脂解激活脂蛋白受体（LSR）是一种多功能蛋白，最为众所周知的是它在上皮三细胞紧密连接的组装和脂蛋白的肝清除中的作用。在这里，我们研究了LSR是否对肠道上皮细胞的稳态和肠道疾病的发病机制有贡献。通过使用多个有条件的敲除小鼠模型和体外培养的器官样品，我们发现LSR在肠道干细胞中的消失导致Paneth细胞的消失，但不影响其他细胞谱系的分化。机制研究揭示了LSR缺乏通过调节YAP的磷酸化和蛋白酶体降解增加了YAP的丰度。通过利用功能的增强和减弱研究，我们展示了LSR通过增强小肠上皮中的Paneth细胞分化来保护免疫性坏死性肠炎。因此，该研究确定了LSR作为YAP活性的上游负调节因子，也是促进Paneth细胞分化的必需因子，并且是坏死性肠炎的潜在治疗靶点。版权所有©2023作者。由Elsevier Inc.出版，保留所有权利。

Lipolysis-stimulated lipoprotein receptor (LSR) is a multi-functional protein that is best known for its roles in assembly of epithelial tricellular tight junctions and hepatic clearance of lipoproteins. Here, we investigated whether LSR contributes to intestinal epithelium homeostasis and pathogenesis of intestinal disease. By using multiple conditional deletion mouse models and ex vivo cultured organoids, we find that LSR elimination in intestinal stem cells results in the disappearance of Paneth cells without affecting the differentiation of other cell lineages. Mechanistic studies reveal that LSR deficiency increases abundance of YAP by modulating its phosphorylation and proteasomal degradation. Using gain- and loss-of-function studies, we show that LSR protects against necrotizing enterocolitis through enhancement of Paneth cell differentiation in small-intestinal epithelium. Thus, this study identifies LSR as an upstream negative regulator of YAP activity, an essential factor for Paneth cell differentiation, and a potential therapeutic target for necrotizing enterocolitis.Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.