Liu Tianya, Gou Lingshan, Yan Shirong, Huang Tonghui
Department of Pharmacy, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu 221004, P.R. China.
Jiangsu Province Key Laboratory of Anesthesiology, School of Anesthesiology, Xuzhou Medical University, Xuzhou, Jiangsu 221004, P.R. China.
Exp Ther Med. 2020 Jul;20(1):521-529. doi: 10.3892/etm.2020.8700. Epub 2020 Apr 29.
Acetyl-coenzyme A carboxylase (ACC) is a critical regulator of fatty acid metabolism and represents a promising therapeutic target for metabolic diseases, including obesity, type 2 diabetes and non-alcoholic fatty liver disease. Recently, a novel ACC inhibitor, PP-7a, was developed by our group by utilizing a structure-based drug design. In the present study, the pharmacological effects of PP-7a on the metabolic dysregulation in mice with high-fat diet (HFD)-induced obesity and the underlying mechanisms were investigated. The inhibitory effect on ACC activities was confirmed by assessing the level of malonyl-CoA, a product synthesized by the catalyzation of ACC. Following 16 weeks of being fed an HFD, the mice were administered PP-7a (15, 45 or 75 mg/kg) for 4 weeks. The effects of PP-7a on weight gain, glucose intolerance, hepatic lipid accumulation and the increase of serum triglyceride (TG), total cholesterol (TC) and free fatty acids (FFA) in mice were assessed. CP-640186 was used as a positive control drug and administered in the same manner as PP-7a. Chronic administration of PP-7a lowered the malonyl-CoA levels in liver and heart tissues of mice in the HFD group. In addition, HFD-induced weight gain and glucose intolerance were improved by PP-7a treatment in the mice fed the HFD. Furthermore, PP-7a suppressed hepatic lipid accumulation and the increase in TG, TC and FFA levels. Taken together, these results suggest that ACC inhibition by PP-7a may have a beneficial effect on metabolic dysregulation in obese mice.
乙酰辅酶A羧化酶（ACC）是脂肪酸代谢的关键调节因子，是包括肥胖症、2型糖尿病和非酒精性脂肪性肝病在内的代谢性疾病的一个有前景的治疗靶点。最近，我们小组利用基于结构的药物设计开发了一种新型ACC抑制剂PP-7a。在本研究中，研究了PP-7a对高脂饮食（HFD）诱导的肥胖小鼠代谢失调的药理作用及其潜在机制。通过评估丙二酰辅酶A（ACC催化合成的一种产物）的水平来确认对ACC活性的抑制作用。在给予高脂饮食16周后，给小鼠施用PP-7a（15、45或75mg/kg），持续4周。评估PP-7a对小鼠体重增加、葡萄糖不耐受、肝脏脂质积累以及血清甘油三酯（TG）、总胆固醇（TC）和游离脂肪酸（FFA）升高的影响。CP-640186用作阳性对照药物，并以与PP-7a相同的方式给药。长期施用PP-7a可降低高脂饮食组小鼠肝脏和心脏组织中的丙二酰辅酶A水平。此外，在喂食高脂饮食的小鼠中，PP-7a治疗改善了高脂饮食诱导的体重增加和葡萄糖不耐受。此外，PP-7a抑制了肝脏脂质积累以及TG、TC和FFA水平的升高。综上所述，这些结果表明PP-7a抑制ACC可能对肥胖小鼠的代谢失调具有有益作用。
