Trimetazidine improves hepatic lipogenesis and steatosis in non-alcoholic fatty liver disease via AMPK-ChREBP pathway
Trimetazidine improves hepatic lipogenesis and steatosis in non-alcoholic fatty liver disease via AMPK-ChREBP pathway
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DOI：
10.3892/mmr.2020.11309
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发表时间：
2020-09-01
影响因子：
3.4
通讯作者：
Liu, Xingde
中科院分区：
文献类型：
--
作者：
Zhang, Ying;Li, Can;Liu, Xingde
临床研究表明曲美他嗪（TMZ）与他汀类药物具有协同降血脂作用，但其机制尚不清楚。本研究旨在探讨TMZ在非酒精性脂肪性肝病（NAFLD）中的作用。通过研究TMZ对NAFLD的治疗，发现高脂饮食（HFD）小鼠在几个生理指标方面表现出显著变化，包括体重、血脂和葡萄糖耐量。值得注意的是，HFD小鼠中的肝细胞大疱性脂肪变性和纤维化通过8周的TMZ治疗大大减弱。本研究的结果还表明，与HFD组相比，HFD + TMZ组的碳水化合物反应元件结合蛋白（ChREBP）、脂肪酸合成酶和乙酰辅酶A羧化酶的表达均显著降低。为了证实这一假设，在体外，棕榈酸酯处理的肝癌细胞系（HepG 2）和TMZ处理的HepG 2细胞中获得了类似的结果。此外，TMZ显著上调AMP活化蛋白激酶（AMPK）信号通路并降低细胞中叉头框O 1（FOXO 1）的表达，而AMPK抑制剂化合物C消除了TMZ控制的这些作用。本研究报告，敲低FOXO 1表达的FOXO 1小干扰RNA导致ChREBP蛋白表达和转录后活性的降低。总之，据作者所知，本研究首次揭示了TMZ在肝脂肪变性中的新作用; TMZ通过激活AMPK-FOXO 1通路改善了ChREBP诱导的novolipogenesis。
Clinical studies have demonstrated that trimetazidine (TMZ) possesses a synergistic hypolipidemic effect together with statins, but the underlying mechanism remains to be elucidated. The present study aimed to investigate the role of TMZ in non-alcoholic fatty liver disease (NAFLD). By investigating the TMZ treatment of NAFLD, it was identified that high-fat diet (HFD) mice exhibit significant changes in several physiologic indices, including body weight, plasma lipids and glucose tolerance. Notably, hepatocyte bullous steatosis and fibrosis in HFD mice are greatly attenuated by 8 weeks of TMZ treatments. The results of the present study also indicated that the expression of carbohydrate-responsive element-binding protein (ChREBP), fatty acid synthase and acetyl-CoA carboxylase were all significantly reduced in the HFD + TMZ group compared with the HFD group. In order to confirm the hypothesisin vitro, the palmitate-treated liver cancer cell line (HepG2) was employed and similar results were obtained in TMZ-treated HepG2 cells. Furthermore, TMZ markedly upregulated the AMP-activated protein kinase (AMPK) signaling pathway and reduced the expression of forkhead box O1 (FOXO1) in the cells, while these effects controlled by TMZ were abolished by the AMPK inhibitor Compound C. The present study reported that knockdown of FOXO1 expression by FOXO1 small interfering RNA resulted in a reduction of ChREBP protein expression and post-transcriptional activity. In summary, for the first time, to the best of the authors' knowledge, the present study revealed a novel role of TMZ in hepatic steatosis; TMZ ameliorated ChREBP-inducedde novolipogenesis by activating the AMPK-FOXO1 pathway.