Salsalate attenuates diet induced non-alcoholic steatohepatitis in mice by decreasing lipogenic and inflammatory processes
Salsalate attenuates diet induced non-alcoholic steatohepatitis in mice by decreasing lipogenic and inflammatory processes
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DOI：
10.1111/bph.13315
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发表时间：
2015-11-01
影响因子：
7.3
通讯作者：
van den Hoek, Anita M.
中科院分区：
文献类型：
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作者：
Liang, Wen;Verschuren, Lars;van den Hoek, Anita M.
背景和目的水杨酸（水杨酸）是一种抗炎药，最近发现它对葡萄糖和脂质代谢产生有益的代谢作用。尽管之前已提出其在预防和治疗多种血管疾病（包括 2 型糖尿病和代谢综合征）方面的用途，但水杨酸预防非酒精性脂肪性肝炎 (NASH) 的潜力仍不清楚。因此，本研究的目的是确定双水杨酸对 NASH 发展的影响。实验方法转基因 APOE*3Leiden。 CETP小鼠喂食高脂肪和高胆固醇饮食，含或不含双水杨酸12周和20周。评估了对体重、血浆生化变量、肝脏组织学和肝脏基因表达的影响。 主要结果水杨酸盐可预防体重增加，改善血脂异常和胰岛素抵抗，并改善饮食诱发的 NASH，如减少肝脏微泡和大泡脂肪变性、减少肝脏炎症和减少纤维化的发展所示。水杨酸通过增加 β-氧化和减少脂肪生成来影响脂质代谢，如激活 PPAR-α、PPAR-γ 共激活剂 1β、RXR-α 以及抑制转录因子 MLXIPL/ChREBP 控制的基因所示。通过下调 NF-κ B 通路来减少炎症，通过下调 TGF-β 信号传导来阻止纤维化的发展。结论和意义水杨酸对 NASH 的发生和纤维化的进展具有预防作用。这些数据表明水杨酸在预防 NASH 方面的临床应用。
BACKGROUND AND PURPOSESalsalate (salicylsalicylic acid) is an anti-inflammatory drug that was recently found to exert beneficial metabolic effects on glucose and lipid metabolism. Although its utility in the prevention and management of a wide range of vascular disorders, including type 2 diabetes and metabolic syndrome has been suggested before, the potential of salsalate to protect against non-alcoholic steatohepatitis (NASH) remains unclear. The aim of the present study was therefore to ascertain the effects of salsalate on the development of NASH.EXPERIMENTAL APPROACHTransgenic APOE*3Leiden. CETP mice were fed a high-fat and high-cholesterol diet with or without salsalate for 12 and 20 weeks. The effects on body weight, plasma biochemical variables, liver histology and hepatic gene expression were assessed.KEY RESULTSSalsalate prevented weight gain, improved dyslipidemia and insulin resistance and ameliorated diet-induced NASH, as shown by decreased hepatic microvesicular and macrovesicular steatosis, reduced hepatic inflammation and reduced development of fibrosis. Salsalate affected lipid metabolism by increasing beta-oxidation and decreasing lipogenesis, as shown by the activation of PPAR-alpha, PPAR-gamma co-activator 1 beta, RXR-alpha and inhibition of genes controlled by the transcription factor MLXIPL/ChREBP. Inflammation was reduced by down-regulation of the NF-kappa B pathway, and fibrosis development was prevented by down-regulation of TGF-beta signalling.CONCLUSIONS AND IMPLICATIONSSalsalate exerted a preventive effect on the development of NASH and progression to fibrosis. These data suggest a clinical application of salsalate in preventing NASH.