Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara 634-8521, Japan.
Sanwa Kagaku Kenkyusho, Co., Ltd., Nagoya, Aichi 461-8631, Japan.
Cells. 2019 Sep 26;8(10):1153. doi: 10.3390/cells8101153.
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.
高血糖和高胰岛素血症激活肝星状细胞（HSCs）的增殖潜能，并促进肝纤维化。二肽基肽酶-4（DPP-4）抑制剂是一种抗糖尿病药物，据报道可抑制 HSC 的增殖。此外，武田 G 蛋白偶联受体 5（TGR5）激动剂可诱导肠 L 细胞释放胰高血糖素样肽，从而维持血糖稳态。本研究评估了 TGR5 激动剂和 DPP-4 抑制剂联合对糖尿病相关肝纤维化发展的影响。雄性糖尿病大鼠接受腹腔注射猪血清（PS）以诱导肝纤维化，并给予以下药物口服治疗：齐墩果酸（OA）作为 TGR5 激动剂，阿那格列汀（ANA）作为 DPP-4 抑制剂，以及两者联合用药。OA 或 ANA 治疗可显著改善血糖状态，并减轻糖尿病大鼠的肝内脂肪变性和脂质过氧化。PS 诱导的肝纤维化发展也被两种药物中的任意一种治疗显著抑制，并且两者的联合使用相互增强了抗纤维化作用。粪便微生物组表明，两种药物均抑制了厚壁菌门/拟杆菌门比值的增加，这是与代谢综合征相关的肠道菌群失调的指标。此外，ANA 可直接抑制体外 HSC 的增殖和促纤维化活性。综上所述，TGR5 激动剂和 DPP-4 抑制剂似乎是糖尿病患者对抗肝纤维化的一种新策略。
