Gallic acid impairs fructose-driven de novo lipogenesis and ameliorates hepatic steatosis via AMPK-dependent suppression of SREBP-1/ACC/ FASN cascade
Gallic acid impairs fructose-driven de novo lipogenesis and ameliorates hepatic steatosis via AMPK-dependent suppression of SREBP-1/ACC/ FASN cascade
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没食子酸通过 AMPK 依赖性抑制 SREBP-1/ACC/FASN 级联损害果糖驱动的从头脂肪生成并改善肝脂肪变性
DOI：
10.1016/j.ejphar.2022.175457
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发表时间：
2022
影响因子：
5
通讯作者：
Zhenpeng Qiu
中科院分区：
文献类型：
--
作者：
Yuzhen Lu;Cong Zhang;Yingying Song;Liang Chen;Xin Chen;Guohua Zheng;Yuan Yang;Peng Cao;Zhenpeng Qiu
越来越多的证据表明，去新生脂肪形成是促进非酒精性脂肪性肝病（NAFLD）进展的典型特征。没食子酸（GA）是一种天然存在的酚酸，具有代谢性疾病相关的临床意义和临床前益处。本研究旨在评估GA在果糖诱导的NAFLD小鼠模型中的抗脂肪变性潜力，该模型具有肝脂肪生成表型。结果表明，GA减轻了果糖喂养小鼠的肝脏脂肪变性、氧化应激和炎症反应。从机制上讲，GA处理恢复了AMP活化蛋白激酶α（AMPKα）的磷酸化，导致促脂肪生成因子的下调，包括固醇调节元件结合蛋白-1（SREBP-1），脂肪酸合成酶（FATCH）和乙酰辅酶A羧化酶（ACC），在小鼠肝细胞和体外。此外，计算对接分析表明GA可以直接与AMPKα/β亚基相互作用以稳定其活化。这些结果表明GA通过AMPK依赖性抑制SREBP-1/ACC/Fn级联反应抑制肝脏脂肪生成来改善果糖诱导的肝脂肪变性。总之，这项研究表明，GA补充剂可能是NAFLD的一种有前途的治疗策略，特别是在肝脏脂肪生成增强的亚组中。
Accumulating evidence suggests thatde novolipogenesis is a typical characteristic facilitating nonalcoholic fatty liver disease (NAFLD) progression. Gallic acid (GA) is a naturally occurring phenolic acid with metabolic disease-related clinical significance and preclinical benefits. This study aimed to evaluate the anti-steatotic potentials of GA in a fructose-induced NAFLD mouse model featuring a hepatic lipogenic phenotype. The results revealed that GA alleviated hepatic steatosis, oxidative stress, and inflammatory response in fructose-fed mice. Mechanistically, GA treatment restored AMP-activated protein kinase α (AMPKα) phosphorylation, resulting in downregulations of pro-lipogenic factors, including sterol regulatory element binding protein-1 (SREBP-1), fatty acid synthetase (FASN), and acetyl-CoA carboxylase (ACC), in hepatocytes of mice andin vitro. Furthermore, computational docking analysis indicated that GA could directly interact with AMPKα/β subunits to stabilize its activation. These results suggest that GA ameliorates fructose-induced hepatosteatosis by restraining hepatic lipogenesisviaAMPK-dependent suppression of the SREBP-1/ACC/FASN cascade. Altogether, this study demonstrates that GA supplement may be a promising therapeutic strategy in NAFLD, especially in the subset with enhanced hepatic lipogenesis.