Knockout of Cyp26a1 and Cyp26b1 during postnatal life causes reduced lifespan, dermatitis, splenomegaly, and systemic inflammation in mice

Abstract

All-trans-retinoic acid (atRA), the active metabolite of vitamin A, is an essential signaling molecule in all chordates. Global knockouts of the atRA clearing enzymes Cyp26a1 or Cyp26b1 are embryonic lethal. In adult rodents, inhibition of Cyp26a1 and Cyp26b1 increases atRA concentrations and signaling. However, postnatal knockout of Cyp26a1 does not cause a severe phenotype. We hypothesized that Cyp26b1 is the main atRA clearing Cyp in postnatal mammals. This hypothesis was tested by generating tamoxifen-inducible knockout mouse models of Cyp26b1 alone or with Cyp26a1. Both mouse models showed dermatitis, blepharitis, and splenomegaly. Histology showed infiltration of inflammatory cells including neutrophils and T lymphocytes into the skin and hyperkeratosis/hyperplasia of the nonglandular stomach. The mice lacking both Cyp26a1 and Cyp26b1 also had a reduced lifespan, failed to gain weight, and showed fat atrophy. There were significant changes in vitamin A homeostasis. Postnatal knockout of Cyp26b1 resulted in increased atRA concentrations in the skin while the postnatal knockout of both Cyp26a1 and Cyp26b1 resulted in increased atRA concentrations in the liver, serum, skin, spleen, and intestines. This study demonstrates the paramount role of Cyp26b1 in regulating retinoid homeostasis in postnatal life. K E Y W O R D S cytochrome P450, dermatitis, inflammation, retinoic acid, vitamin A 2 | SNYDER Et al. 2 | MATERIALS AND METHODS 2.1 | Ethics statement, animal care, and breeding All the procedures involving mice prior to the commencement of these studies were approved by the Washington State University Committee on the Use and Care of Animals. The mouse colonies were maintained in a temperature-and humidity-controlled environment with food and water provided ad libitum. The mice were fed LabDiet 5K67 containing 1.5 ppm of carotene and 20 IU/g of vitamin

Retinoids in the Pathogenesis and Treatment of Liver Diseases

“…Whereas Cyp26a1 knockout during development is lethal to the embryos [ 45 ], Cyp26a1 knockout in adult mice results in a relatively mild phenotype [ 46 ]. In contrast, Cyp26b1 knockout in adult mice reduces lifespan and causes systemic inflammation [ 47 ]. Whether this Cyp26b1 knockout phenotype is related to the dysfunctional stemness phenotype of hematopoietic stem cells described above is not clear at present, nor is it clear that these effects of Cyp26a1 or Cyp26b1 are mediated exclusively by their effect on retinoid metabolism.…”

Loss of Claudin-3 Impairs Hepatic Metabolism, Biliary Barrier Function, and Cell Proliferation in the Murine Liver

“…These events took place in Cldn3 -/- mice as well. When comparing the gene expression in aged Cldn3 -/- vs aged Cldn3 +/+ mice by RNA-seq, we found a lower expression of lipid metabolism–related genes Apol9a/b 52 and Cyp26a1 53 in the knockout animals. In conjunction, we also observed a lower amount of lipids in aged Cldn3 -/- compared with aged Cldn3 +/+ liver.…”

Global Deletion of ALDH1A1 and ALDH1A2 Genes Does Not Affect Viability but Blocks Spermatogenesis

“…However, given the prevalence of the RA signaling system in biology and its absolute requirement in embryogenesis there was serious concern about developing a contraceptive approach for the testis that could have serious consequences for other organ systems. Previously it has been shown that global deletions of the genes for Cyp26A1 and Cyp26b1, the enzymes involved in RA homeostasis, lead to increased concentrations of RA in several organs, reduced lifespan, failure to gain weight, and fat atrophy ( 23 ). So, increased RA concentrations in adult mice led to severe physiological consequences.…”