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

ABSTRACT: 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.

SUBMITTER: Vagany V 

PROVIDER: S-EPMC8639769 | biostudies-literature |

REPOSITORIES: biostudies-literature