Distinct cytoprotective roles of pyruvate and ATP by glucose metabolism on epithelial necroptosis and crypt proliferation in ischaemic gut

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• 作者：Ching‐Ying Huang ; Wei‐Ting Kuo ; Chung‐Yen Huang ; Tsung‐Chun Lee ; Chin‐Tin Chen ; Wei‐Hao Peng ; Kuo‐Shyan Lu ; Chung‐Yi Yang ; Linda Chia‐Hui Yu
• 刊名：The Journal of Physiology
• 出版年：2017
• 出版时间：15 January 2017
• 年：2017
• 卷：595
• 期：2
• 页码：505-521
• 全文大小：2.7MB
• ISSN：1469-7793

文摘

Mesenteric ischaemia/reperfusion induces epithelial death in both forms of apoptosis and necrosis, leading to villus denudation and gut barrier damage. It remains unclear whether programmed cell necrosis [i.e. receptor-interacting protein kinase (RIP)-dependent necroptosis] is involved in ischaemic injury. Previous studies have demonstrated that enteral glucose uptake by sodium-glucose transporter 1 ameliorated ischaemia/reperfusion-induced epithelial injury, partly via anti-apoptotic signalling and maintenance of crypt proliferation. Glucose metabolism is generally assumed to be cytoprotective; however, the roles played by glucose metabolites (e.g. pyruvate and ATP) on epithelial cell death and crypt dysfunction remain elusive. The present study aimed to investigate the cytoprotective effects exerted by distinct glycolytic metabolites in ischaemic gut. Wistar rats subjected to mesenteric ischaemia were enterally instilled glucose, pyruvate or liposomal ATP. The results showed that intestinal ischaemia caused RIP1-dependent epithelial necroptosis and villus destruction accompanied by a reduction in crypt proliferation. Enteral glucose uptake decreased epithelial cell death and increased crypt proliferation, and ameliorated mucosal histological damage. Instillation of cell-permeable pyruvate suppressed epithelial cell death in an ATP-independent manner and improved the villus morphology but failed to maintain crypt function. Conversely, the administration of liposomal ATP partly restored crypt proliferation but did not reduce epithelial necroptosis and histopathological injury. Lastly, glucose and pyruvate attenuated mucosal-to-serosal macromolecular flux and prevented enteric bacterial translocation upon blood reperfusion. In conclusion, glucose metabolites protect against ischaemic injury through distinct modes and sites, including inhibition of epithelial necroptosis by pyruvate and the promotion of crypt proliferation by ATP.