乙酰辅酶A羧化酶抑制剂联合非诺贝特对小鼠非酒精性脂肪肝的治疗效果

摘要 目的：探讨乙酰辅酶A羧化酶抑制剂（MK-4074）联合非诺贝特对小鼠非酒精性脂肪肝（NAFLD）的脂质含量以及肝功能的改善效果。方法：20只C57BL/6小鼠给予60%高脂饲料连续喂养8周构建NAFLD小鼠模型后,随机分为安慰剂组、MK-4074组、非诺贝特组以及MK-4074联合非诺贝特治疗组,每组各5只,继续高脂喂养并分别给予安慰剂（Placebo）、MK-4074（10 mg/kg/天）、非诺贝特（30 mg/kg/天）、以及MK-4074（10 mg/kg/天）+ 非诺贝特（30 mg/kg/天）治疗持续8周。治疗结束后对小鼠体重、肝指数、肝脏脂质含量、肝功能以及肝脏病理和肝脏中性粒细胞和巨噬细胞浸润情况进行分析。结果：与安慰剂组相比,单用MK-4074治疗可显著降低肝指数、肝脏甘油三酯（TG）、胆固醇（TC）、非酯化脂肪酸（NEFA）的含量以及血清ALT和AST水平,而对小鼠体重和血清TC没有显著影响;单用非诺贝特可显著降低小鼠体重,肝脏TG、TC、NEFA以及血清TG、 ALT和AST水平,对小鼠的肝指数、血清TC没有显著影响;而MK-4074与非诺贝特联合治疗可显著降低小鼠体重、肝脏TG、TC、NEFA,以及血清TG、ALT和AST水平,降低肝脏脂质积累以及中性粒细胞与巨噬细胞浸润,效果优于MK-4074或非诺贝特单药治疗。结论：MK-4074联合非诺贝特可显著减少NAFLD小鼠肝脏的脂质含量,改善肝功能。

Therapeutic Effect of Acetyl CoA Carboxylase Inhibitor Combined with Fenofibrate on Nonalcoholic Fatty Liver Mouse Model

ABSTRACT Objective: To explore the effect of acetyl CoA carboxylase inhibitor (MK-4074) combined with fenofibrate on hepatic lipid content and liver function in NAFLD mouse model. Methods: A total of 20 C57BL/6 mice were fed with high-fat diet(HFD) for 8 weeks to construct NAFLD mouse models, and they were randomly divided into four groups(placebo, MK-4074, fenofibrate and MK-4074 combined with fenofibrate. After 8-week HFD feeding, they were treated respectively with placebo, MK-4074 (10 mg/kg/day), fenofibrate (30 mg/kg/day) and MK-4074 (10 mg/kg/day) combined with fenofibrate (30 mg/kg/day) for additional 8 weeks on the same diet. The body weight, liver/body ratio, hepatic lipid content, liver function and hepatic pathology as well as infiltration of neutrophil and macrophage of mice were analyzed to compare the effect of treatment. Results: Compared with the placebo group, MK-4074 treatment can significantly reduce liver/body ratio, hepatic triglyceride (TG), cholesterol (TC) and non-esterified fatty acid (NEFA) content as well as serum ALT and AST levels, but has no significant effect on body weight and serum TC levels. Fenofibrate treatment can significantly reduce the body weight of mice, hepatic TG, TC, and NEFA as well as the levels of serum TG, ALT and AST, while the liver/body ratio of mice and serum TC levels were not affected. The combined treatment of MK-4074 and fenofibrate can significantly reduce the body weight of mice, hepatic TG, TC and NEFA contents as well as serum TG, ALT and AST levels, and pathologically improve hepatic lipid accumulation and infiltration of neutrophil and macrophage of mice, and the effect of combined therapy is better than monotherapy of MK-4074 or fenofibrate. Conclusion: MK-4074 combined with fenofibrate can significantly reduce the lipid content in the liver of NAFLD mice, and improve liver function.