乙酰辅酶A羧化酶抑制剂的研究进展

非酒精性脂肪肝病是以肝细胞内脂肪过度沉积为主要特征的代谢性疾病,脂肪主要以甘油三酯的形式存在,由甘油和脂肪酸通过酯化作用形成;而且肿瘤细胞中脂肪酸的合成异常活跃,明显高于正常细胞,为肿瘤细胞旺盛的增殖、发育过程中生物膜的形成、信号分子和能量的产生提供必要的脂质底物。乙酰辅酶A羧化酶(acetyl-CoA carboxylase,ACC)是脂肪酸从头合成过程的限速酶,同时也是催化该脂肪酸合成通路中第一步反应的酶;其催化生成的产物丙二酰辅酶A亦能抑制脂肪酸的氧化。因此,ACC抑制能降低脂肪酸合成和促进脂肪酸氧化,降低体内脂肪酸的含量,进而减弱肝细胞内脂肪的堆积来达到改善非酒精性脂肪肝病;同时体内脂肪酸含量的降低使肿瘤细胞发育所必须的脂质底物得不到满足,从而能够抑制肿瘤组织的发育,所以乙酰辅酶A羧化酶抑制剂有望成为新型治疗非酒精性脂肪肝病和肿瘤的药物。本文对ACC的结构特点、作用机制及其抑制剂的研究进展进行了综述。

Research progress in acetyl-CoA carboxylase inhibitors

Non-alcoholic fatty liver disease(NAFLD)is characterized by excessive fat deposition in hepatocytes, fat accumulates mainly in the form of triglycerides, triglycerides derive from esterification of glycerol and free fatty acids; and the synthesis of fatty acid is abnormally active in tumor cells, which is significantly higher than that of normal cells, providing necessary lipid substrates for the formation of biofilms, the production of signaling molecules and energy during the proliferation and development of tumor cells. Acetyl-CoA carboxylase(ACC)is the limiting-rate enzyme of de novo lipogenesis. And it is also an enzyme that catalyzes the first step of the fatty acid synthesis pathway; its catalyzed product, malonyl-CoA, also inhibits the oxidation of fatty acids. ACC inhibition can reduce fatty acid synthesis and promote fatty acid oxidation, which reduce the amount of fatty acids in the body. Hence, attenuating fat accumulation could improve NAFLD, and reduction of fatty acid content inhibits development of tumor tissues because lipid substrates could not satisfy the requirement of cancer cells. Therefore, ACC inhibitors have potential to be the novel drugs that can treat NAFLD and cancer. The recent research progress on ACC inhibitors is reviewed in this paper.