Department of Comparative Medicine, School of Medicine, University of Washington, Seattle, WA, USA.
Department of Pharmaceutics, School of Pharmacy, University of Washington, Seattle, WA, USA.
FASEB J. 2020 Dec;34(12):15788-15804. doi: 10.1096/fj.202001734R. Epub 2020 Oct 26.
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.
全反式视黄酸（atRA）是维生素 A 的活性代谢物，是所有脊索动物中必不可少的信号分子。atRA 清除酶 Cyp26a1 或 Cyp26b1 的全球敲除都是胚胎致死的。在成年啮齿动物中，抑制 Cyp26a1 和 Cyp26b1 会增加 atRA 浓度和信号转导。然而，Cyp26a1 的出生后敲除不会导致严重的表型。我们假设 Cyp26b1 是出生后哺乳动物中主要的 atRA 清除 Cyp。通过生成 Cyp26b1 单独或与 Cyp26a1 一起的他莫昔芬诱导型敲除小鼠模型来检验这一假说。这两种小鼠模型均表现出皮炎、睑炎和脾肿大。组织学显示炎性细胞浸润，包括中性粒细胞和 T 淋巴细胞浸润皮肤和非腺体胃的过度角化/增生。同时缺乏 Cyp26a1 和 Cyp26b1 的小鼠的寿命也缩短，体重增加失败，并且出现脂肪萎缩。维生素 A 稳态发生了显著变化。出生后敲除 Cyp26b1 会导致皮肤中 atRA 浓度增加，而 Cyp26a1 和 Cyp26b1 的出生后敲除会导致肝脏、血清、皮肤、脾脏和肠道中 atRA 浓度增加。这项研究证明了 Cyp26b1 在调节出生后生命中类视黄醇稳态中的首要作用。
