Center for the Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, TX 75390-8505, USA.
Department of Internal Medicine, Division of Gastroenterology, University of Texas Southwestern Medical Center, Dallas, TX 75390-8505, USA.
Dis Model Mech. 2023 Sep 1;16(9). doi: 10.1242/dmm.050043. Epub 2023 Sep 8.
Intestinal immunity is dependent on barrier function to maintain quiescence. The mechanisms for the maintenance of this barrier are not fully understood. Delta 4-desaturase, sphingolipid 2 (DEGS2) is a lipid desaturase and hydroxylase that catalyzes the synthesis of ceramide and phytoceramide from dihydroceramide. Using a forward genetic approach, we found and validated a mutation in Degs2 as causative of increasing susceptibility to colitis and altering the phytoceramide balance in the colon. DEGS2 is expressed in the intestinal epithelium, and the colitis phenotype is dependent on the non-hematopoietic compartment of the mouse. In the absence of DEGS2, the colon lacks phytoceramides and accumulates large amounts of the precursor lipid dihydroceramide. In response to dextran sodium sulfate (DSS)-induced colitis, colonic epithelial cells in DEGS2-deficient mice had increased cell death and decreased proliferation compared to those in wild-type mice. These findings demonstrate that DEGS2 is needed to maintain epithelial integrity, protect against DSS-induced colitis and maintain lipid balance in vivo.
肠道免疫依赖于屏障功能来维持静止状态。维持这种屏障的机制尚未完全了解。Delta 4-去饱和酶，鞘脂 2（DEGS2）是一种脂质去饱和酶和羟化酶，可催化二氢神经酰胺合成神经酰胺和植物神经酰胺。我们采用正向遗传方法，发现并验证了 Degs2 中的突变是导致结肠炎易感性增加和改变结肠植物神经酰胺平衡的原因。DEGS2 在肠上皮细胞中表达，结肠炎表型依赖于小鼠的非造血部分。在缺乏 DEGS2 的情况下，结肠缺乏植物神经酰胺并积累大量前体脂质二氢神经酰胺。在葡聚糖硫酸钠（DSS）诱导的结肠炎反应中，与野生型小鼠相比，DEGS2 缺陷型小鼠的结肠上皮细胞死亡增加，增殖减少。这些发现表明，DEGS2 对于维持上皮完整性、预防 DSS 诱导的结肠炎和维持体内脂质平衡是必需的。
