Li Jingjing, Chen Changmai, Zhang Wei, Bi Jing'ai, Yang Guang, Li Erguang
State Key Laboratory of Pharmaceutical Biotechnology, Medical School, Nanjing University, Nanjing, China.
Jiangsu Key Laboratory of Molecular Medicine, Medical School, Nanjing University, Nanjing, China.
Basic Clin Pharmacol Toxicol. 2021 Mar;128(3):394-409. doi: 10.1111/bcpt.13535. Epub 2020 Nov 27.
Salsalate, an ester formed by 2 salicylic acid molecules, has beneficial effect against metabolic disorders in clinical trials and in animal studies. This study focused on the mechanistic aspects of salsalate activity against non-alcoholic fatty liver disease (NAFLD). Using high-fat diet (HFD) fed mice, we showed that salsalate treatment decreased body-weight gains, reduced white adipose tissue mass and improved glycaemic control. Mice in salsalate-treated group also had reduced obese adipose tissue and hepatic macrophage infiltration and inflammation and adipogenesis gene expression. Histology analysis revealed predominant decreases in hepatosteatosis, including both macrovesicular and microvesicular steatoses. The treatment reversed AMPK activity repression that was accompanied by reduced caspase-6 activity and cleavage. Enzymatic assay and cell culture studies showed that salsalate promoted AMPK activation by directly activating AMPK. This study links salsalate effect against metabolic disorders to its activity on reversion of AMPK repression in NAFLD mice and on suppression of adipogenic gene induction.
双水杨酸酯是由2个水杨酸分子形成的一种酯，在临床试验和动物研究中对代谢紊乱具有有益作用。本研究聚焦于双水杨酸酯抗非酒精性脂肪性肝病（NAFLD）活性的作用机制。使用高脂饮食（HFD）喂养的小鼠，我们发现双水杨酸酯治疗可降低体重增加、减少白色脂肪组织量并改善血糖控制。双水杨酸酯治疗组的小鼠还减少了肥胖脂肪组织和肝脏巨噬细胞浸润以及炎症和脂肪生成基因表达。组织学分析显示肝脂肪变性明显减轻，包括大泡性和小泡性脂肪变性。该治疗逆转了伴随半胱天冬酶-6活性和切割减少的AMPK活性抑制。酶活性测定和细胞培养研究表明，双水杨酸酯通过直接激活AMPK促进AMPK活化。本研究将双水杨酸酯对代谢紊乱的作用与其对NAFLD小鼠中AMPK抑制的逆转活性以及对脂肪生成基因诱导的抑制联系起来。
