Bahirat Umakant Ashok, Talwar Rashmi, Shenoy Rekha Raghuveer, Nemmani Kumar V S, Goel Rajan Naresh
Department of Pharmacology, Novel Drug Discovery and Development (NDDD), Lupin Limited (Research Park), 46A/47A, Village Nande, Taluka Mulshi, Pune, Maharashtra, 412115, India.
Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, Karnataka, 576104, India.
Med Mol Morphol. 2019 Mar;52(1):36-43. doi: 10.1007/s00795-018-0200-4. Epub 2018 Jun 29.
Non-alcoholic steatohepatitis (NASH) is characterized by the presence of hepatic steatosis, oxidative stress, inflammation, and hepatocyte injury with or without fibrosis. In this study, we explored the effect of APD668, a GPR119 agonist alone or in combination with linagliptin, a DPPIV inhibitor, on the progression of steatohepatitis in a murine model of NASH with diabetes. A novel NASH model with diabetes was generated by administration of streptozotocin injection to neonatal C57BL/6 mice (2-3 days old) combined with a high-fat diet feeding from the age of 4 weeks. The plasma biochemical parameters, oxidative stress, inflammation and histopathological changes were assessed. APD668 alone showed reduction in plasma glucose (- 39%, P < 0.05) and triglyceride level (- 26%) whereas a combined treatment of APD668 with linagliptin resulted in a more pronounced reduction in plasma glucose (- 52%, P < 0.001) and triglyceride (- 50%, P < 0.05) in NASH mice. In addition, co-administration of APD668 with linagliptin demonstrated a significant decrease in hepatic triglyceride, NAS score, hepatic TBARS and hepatic TNF-α in NASH mice with diabetes. These findings suggest that GPR119 receptor agonists in combination with DPPIV inhibitors may represent a promising therapeutic strategy for the treatment of NASH.
非酒精性脂肪性肝炎（NASH）的特征是存在肝脂肪变性、氧化应激、炎症以及伴有或不伴有纤维化的肝细胞损伤。在本研究中，我们探究了GPR119激动剂APD668单独使用或与二肽基肽酶IV（DPPIV）抑制剂利格列汀联合使用对患有糖尿病的NASH小鼠模型中脂肪性肝炎进展的影响。通过对新生C57BL/6小鼠（2 - 3日龄）注射链脲佐菌素并从4周龄开始给予高脂饮食，建立了一种新的糖尿病NASH模型。评估了血浆生化参数、氧化应激、炎症和组织病理学变化。单独使用APD668可使血浆葡萄糖水平降低（-39%，P < 0.05）和甘油三酯水平降低（-26%），而APD668与利格列汀联合治疗可使患有NASH的小鼠血浆葡萄糖水平更显著降低（-52%，P < 0.001）和甘油三酯水平降低（-50%，P < 0.05）。此外，在患有糖尿病的NASH小鼠中，APD668与利格列汀联合给药可使肝甘油三酯、NAS评分、肝脏丙二醛和肝脏肿瘤坏死因子-α显著降低。这些发现表明，GPR119受体激动剂与DPPIV抑制剂联合使用可能是治疗NASH的一种有前景的治疗策略。
