Department of Microbiology and Immunology, Dalhousie University, Halifax, NS, Canada.
Department of Pediatrics, Dalhousie University, Izaak Walton Killam (IWK) Health Centre, Halifax, NS, Canada.
Cell Death Dis. 2024 Jul 28;15(7):536. doi: 10.1038/s41419-024-06925-x.
Intestinal epithelial cells line the luminal surface to establish the intestinal barrier, where the cells play essential roles in the digestion of food, absorption of nutrients and water, protection from microbial infections, and maintaining symbiotic interactions with the commensal microbial populations. Maintaining and coordinating all these functions requires tight regulatory signaling, which is essential for intestinal homeostasis and organismal health. Dysfunction of intestinal epithelial cells, indeed, is linked to gastrointestinal disorders such as irritable bowel syndrome, inflammatory bowel disease, and gluten-related enteropathies. Emerging evidence suggests that peroxisome metabolic functions are crucial in maintaining intestinal epithelial cell functions and intestinal epithelium regeneration and, therefore, homeostasis. Here, we investigated the molecular mechanisms by which peroxisome metabolism impacts enteric health using the fruit fly Drosophila melanogaster and murine model organisms and clinical samples. We show that peroxisomes control cellular cholesterol, which in turn regulates the conserved yes-associated protein-signaling and contributes to intestinal epithelial structure and epithelial barrier function. Moreover, analysis of intestinal organoid cultures derived from biopsies of patients affected by Crohn's Disease revealed that the dysregulation of peroxisome number, excessive cellular cholesterol, and inhibition of Yap-signaling are markers of disease and could be novel diagnostic and/or therapeutic targets for treating Crohn's Disease. Our studies provided mechanistic insights on peroxisomal signaling in intestinal epithelial cell functions and identified cholesterol as a novel metabolic regulator of yes-associated protein-signaling in tissue homeostasis.
肠道上皮细胞排列在腔面以建立肠道屏障，在那里细胞在食物消化、营养物质和水吸收、微生物感染保护以及与共生微生物群保持共生相互作用方面发挥着重要作用。维持和协调所有这些功能需要严格的调节信号，这对于肠道内稳态和机体健康是必不可少的。事实上，肠道上皮细胞功能障碍与胃肠道疾病如肠易激综合征、炎症性肠病和与麸质相关的肠病有关。新出现的证据表明，过氧化物酶体代谢功能对于维持肠道上皮细胞功能和肠道上皮细胞再生以及因此的内稳态至关重要。在这里，我们使用果蝇和小鼠模型生物和临床样本研究了过氧化物酶体代谢影响肠道健康的分子机制。我们表明过氧化物酶体控制细胞胆固醇，而胆固醇反过来又调节保守的 yes 相关蛋白信号传导，并有助于肠道上皮结构和上皮屏障功能。此外，对来自患有克罗恩病的患者活检衍生的肠类器官培养物的分析表明，过氧化物酶体数量的失调、细胞胆固醇过多和 Yap 信号传导的抑制是疾病的标志物，并且可能是治疗克罗恩病的新的诊断和/或治疗靶点。我们的研究提供了关于过氧化物酶体信号在肠道上皮细胞功能中的机制见解，并确定胆固醇是组织稳态中 yes 相关蛋白信号传导的新型代谢调节剂。
