DMEM (Dynamique du Muscle et Métabolisme), INRAE, University Montpellier, 34060 Montpellier, France.
Int J Mol Sci. 2021 Mar 2;22(5):2489. doi: 10.3390/ijms22052489.
P43 is a truncated form of thyroid hormone receptor α localized in mitochondria, which stimulates mitochondrial respiratory chain activity. Previously, we showed that deletion of p43 led to reduction of pancreatic islet density and a loss of glucose-stimulated insulin secretion in adult mice. The present study was designed to determine whether p43 was involved in the processes of β cell development and maturation. We used neonatal, juvenile, and adult p43-/- mice, and we analyzed the development of β cells in the pancreas. Here, we show that p43 deletion affected only slightly β cell proliferation during the postnatal period. However, we found a dramatic fall in p43-/- mice of MafA expression (V-Maf Avian Musculoaponeurotic Fibrosarcoma Oncogene Homolog A), a key transcription factor of beta-cell maturation. Analysis of the expression of antioxidant enzymes in pancreatic islet and 4-hydroxynonenal (4-HNE) (a specific marker of lipid peroxidation) staining revealed that oxidative stress occurred in mice lacking p43. Lastly, administration of antioxidants cocktail to p43-/- pregnant mice restored a normal islet density but failed to ensure an insulin secretion in response to glucose. Our findings demonstrated that p43 drives the maturation of β cells via its induction of transcription factor MafA during the critical postnatal window.
P43 是一种定位于线粒体的甲状腺激素受体 α 的截断形式，可刺激线粒体呼吸链活性。此前，我们发现 p43 缺失会导致成年小鼠胰岛密度降低和葡萄糖刺激的胰岛素分泌丧失。本研究旨在确定 p43 是否参与β细胞发育和成熟过程。我们使用新生、幼年和成年 p43-/- 小鼠，并分析了胰腺中β细胞的发育。在这里，我们发现 p43 缺失仅轻微影响出生后期间的β细胞增殖。然而，我们发现 p43-/- 小鼠的 MafA 表达（β细胞成熟的关键转录因子）显著下降。对胰岛中抗氧化酶的表达和 4-羟壬烯醛（一种特定的脂质过氧化标志物）染色的分析表明，p43 缺失的小鼠发生了氧化应激。最后，给 p43-/- 孕鼠施用抗氧化鸡尾酒可恢复正常的胰岛密度，但未能确保对葡萄糖的胰岛素分泌反应。我们的研究结果表明，p43 通过在关键的出生后窗口期诱导转录因子 MafA 来驱动β细胞的成熟。
