Ohgaku Seiichiro, Ida Shogo, Ohashi Natsuko, Morino Katsutaro, Ishikado Atsushi, Yanagimachi Tsuyoshi, Murata Koichiro, Sato Daisuke, Ugi Satoshi, Nasiri Ali, Shulman Gerald I, Maegawa Hiroshi, Kume Shinji, Fujita Yukihiro
Department of Medicine, Shiga University of Medical Science, Otsu 520-2192, Japan.
Department of Stem Cell Biology and Regenerative Medicine, Shiga University of Medical Science, Otsu 520-2192, Japan.
Heliyon. 2024 Jul 14;10(14):e34490. doi: 10.1016/j.heliyon.2024.e34490. eCollection 2024 Jul 30.
Endothelial cells have a crucial function in transporting and exchanging various nutrients. -GlcNAcylation, mediated by -GlcNAc transferase (OGT), involves the addition of -acetylglucosamine to proteins and serves as an intracellular nutrient sensing mechanism. However, the role of -GlcNAcylation in endothelial cells remains poorly understood.
This study investigated the role of -GlcNAcylation in endothelial cells.
Endothelial-cell-specific -knockout mice (-ECKO) were generated by crossing -floxed mice (-flox) with Cre ER mice. -ECKO mice and -flox control mice were subjected to a normal or high-fat diet, and their body weight, glucose metabolism, and lipid metabolism were examined.
-ECKO mice exhibited reduced body weight compared with flox control mice under a high-fat diet. Lipid absorption was significantly impaired in -ECKO mice. Changes in the intercellular junctions of small intestinal lacteal endothelial cells from a button-like to a zipper-like configuration were observed. Furthermore, -ECKO mice showed decreased expression of VEGFR3. The administration of a nitric oxide donor restored lipid absorption and reversed the morphological alterations in -ECKO mice.
These findings demonstrate the critical role of -GlcNAcylation in endothelial cells in lipid absorption in the intestine through the modulation of lacteal junction morphology. These results provide novel insight into the metabolic regulatory mechanisms under physiological conditions and have implications for the development of new therapeutic strategies for obesity.
内皮细胞在多种营养物质的运输和交换中发挥着关键作用。由O-连接N-乙酰葡糖胺转移酶（OGT）介导的O-GlcNAc糖基化作用，涉及将O-乙酰葡糖胺添加到蛋白质上，并作为一种细胞内营养感知机制。然而，O-GlcNAc糖基化在内皮细胞中的作用仍知之甚少。
本研究调查了O-GlcNAc糖基化在内皮细胞中的作用。
通过将O-侧翼小鼠（O-flox）与Cre-ER小鼠杂交，生成内皮细胞特异性O基因敲除小鼠（O-ECKO）。对O-ECKO小鼠和O-flox对照小鼠进行正常饮食或高脂饮食，并检测它们的体重、葡萄糖代谢和脂质代谢。
在高脂饮食条件下，与flox对照小鼠相比，O-ECKO小鼠体重减轻。O-ECKO小鼠的脂质吸收显著受损。观察到小肠乳糜管内皮细胞的细胞间连接从纽扣状变为拉链状。此外，O-ECKO小鼠的VEGFR3表达降低。给予一氧化氮供体可恢复O-ECKO小鼠的脂质吸收并逆转其形态学改变。
这些发现表明O-GlcNAc糖基化通过调节乳糜管连接形态，在内皮细胞对肠道脂质吸收中起关键作用。这些结果为生理条件下的代谢调节机制提供了新的见解，并对肥胖症新治疗策略的开发具有启示意义。
