State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
University of Chinese Academy of Sciences, Beijing, 100049, China.
Acta Pharmacol Sin. 2020 Nov;41(11):1446-1456. doi: 10.1038/s41401-020-0413-7. Epub 2020 May 12.
Dipeptidyl peptidase 4 (DPP4), a ubiquitously expressed protease that cleaves off the N-terminal dipeptide from proline and alanine on the penultimate position, has important roles in many physiological processes. In the present study, experimental colitis was induced in mice receiving 3% dextran sulfate sodium (DSS) in drinking water. We found that mice with DSS-induced colitis had significantly increased intestinal DPP activity and decreased serum DPP activity, suggesting a probable correlation of DPP4 with experimental colitis. Then, we investigated whether sitagliptin, a specific DPP4 inhibitor could protect against DSS-induced colitis. We showed that oral administration of single dose of sitagliptin (30 mg/kg) on D7 remarkably inhibited DPP enzyme activity in both serum and intestine of DSS-induced colitic mice. Repeated administration of sitagliptin (10, 30 mg/kg, bid, from D0 to D8) significantly ameliorated DSS-induced colitis, including reduction of disease activity index (DAI) and body weight loss, improvement of histological score and colon length. Sitagliptin administration dose-dependently increased plasma concentrations of active form of GLP-1 and colonic expression of GLP-2R. Co-administration of GLP-2R antagonist GLP-2 (500 μg/kg, bid, sc) abolished the protective effects of sitagliptin in DSS-induced colitic mice. Moreover, sitagliptin administration significantly decreased the ratio of apoptotic cells and increased the ratio of proliferative cells in colon epithelium of DSS-induced colitic mice, and this effect was also blocked by GLP-2. Taken together, our results demonstrate that sitagliptin could attenuate DSS-induced experimental colitis and the effects can be attributed to the enhancement of GLP-2 action and the subsequent protective effects on intestinal barrier by inhibiting epithelial cells apoptosis and promoting their proliferation. These findings suggest sitagliptin as a novel therapeutic approach for the treatment of ulcerative colitis.
二肽基肽酶 4（DPP4）是一种广泛表达的蛋白酶，能够从倒数第二位的脯氨酸和丙氨酸上切下 N 端二肽，在许多生理过程中发挥着重要作用。在本研究中，我们用含 3%葡聚糖硫酸钠（DSS）的饮用水诱导小鼠实验性结肠炎。我们发现，DSS 诱导的结肠炎小鼠的肠道 DPP 活性显著升高，而血清 DPP 活性降低，提示 DPP4 可能与实验性结肠炎有关。接着，我们研究了 DPP4 抑制剂西他列汀是否可以预防 DSS 诱导的结肠炎。结果表明，D7 单次给予西他列汀（30mg/kg）可显著抑制 DSS 诱导的结肠炎小鼠血清和肠道中的 DPP 酶活性。重复给予西他列汀（10、30mg/kg，bid，从 D0 至 D8）可显著改善 DSS 诱导的结肠炎，包括降低疾病活动指数（DAI）和体重减轻，改善组织学评分和结肠长度。西他列汀给药剂量依赖性地增加了血浆中 GLP-1 的活性形式和结肠中 GLP-2R 的表达。同时给予 GLP-2R 拮抗剂 GLP-2（500μg/kg，bid，sc）可消除西他列汀对 DSS 诱导的结肠炎小鼠的保护作用。此外，西他列汀给药可显著降低 DSS 诱导的结肠炎小鼠结肠上皮细胞中凋亡细胞的比例，增加增殖细胞的比例，而这种作用也被 GLP-2 阻断。综上所述，我们的结果表明，西他列汀可减轻 DSS 诱导的实验性结肠炎，其作用可归因于抑制上皮细胞凋亡和促进其增殖，从而增强 GLP-2 的作用并对肠道屏障产生保护作用。这些发现提示西他列汀可能成为治疗溃疡性结肠炎的一种新方法。
