficient for the number of offspring and survival. In both wild type (WT +/+) and +/− mice expression of ALAS1 RNA was greatest in liver and harderian gland and much lower in kidney, lung, heart, brain and spleen. The effects of one WT ALAS1 allele in +/− mice on mRNA levels in liver and harderian gland were less marked compared to brain and other organs that were examined. Many other genes were up-regulated by heterozygosity in liver and brain but to a minimal extent. Hepatic heme oxygenase 1 (HMOX1) mRNA expression was significantly lower in +/− mice but not in brain. No elevated translation of WT allele ALAS1 mRNA was detected in +/− liver as a compensatory mechanism for the disabled allele. Fasting induced ALAS1 mRNA in both WT and +/− mice but only in +/− was this manifest as increased ALAS1 protein. The hepatic protoporphyria-inducing drug 4-ethyl-DDC caused induction of hepatic ALAS1 mRNA and protein levels in both WT and +/− mice but markedly less in the mice with only one intact allele. The findings illustrate the complex response of ALAS1 expression for heme demand but limited evidence that upregulation of a wild type allele can compensate for a null allele.
format	article
author	Viktoria Vagany Susan Robinson Tatyana Chernova Andrew G. Smith
author_facet	Viktoria Vagany Susan Robinson Tatyana Chernova Andrew G. Smith
author_sort	Viktoria Vagany
title	Complex response to physiological and drug-induced hepatic heme demand in monoallelic ALAS1 mice
title_short	Complex response to physiological and drug-induced hepatic heme demand in monoallelic ALAS1 mice
title_full	Complex response to physiological and drug-induced hepatic heme demand in monoallelic ALAS1 mice
title_fullStr	Complex response to physiological and drug-induced hepatic heme demand in monoallelic ALAS1 mice
title_full_unstemmed	Complex response to physiological and drug-induced hepatic heme demand in monoallelic ALAS1 mice
title_sort	complex response to physiological and drug-induced hepatic heme demand in monoallelic alas1 mice
publisher	Elsevier
publishDate	2021
url	https://doaj.org/article/03f78fad1f0040c5a05adcf272320377
work_keys_str_mv	AT viktoriavagany complexresponsetophysiologicalanddruginducedhepatichemedemandinmonoallelicalas1mice AT susanrobinson complexresponsetophysiologicalanddruginducedhepatichemedemandinmonoallelicalas1mice AT tatyanachernova complexresponsetophysiologicalanddruginducedhepatichemedemandinmonoallelicalas1mice AT andrewgsmith complexresponsetophysiologicalanddruginducedhepatichemedemandinmonoallelicalas1mice
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Complex response to physiological and drug-induced hepatic heme demand in monoallelic ALAS1 mice

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