Xie Zhifu, Zhang Mei, Song Qian, Cheng Long, Zhang Xinwen, Song Gaolei, Sun Xinyu, Gu Min, Zhou Chendong, Zhang Yangming, Zhu Kexin, Yin Jianpeng, Chen Xiaoyan, Li Jingya, Nan Fajun
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
University of Chinese Academy of Sciences, Beijing 100049, China.
Acta Pharm Sin B. 2023 Feb;13(2):739-753. doi: 10.1016/j.apsb.2022.06.011. Epub 2022 Jun 18.
Hepatic cholesterol accumulation is an important contributor to hypercholesterolemia, which results in atherosclerosis and cardiovascular disease (CVD). ATP-citrate lyase (ACLY) is a key lipogenic enzyme that converts cytosolic citrate derived from tricarboxylic acid cycle (TCA cycle) to acetyl-CoA in the cytoplasm. Therefore, ACLY represents a link between mitochondria oxidative phosphorylation and cytosolic lipogenesis. In this study, we developed the small molecule with an enedioic acid structural moiety as a novel ACLY inhibitor, and its CoA-conjugated form -CoA inhibited ACLY activity with an IC = 5.31 ± 1.2 μmol/L . treatment reduced lipogenesis, and increased cholesterol efflux and . was rapidly absorbed after oral administration, exhibited a higher blood exposure than that of the approved ACLY inhibitor bempedoic acid (BA) used for hypercholesterolemia. Chronic treatment in hamsters and rhesus monkeys resulted in remarkable improvement of hyperlipidemia. Once daily oral administration of for 24 weeks prevented the occurrence of atherosclerosis in ApoE mice to a greater extent than that of BA treatment. Taken together, our data suggest that inhibition of ACLY by represents a promising strategy for the treatment of hypercholesterolemia.
肝脏胆固醇蓄积是高胆固醇血症的一个重要促成因素，高胆固醇血症会导致动脉粥样硬化和心血管疾病（CVD）。ATP-柠檬酸裂解酶（ACLY）是一种关键的脂肪生成酶，它将三羧酸循环（TCA循环）产生的胞质柠檬酸转化为细胞质中的乙酰辅酶A。因此，ACLY代表了线粒体氧化磷酸化和胞质脂肪生成之间的联系。在本研究中，我们开发了一种具有烯二酸结构部分的小分子作为新型ACLY抑制剂，其辅酶A共轭形式-CoA以IC = 5.31±1.2μmol/L抑制ACLY活性。 治疗降低了脂肪生成，并增加了胆固醇流出和 。 口服给药后迅速吸收，与用于治疗高胆固醇血症的已批准ACLY抑制剂贝派地酸（BA）相比，具有更高的血药暴露量。在仓鼠和恒河猴中进行慢性 治疗导致高脂血症有显著改善。每天一次口服 持续24周，在更大程度上预防了ApoE小鼠动脉粥样硬化的发生，比BA治疗效果更好。综上所述，我们的数据表明， 抑制ACLY代表了一种有前景的高胆固醇血症治疗策略。
