Cardiovascular and Metabolic Drug Discovery Unit (Y.O.T., J.S., M.W.), Drug Metabolism & Pharmacokinetics Research Laboratories (S.I., K.A.), Biomolecular Research Laboratories (M.S.), and Drug Safety Research Laboratories (H.Yasu.), Takeda Pharmaceutical Company Limited, Kanagawa, Japan; and Gastroenterology Drug Discovery Unit, Takeda Pharmaceutical Company Limited, Cambridge, Massachusetts (D.M.E., H.Yash.).
Cardiovascular and Metabolic Drug Discovery Unit (Y.O.T., J.S., M.W.), Drug Metabolism & Pharmacokinetics Research Laboratories (S.I., K.A.), Biomolecular Research Laboratories (M.S.), and Drug Safety Research Laboratories (H.Yasu.), Takeda Pharmaceutical Company Limited, Kanagawa, Japan; and Gastroenterology Drug Discovery Unit, Takeda Pharmaceutical Company Limited, Cambridge, Massachusetts (D.M.E., H.Yash.)
J Pharmacol Exp Ther. 2021 Nov;379(3):280-289. doi: 10.1124/jpet.121.000786. Epub 2021 Sep 17.
Acetyl-CoA carboxylase (ACC) 1 and ACC2 are essential rate-limiting enzymes that synthesize malonyl-CoA (M-CoA) from acetyl-CoA. ACC1 is predominantly expressed in lipogenic tissues and regulates the de novo lipogenesis flux. It is upregulated in the liver of patients with nonalcoholic fatty liver disease (NAFLD), which ultimately leads to the formation of fatty liver. Therefore, selective ACC1 inhibitors may prevent the pathophysiology of NAFLD and nonalcoholic steatohepatitis (NASH) by reducing hepatic fat, inflammation, and fibrosis. Many studies have suggested ACC1/2 dual inhibitors for treating NAFLD/NASH; however, reports on selective ACC1 inhibitors are lacking. In this study, we investigated the effects of compound-1, a selective ACC1 inhibitor for treating NAFLD/NASH, using preclinical in vitro and in vivo models. Compound-1 reduced M-CoA content and inhibited the incorporation of [C] acetate into fatty acids in HepG2 cells. Additionally, it reduced hepatic M-CoA content and inhibited de novo lipogenesis in C57BL/6J mice after a single dose. Furthermore, compound-1 treatment of 8 weeks in Western diet-fed melanocortin 4 receptor knockout mice-NAFLD/NASH mouse model-improved liver hypertrophy and reduced hepatic triglyceride content. The reduction of hepatic M-CoA by the selective ACC1 inhibitor was highly correlated with the reduction in hepatic steatosis and fibrosis. These findings support further investigations of the use of this ACC1 inhibitor as a new treatment of NFLD/NASH. SIGNIFICANCE STATEMENT: This is the first study to demonstrate that a novel selective inhibitor of acetyl-CoA carboxylase (ACC) 1 has anti-nonalcoholic fatty liver disease (NAFLD) and anti-nonalcoholic steatohepatitis (NASH) effects in preclinical models. Treatment with this compound significantly improved hepatic steatosis and fibrosis in a mouse model. These findings support the use of this ACC1 inhibitor as a new treatment for NAFLD/NASH.
乙酰辅酶 A 羧化酶 (ACC)1 和 ACC2 是合成丙二酰辅酶 A (M-CoA) 的必需限速酶，由乙酰辅酶 A 合成。ACC1 主要在脂肪生成组织中表达，调节从头脂肪生成通量。在非酒精性脂肪性肝病 (NAFLD) 患者的肝脏中，ACC1 上调，最终导致脂肪肝的形成。因此，选择性 ACC1 抑制剂可通过减少肝脂肪、炎症和纤维化来预防 NAFLD 和非酒精性脂肪性肝炎 (NASH) 的病理生理学。许多研究表明，使用 ACC1/2 双重抑制剂治疗 NAFLD/NASH；然而，缺乏选择性 ACC1 抑制剂的报道。在这项研究中，我们使用临床前体外和体内模型研究了用于治疗 NAFLD/NASH 的选择性 ACC1 抑制剂化合物 1 的作用。化合物 1 降低了 M-CoA 含量，并抑制了 [C] 乙酸盐在 HepG2 细胞中掺入脂肪酸。此外，它在单次给药后降低了 C57BL/6J 小鼠的肝 M-CoA 含量并抑制了从头脂肪生成。此外，化合物 1 在 Western 饮食喂养的黑皮质素 4 受体敲除小鼠 -NAFLD/NASH 小鼠模型中治疗 8 周，改善了肝肥大并降低了肝甘油三酯含量。选择性 ACC1 抑制剂降低肝 M-CoA 与降低肝脂肪变性和纤维化高度相关。这些发现支持进一步研究使用这种 ACC1 抑制剂作为治疗非酒精性脂肪肝疾病 (NFLD)/非酒精性脂肪性肝炎 (NASH) 的新方法。意义声明：这是第一项证明新型乙酰辅酶 A 羧化酶 (ACC)1 抑制剂在临床前模型中具有抗非酒精性脂肪性肝病 (NAFLD) 和抗非酒精性脂肪性肝炎 (NASH) 作用的研究。这种化合物的治疗显著改善了小鼠模型中的肝脂肪变性和纤维化。这些发现支持使用这种 ACC1 抑制剂作为治疗 NAFLD/NASH 的新方法。
