Sanjay K V, Vishwakarma Santosh, Zope Bharat Ravindra, Mane Vishal Subhash, Mohire Sunil, Dhakshinamoorthy Saravanakumar
Discovery Biology and Pharmacology, Jubilant Biosys Ltd, Bangalore, 560022, India.
Curr Res Pharmacol Drug Discov. 2021 Sep 4;2:100051. doi: 10.1016/j.crphar.2021.100051. eCollection 2021.
Non-alcoholic fatty liver disease (NAFLD) and Non-alcoholic steatohepatitis (NASH) are chronic liver disorders, the prevalence of which is increasing worldwide. Long term High Fat Diet (HFD) induced NASH animal models closely mimic the characteristics of human NASH and hence used by investigators as a model system for studying the mechanism of action of new drugs. Bempedoic acid (ETC-1002), a ATP citrate lyase (ACLY) inhibitor that lowers the LDL cholesterol was recently approved by US FDA for the treatment of heterozygous familial hypercholesterolemia (HeFH) and established atherosclerotic cardiovascular disease (ASCVD). ACLY is one of the genes modulated in NASH patients and hence we studied the effect of ACLY inhibitor Bempedoic acid in long term HFD induced NASH animal model to understand the pharmacological benefits and the associated mechanism of action of this newly approved drug in NASH. Mice fed with 60% Kcal High Fat Diet for 32 weeks were used for the study and the animals were given Bempedoic acid for 5 weeks at doses of 10 mg kg, po, qd, and 30 mg kg, po, qd. Bempedoic acid treatment resulted in inhibition of body weight gain and improved the glycemic control. Bempedoic acid treated group showed statistically significant reduction in plasma ALT, AST, hepatic triglycerides (TG) and total cholesterol (TC), along with statistically significant reduction in steatosis score by histological analysis. Hepatic gene expression analysis showed significant reduction in inflammatory and fibrotic genes such as & . Histological analysis showed significant improvement in NAS score. Overall, Bempedoic acid alleviated HFD induced Non-Alcoholic Steatohepatitis through inhibition of body weight gain, improvement in glycemic control, reduction of hepatic triglycerides & total cholesterol, modulation of inflammatory & fibrotic genes, and improvement in NAS score. Hence, Bempedoic acid can be a potential therapeutic option for metabolic syndrome and NASH.
非酒精性脂肪性肝病（NAFLD）和非酒精性脂肪性肝炎（NASH）是慢性肝脏疾病，其在全球范围内的患病率正在上升。长期高脂饮食（HFD）诱导的NASH动物模型密切模拟人类NASH的特征，因此被研究人员用作研究新药作用机制的模型系统。贝派地酸（ETC-1002）是一种ATP柠檬酸裂解酶（ACLY）抑制剂，可降低低密度脂蛋白胆固醇，最近被美国食品药品监督管理局（FDA）批准用于治疗杂合子家族性高胆固醇血症（HeFH）和已确诊的动脉粥样硬化性心血管疾病（ASCVD）。ACLY是在NASH患者中被调节的基因之一，因此我们在长期HFD诱导的NASH动物模型中研究了ACLY抑制剂贝派地酸的作用，以了解这种新批准药物在NASH中的药理益处和相关作用机制。用含60%千卡高脂饮食喂养32周的小鼠用于该研究，动物以10毫克/千克、口服、每日一次和30毫克/千克、口服、每日一次的剂量给予贝派地酸5周。贝派地酸治疗导致体重增加受到抑制，并改善了血糖控制。贝派地酸治疗组的血浆谷丙转氨酶（ALT）、谷草转氨酶（AST）、肝甘油三酯（TG）和总胆固醇（TC）在统计学上显著降低，通过组织学分析，脂肪变性评分也在统计学上显著降低。肝脏基因表达分析显示炎症和纤维化基因如&显著减少。组织学分析显示NAS评分有显著改善。总体而言，贝派地酸通过抑制体重增加、改善血糖控制、降低肝甘油三酯和总胆固醇、调节炎症和纤维化基因以及改善NAS评分，减轻了HFD诱导的非酒精性脂肪性肝炎。因此，贝派地酸可能是代谢综合征和NASH的一种潜在治疗选择。
