Complex response to physiological and drug-induced hepatic heme demand in monoallelic ALAS1 mice
| Autor: | Andrew G. Smith, Tatyana Chernova, Viktoria Vágány, Susan W. Robinson |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Drug
Medicine (General) Chemistry QH301-705.5 media_common.quotation_subject ALAS1 Cell biology Semi null mice chemistry.chemical_compound Endocrinology Complex response R5-920 Genetics Compensation complex regulation Hepatic response Biology (General) Molecular Biology Heme Aminolevulinic acid synthase 1 media_common |
| Zdroj: | Molecular Genetics and Metabolism Reports, Vol 29, Iss, Pp 100818-(2021) |
| ISSN: | 2214-4269 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|