| First Author | Vagany V | Year | 2021 |
| Journal | Mol Genet Metab Rep | Volume | 29 |
| Pages | 100818 | PubMed ID | 34900592 |
| Mgi Jnum | J:325274 | Mgi Id | MGI:7284457 |
| Doi | 10.1016/j.ymgmr.2021.100818 | Citation | Vagany V, et al. (2021) Complex response to physiological and drug-induced hepatic heme demand in monoallelic ALAS1 mice. Mol Genet Metab Rep 29:100818 |
| abstractText | 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 betaGEO 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. |
