Pancreas protective effects of Urolithin A on type 2 diabetic mice induced by high fat and streptozotocin via regulating autophagy and AKT/mTOR signaling pathway
Pancreas protective effects of Urolithin A on type 2 diabetic mice induced by high fat and streptozotocin via regulating autophagy and AKT/mTOR signaling pathway
复制标题
尿石素A通过调节自噬和AKT/mTOR信号通路对高脂和链脲佐菌素诱导的2型糖尿病小鼠胰腺的保护作用
DOI：
10.1016/j.jep.2019.112479
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发表时间：
2020
影响因子：
5.4
通讯作者：
Li Xuejun
中科院分区：
文献类型：
--
作者：
Tuohetaerbaike Bahetibieke;Zhang Yan;Tian Yali;Zhang Nan Nan;Kang Jinsen;Mao Xinmin;Zhang Yanzhi;Li Xuejun
尿石素A（Urolithin A，UroA）是浆果、石榴和余甘子等中草药中鞣花酸的主要肠道微生物代谢产物，具有抗炎、抗氧化、抗肿瘤等作用，抗肿瘤和促自噬作用。本研究的目的是评估抗糖尿病和胰腺炎的作用。采用高脂饮食诱导2型糖尿病小鼠模型，观察UroA对2型糖尿病小鼠的保护作用，并初步探讨UroA对自噬的影响及其机制（HFD; 60%能量作为脂肪）和低剂量链脲佐菌素（85 mg/kg）注射。给小鼠施用UroA（50 mg/kg/d）单独给药或UroA-氯喹结果UroA可明显改善糖尿病小鼠的高饮水量、高尿量等症状，显著降低空腹血糖（FBG）、糖负荷后血糖、糖化血红蛋白（GHb）、血浆C肽、丙二醛（MDA）和白细胞介素1 β（IL-1 β）水平，还原型谷胱甘肽（GSH）、白细胞介素-10含量和葡萄糖耐量增加。UroA还改善了胰腺功能指数，如HOMA-β，通过光学显微镜和透射电子显微镜（TEM）评估的胰腺病理学和超微结构特征改善证明了这一点。因此，UroA减少线粒体肿胀和髓鞘样细胞质内含物。UroA显著上调糖尿病小鼠胰腺中微管相关蛋白1轻链3-II（LC 3 II）和beclin 1的蛋白水平，下调死骨小体1（p62）的蛋白水平，同时下调凋亡蛋白切割的caspase 3的表达。此外，它还增加了蛋白激酶B（p-Akt）和哺乳动物雷帕霉素靶蛋白（p-mTOR）的磷酸化水平。UroA对糖尿病的这些作用中的大多数被逆转治疗与自噬抑制剂chloroquine.ConclusionsOur研究结果表明，胰腺保护作用UroA对糖尿病的部分介导的自噬和AKT/mTOR信号通路的调节。
Ethnopharmacological relevanceUrolithin A (UroA), the main intestinal microflora metabolite of ellagic acid of berries, pomegranate,and some other traditional chinese herbals such as emblica officinalis,etc,has been reported to exhibit anti-inflammatory, anti-oxidative, anti-tumor and pro-autophagy effects.Aim of the studyThis study evaluated the anti-diabetic and pancreas-protective effects of UroA using a mice model of type 2 diabetes and preliminarily explored its effect on autophagy as well as the mechanism involved.Materials and methodsType 2 diabetes model was induced by high-fat diet (HFD; 60% energy as fat) and low-dose streptozotocin (85 mg/kg) injection. Mice were administered with UroA (50 mg/kg/d) alone or UroA-chloroquine (autophagy inhibitor) combination for 8 weeks.ResultsUroA improved symptoms of diabetic mice such as high water intake volume, high urine volume, significantly decreased fasting blood glucose (FBG), after-glucose-loading glucose, glycated hemoglobin (GHb) levels, plasma C-peptide, malondialdehyde (MDA) and interleukin-1 β level, increased reduced glutathione (GSH), interleukin-10 content, and glucose tolerance. UroA also improved pancreatic function indexes such as HOMA-β as evidenced by improved pathological and ultrastructural features of the pancreas assessed by light microscopy and transmission electron microscopy (TEM). Accordingly, UroA decreased mitochondrial swelling and myelin-like cytoplasmic inclusions. UroA significantly upregulated the protein levels of microtubule-associated protein 1 light chain 3-II (LC3II) and beclin1, downregulated sequestosome 1 (p62) accompanied by decreased expression of apoptotic protein cleaved caspase3 in pancreas of diabetic mice. In addition, it increased the phosphorylation level of protein kinase B (p-Akt) and mammalian target of rapamycin (p-mTOR). Most of these effects of UroA were reversed by treatment with autophagy inhibitor chloroquine.ConclusionsOur findings reveal that the pancreas protective effects of UroA against diabetes were partially mediated by its regulation of autophagy and AKT/mTOR signal pathway.