Non-alcoholic fatty liver disease (NAFLD), characterized by hepatic steatosis, is a common metabolic liver disease worldwide. Currently, satisfactory drugs for NAFLD treatment remain lacking. Obesity and diabetes are the leading causes of NAFLD, and compounds with anti-obesity and anti-diabetic activities are considered suitable candidates for treating NAFLD. In this study, biochemical and histological assays revealed that a natural lignan schisanhenol (SAL) effectively decreased lipid accumulation and improved hepatic steatosis in free fatty acid (FFA)-treated HepG2 cells and high-fat diet (HFD)-induced NAFLD mice. Further, molecular analyses, microRNA (miRNA)-seq, and bioinformatics analyses revealed that SAL may improve NAFLD by targeting the miR-802/adenosine monophosphate-activated protein kinase (AMPK) pathway. Liver-specific overexpression of miR-802 in NAFLD mice significantly impaired SAL-mediated liver protection and decreased the protein levels of phosphorylated (p)-AMPK and PRKAB1. Dual-luciferase assay analysis further confirmed that miR-802 inhibits hepatic AMPK expression by binding to the 3' untranslated region of mouse or human . Additionally, genetic silencing of blocked SAL-induced AMPK pathway activation in FFA-treated HepG2 cells. The results demonstrate that SAL is an effective drug candidate for treating NAFLD through regulating miR-802/AMPK-mediated lipid metabolism.

中文翻译：

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五味子酚通过抑制 miR-802 激活 AMPK 介导的肝脂质代谢调节来改善非酒精性脂肪肝


非酒精性脂肪肝病（NAFLD）以肝脂肪变性为特征，是世界范围内常见的代谢性肝病。目前，NAFLD治疗尚缺乏令人满意的药物。肥胖和糖尿病是 NAFLD 的主要原因，具有抗肥胖和抗糖尿病活性的化合物被认为是治疗 NAFLD 的合适候选者。在这项研究中，生化和组织学检测表明，天然木脂素五味子酚 (SAL) 可以有效减少游离脂肪酸 (FFA) 处理的 HepG2 细胞和高脂饮食 (HFD) 诱导的 NAFLD 小鼠的脂质积累并改善肝脏脂肪变性。此外，分子分析、microRNA (miRNA)-seq 和生物信息学分析表明，SAL 可以通过靶向 miR-802/腺苷单磷酸激活蛋白激酶 (AMPK) 途径来改善 NAFLD。 NAFLD 小鼠肝脏特异性过度表达 miR-802 显着损害 SAL 介导的肝脏保护，并降低磷酸化 (p)-AMPK 和 PRKAB1 的蛋白水平。双荧光素酶分析进一步证实 miR-802 通过与小鼠或人的 3' 非翻译区结合来抑制肝脏 AMPK 表达。此外，在 FFA 处理的 HepG2 细胞中，基因沉默阻断了 SAL 诱导的 AMPK 通路激活。结果表明，SAL 是通过调节 miR-802/AMPK 介导的脂质代谢来治疗 NAFLD 的有效候选药物。