Intestinal epithelial PKM2 serves as a safeguard against experimental colitis via activating β-catenin signaling
Intestinal epithelial PKM2 serves as a safeguard against experimental colitis via activating β-catenin signaling
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肠上皮 PKM2 通过激活 β-catenin 信号传导来预防实验性结肠炎
DOI：
10.1038/s41385-019-0197-6
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发表时间：
2019
影响因子：
8
通讯作者：
Ke Zen
中科院分区：
文献类型：
--
作者：
Xinlei Sun;Li Yao;Hongwei Liang;Dong Wang;Yueqin He;Yao Wei;Lei Ye;Kai Wang;Limin Li;Jiangning Chen;Chen-Yu Zhang;Guifang Xu;Fang-Yu Wang;Ke Zen
丙酮酸激酶M2（PKM 2）介导的有氧糖酵解已被证明在促进细胞存活和增殖方面发挥关键作用。然而，肠上皮PKM 2在肠道内稳态中的功能知之甚少。在这里，我们调查是否以及如何肠上皮PKM 2调节的形态和功能的成人肠实验性结肠炎。分析克罗恩病和溃疡性结肠炎患者的结肠镜活检，我们发现与非炎症组织相比，患者的肠上皮PKM 2水平显著降低。在葡聚糖硫酸钠诱导的结肠炎小鼠中观察到肠上皮PKM 2的类似减少。此外，与野生型小鼠相比，肠上皮特异性PKM 2敲除（Pkm 2-/-）小鼠表现出更严重的肠道炎症，如结肠缩短、上皮紧密连接破坏、炎性细胞因子水平增加和免疫细胞浸润所证明。基因分析、蛋白质印迹和功能分析表明，细胞存活信号，特别是Wnt/β-catenin途径，与PKM 2活性相关。通过递送PKM 2表达质粒增加小鼠肠上皮PKM 2表达减弱实验性结肠炎。总之，我们的研究表明，肠上皮PKM 2通过激活Wnt/β-catenin信号通路增加结肠炎条件下的细胞存活和伤口愈合。
The pyruvate kinase M2 (PKM2)-mediated aerobic glycolysis has been shown to play a critical role in promoting cell survival and proliferation. However, little is known about the function of intestinal epithelial PKM2 in intestine homeostasis. Here we investigate whether and how intestinal epithelial PKM2 modulates the morphology and function of the adult intestine in experimental colitis. Analyzing colonoscopic biopsies from Crohn's disease and ulcerative colitis patients, we found significantly decreased level of intestinal epithelial PKM2 in patients compared to that in non-inflamed tissues. Similar reduction of intestinal epithelial PKM2 was observed in mice with dextran sulfate sodium-induced colitis. Moreover, intestinal epithelial-specific PKM2-knockout (Pkm2-/-) mice displayed more severe intestinal inflammation, as evidenced by a shortened colon, disruption of epithelial tight junctions, an increase in inflammatory cytokine levels, and immune cell infiltration, when compared to wild-type mice. Gene profiling, western blot, and function analyses indicated that cell survival signals, particularly the Wnt/β-catenin pathways, were associated with PKM2 activity. Increasing mouse intestinal epithelial PKM2 expression via delivery of a PKM2-expressing plasmid attenuated experimental colitis. In conclusion, our studies demonstrate that intestinal epithelial PKM2 increases cell survival and wound healing under the colitic condition via activating the Wnt/β-catenin signaling.