Makdissi Stephanie, Loudhaief Rihab, George Smitha, Weller Tabatha, Salim Minna, Malick Ahsan, Mu Yizhu, Parsons Brendon D, Di Cara Francesca
Department of Microbiology and Immunology, Faculty of Medicine, Dalhousie University, Halifax, NS, Canada.
Department of Pediatrics, Dalhousie University, Izaak Walton Killam (IWK) Health Centre, Halifax, NS, Canada.
iScience. 2025 Feb 4;28(3):111946. doi: 10.1016/j.isci.2025.111946. eCollection 2025 Mar 21.
Intestinal epithelium regeneration and homeostasis must be tightly regulated. Alteration of epithelial homeostasis is a major contributing factor to diseases such as colorectal cancer and inflammatory bowel diseases. Many pathways involved in epithelial regeneration have been identified, but more regulators remain undiscovered. Metabolism has emerged as an overlooked regulator of intestinal epithelium homeostasis. Using the model organism , we found that ether lipids metabolism is required to maintain intestinal epithelial homeostasis. Its dysregulation in intestinal progenitors causes the activation of the unfolded protein response of the endoplasmic reticulum (UPR) that triggers Xbp1 and upregulates the conserved disulfide isomerase PDIA3/ERp60. Activation of the Xbp1-ERp60 signaling causes Jak/Stat-mediated increase in progenitor cells, compromising epithelial barrier function and survival in males but not females. This study identified ether lipids-PDIA3/ERp60 as a key regulator of intestinal progenitor homeostasis in health that, if altered, causes pathological conditions in the intestinal epithelium.
肠道上皮的再生和稳态必须受到严格调控。上皮稳态的改变是导致诸如结直肠癌和炎症性肠病等疾病的主要因素。许多参与上皮再生的途径已被确定，但仍有更多的调节因子有待发现。代谢已成为肠道上皮稳态中一个被忽视的调节因子。利用模式生物，我们发现醚脂代谢对于维持肠道上皮稳态是必需的。其在肠道祖细胞中的失调会导致内质网未折叠蛋白反应（UPR）的激活，从而触发Xbp1并上调保守的二硫键异构酶PDIA3/ERp60。Xbp1-ERp60信号的激活会导致Jak/Stat介导的祖细胞增加，损害男性而非女性的上皮屏障功能和生存能力。这项研究确定醚脂-PDIA3/ERp60是健康状态下肠道祖细胞稳态的关键调节因子，若其发生改变，会导致肠道上皮出现病理状况。
