PDF(Pubmed)
Abstract：
The metal ion transporter SLC39A8 is associated with physiological traits and diseases, including blood manganese (Mn) levels and inflammatory bowel diseases (IBD). The mechanisms by which SLC39A8 controls Mn homeostasis and epithelial integrity remain elusive. Here, we generate Slc39a8 intestinal epithelial cell-specific-knockout (Slc39a8-IEC KO) mice, which display markedly decreased Mn levels in blood and most organs. Radiotracer studies reveal impaired intestinal absorption of dietary Mn in Slc39a8-IEC KO mice. SLC39A8 is localized to the apical membrane and mediates 54Mn uptake in intestinal organoid monolayer cultures. Unbiased transcriptomic analysis identifies alkaline ceramidase 1 (ACER1), a key enzyme in sphingolipid metabolism, as a potential therapeutic target for SLC39A8-associated IBDs. Importantly, treatment with an ACER1 inhibitor attenuates colitis in Slc39a8-IEC KO mice by remedying barrier dysfunction. Our results highlight the essential roles of SLC39A8 in intestinal Mn absorption and epithelial integrity and offer a therapeutic target for IBD associated with impaired Mn homeostasis.
摘要：
金属离子转运体SLC39A8与生理性状和疾病相关,包括血锰（Mn）水平和炎症性肠病（IBD）。SLC39A8控制Mn稳态和上皮完整性的机制仍然难以捉摸。这里,我们产生Slc39a8肠上皮细胞特异性敲除（Slc39a8-IECKO）小鼠，血液和大多数器官中的锰含量显着降低。放射性示踪剂研究揭示Slc39a8-IECKO小鼠饮食中Mn的肠道吸收受损。SLC39A8定位于顶膜并介导肠类器官单层培养物中的54Mn摄取。无偏转录组学分析鉴定了碱性神经酰胺酶1(ACER1)，鞘脂代谢的关键酶，作为SLC39A8相关IBD的潜在治疗靶点。重要的是,ACER1抑制剂治疗通过治疗屏障功能障碍减轻Slc39a8-IECKO小鼠结肠炎.我们的结果强调了SLC39A8在肠道Mn吸收和上皮完整性中的重要作用，并为与Mn稳态受损相关的IBD提供了治疗靶标。
