TGR5 Activation Modulates an Inhibitory Effect on Liver Fibrosis Development Mediated by Anagliptin in Diabetic Rats
TGR5 Activation Modulates an Inhibitory Effect on Liver Fibrosis Development Mediated by Anagliptin in Diabetic Rats
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DOI：
10.3390/cells8101153
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发表时间：
2019-10-01
期刊：
影响因子：
6
通讯作者：
Yoshiji, Hitoshi
中科院分区：
文献类型：
--
作者：
Kaya, Daisuke;Kaji, Kosuke;Yoshiji, Hitoshi
高脂血症和高胰岛素血症激活肝星状细胞（HSC）的增殖潜能并促进肝纤维化。二肽基肽酶-4（DPP-4）抑制剂，抗糖尿病药物，据报道可抑制HSC增殖。此外，Takeda G蛋白偶联受体5（TGR 5）激动剂诱导肠L细胞全身释放胰高血糖素样肽，维持血糖稳态。本研究评估了TGR 5激动剂和DPP-4抑制剂对糖尿病肝纤维化发展的联合作用。雄性糖尿病大鼠腹腔注射猪血清（PS）诱导肝纤维化，并经口给予以下药物：作为TGR 5激动剂的油酸（OA）、作为DPP-4抑制剂的阿格列汀（ANA）以及两种药物的组合。OA或ANA治疗显著改善糖尿病大鼠的血糖状态，并减弱肝内脂肪变性和脂质过氧化反应。PS诱导的肝纤维化的发展也大大抑制治疗与任何代理，和两种药物的组合增强抗纤维化作用。粪便微生物组表明，这两种药物都抑制了厚壁菌门/拟杆菌门比率的增加，这是与代谢综合征相关的生态失调的指标。此外，ANA直接抑制体外HSC增殖和促纤维化活性。总的来说，TGR 5激动剂和DPP-4抑制剂似乎是在糖尿病条件下对抗肝纤维化的新策略。
Hyperglycemia and hyperinsulinemia activate the proliferative potential of hepatic stellate cells (HSCs) and promote hepatic fibrosis. Dipeptidyl peptidase-4 (DPP-4) inhibitors, antidiabetic agents, reportedly inhibit the HSC proliferation. Additionally, Takeda G protein-coupled receptor 5 (TGR5) agonists induce the systemic release of glucagon-like peptides from intestinal L cells, which maintains glycemic homeostasis. This study assessed the combined effect of TGR5 agonist and DPP-4 inhibitor on diabetes-based liver fibrosis development. Male diabetic rats received intraperitoneal injection of porcine serum (PS) to induce liver fibrosis, and they were orally administered the following agents: oleanolic acid (OA) as a TGR5 agonist, anagliptin (ANA) as a DPP-4 inhibitor, and a combination of both agents. Treatment with OA or ANA significantly improved glycemic status and attenuated intrahepatic steatosis and lipid peroxidation in diabetic rats. PS-induced liver fibrosis development was also drastically suppressed by treatment with either agent, and the combination of both reciprocally enhanced the antifibrotic effect. Fecal microbiome demonstrated that both agents inhibited the increase in the Firmicutes/Bacteroidetes ratio, an indicator of dysbiosis related to metabolic syndromes. Furthermore, ANA directly inhibited in vitro HSC proliferative and profibrogenic activities. Collectively, TGR5 agonist and DPP-4 inhibitor appears to be a novel strategy against liver fibrosis under diabetic conditions.