Department of Cell Biology, Graduate School of Medicine, Osaka University, Suita, Japan.
Department of Molecular Biochemistry and Clinical Investigation, Graduate School of Medicine, Osaka University, Suita, Japan.
FASEB J. 2020 Jul;34(7):9450-9465. doi: 10.1096/fj.202000028R. Epub 2020 Jun 4.
Intestinal epithelial cells (IECs) are not only responsible for the digestion and absorption of dietary substrates but also function as a first line of host defense against commensal and pathogenic luminal bacteria. Disruption of the epithelial layer causes malnutrition and enteritis. Rab6 is a small GTPase localized to the Golgi, where it regulates anterograde and retrograde transport by interacting with various effector proteins. Here, we generated mice with IEC-specific deletion of Rab6a (Rab6a mice). While Rab6a mice were born at the Mendelian ratio, they started to show IEC death, inflammation, and bleeding in the small intestine shortly after birth, and these changes culminated in early postnatal death. We further found massive lipid accumulation in the IECs of Rab6a neonates. In contrast to Rab6a neonates, knockout embryos did not show any of these abnormalities. Lipid accumulation and IEC death became evident when Rab6a embryos were nursed by a foster mother, suggesting that dietary milk-derived lipids accumulated in Rab6a-deficient IECs and triggered IEC death. These results indicate that Rab6a plays a crucial role in regulating the lipid transport and maintaining tissue integrity.
肠上皮细胞（IECs）不仅负责消化和吸收膳食底物，还作为宿主防御共生和致病腔细菌的第一道防线。上皮层的破坏会导致营养不良和肠炎。Rab6 是一种定位于高尔基体的小 GTPase，通过与各种效应蛋白相互作用，调节顺行和逆行运输。在这里，我们生成了上皮细胞特异性缺失 Rab6a 的小鼠（Rab6a 小鼠）。虽然 Rab6a 小鼠以孟德尔比例出生，但它们在出生后不久就开始表现出 IEC 死亡、炎症和小肠出血，这些变化最终导致出生后早期死亡。我们进一步发现 Rab6a 新生小鼠的 IEC 中大量脂质堆积。与 Rab6a 新生小鼠不同，敲除胚胎没有表现出任何这些异常。当 Rab6a 胚胎由代孕母亲哺乳时，脂质堆积和 IEC 死亡变得明显，这表明膳食乳源性脂质在 Rab6a 缺陷型 IEC 中积累并触发 IEC 死亡。这些结果表明 Rab6a 在调节脂质运输和维持组织完整性方面发挥着关键作用。
