Loss of Rab6a in the small intestine causes lipid accumulation and epithelial cell death from lactation
Loss of Rab6a in the small intestine causes lipid accumulation and epithelial cell death from lactation
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小肠中 Rab6a 的缺失会导致脂质积累和哺乳期上皮细胞死亡
DOI：
10.1096/fj.202000028r
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发表时间：
2020
期刊：
影响因子：
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通讯作者：
Harada Akihiro
中科院分区：
文献类型：
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作者：
Iwaki Ayano;Moriwaki Kenta;Sobajima Tomoaki;Taniguchi Manabu;Yoshimura Shin‐ichiro;Kunii Masataka;Kanda Satoshi;Kamada Yoshihiro;Miyoshi Eiji;Harada Akihiro
肠上皮细胞(IECS)不仅负责消化和吸收饲料底物，而且是宿主抵抗共生和致病性肠杆菌的第一道防线。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GTP酶，它通过与多种效应蛋白相互作用来调节顺行和逆行转运。在这里，我们产生了IEC特异性缺失Rab6a的小鼠(Rab6a∆IEC小鼠)。虽然Rab6aΔIEC小鼠是按孟德尔比例出生的，但它们在出生后不久就开始出现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。我们进一步发现在Rab6a∆IEC新生儿的IEC中有大量的脂质积聚。与Rab6a∆IEC新生儿相比，基因敲除胚胎没有表现出任何这些异常。当Rab6a∆IEC胚胎由养母哺育时，脂肪堆积和IEC死亡明显，这表明饲料中的乳源性脂质在Rab6a缺乏的IEC中积累并引发IEC死亡。这些结果表明，Rab6a在调节脂质转运和维持组织完整性方面起着至关重要的作用。
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∆IECmice). WhileRab6aΔIECmice 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 ofRab6a∆IECneonates. In contrast toRab6a∆IECneonates, knockout embryos did not show any of these abnormalities. Lipid accumulation and IEC death became evident whenRab6a∆IECembryos 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.