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

Abstract

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.

Irisin Contributes to the Hepatoprotection of Dexmedetomidine during Intestinal Ischemia/Reperfusion

“…It often follows mesentery embolism, intestinal sepsis, hemorrhagic shock, and transplantation and is thought to be the main inducer of multiple organ dysfunction syndrome [31, 32]. Intestinal I/R leads to local intestinal tissue injury and mucosal barrier dysfunction [33–35] and also causes distant organ dysfunction, especially in the liver and lung [7–9]. Certain studies have suggested that the liver is the first organ to be damaged following the intestinal I/R, because its vasculature is coupled with the intestinal circulation [9, 11].…”

Hydrogen Sulfide Gas Exposure Induces Necroptosis and Promotes Inflammation through the MAPK/NF-κB Pathway in Broiler Spleen

“…The finding showed that neoalbaconol-induced necroptosis resulted in energy depletion by downregulated HK1 and HK2 levels [48]. Similarly, pyruvate has a protective role in ischaemic enterocytes; the level of pyruvate was depressed during necroptosis [49]. Moreover, the impairment of Na + /K + -ATPase was detected in cell necrosis [50], and the ATPase viabilities were inhibited obviously during necroptosis [16].…”

Eritoran Suppresses Colon Cancer by Altering a Functional Balance in Toll-like Receptors That Bind Lipopolysaccharide

“…In addition, cancer cells were homogenized, and the supernatant was measured for DNA fragmentation by using a cell death detection ELISA kit (Roche; refs. 19,20,31,32).…”