Lipotoxicity-induced cell death plays a detrimental role in the pathogenesis of metabolic diseases. Ferulic acid, widespread in plant-based food, is a radical scavenger with multiple bioactivities. However, the benefits of ferulic acid against hepatic lipotoxicity are largely unclear. Here, we investigated the protective effect of ferulic acid against palmitate-induced lipotoxicity and clarified its potential mechanisms in AML-12 hepatocytes. AML-12 mouse hepatocytes were exposed to palmitate to mimic lipotoxicity. Different doses (25, 50, and 100 μM) of ferulic acid were added 2 h before palmitate treatment. Cell viability was detected by measuring lactate dehydrogenase release, nuclear staining, and the expression of cleaved-caspase-3. Intracellular reactive oxygen species content and mitochondrial membrane potential were analysed by fluorescent probes. The potential mechanisms were explored by molecular biological methods, including Western blotting and quantitative real-time PCR, and were further verified by siRNA interference. Our data showed that ferulic acid significantly inhibited palmitate-induced cell death, rescued mitochondrial membrane potential, reduced reactive oxygen species accumulation, and decreased inflammatory factor activation, including IL-6 and IL-1beta. Ferulic acid significantly stimulated autophagy in hepatocytes, whereas autophagy suppression blocked the protective effect of ferulic acid against lipotoxicity. Ferulic acid-activated autophagy, which was triggered by SIRT1 upregulation, was mechanistically involved in its anti-lipotoxicity effects. SIRT1 silencing blocked most beneficial changes induced by ferulic acid. We demonstrated that the phytochemical ferulic acid, which is found in plant-based food, protected against hepatic lipotoxicity, through the SIRT1/autophagy pathway. Increased intake of ferulic acid-enriched food is a potential strategy to prevent and/or improve metabolic diseases with lipotoxicity as a typical pathological feature.

中文翻译：

---

阿魏酸通过SIRT1调节的自噬途径减轻脂毒性诱导的肝细胞死亡，并独立于AML-12肝细胞中的AMPK和Akt

脂毒性诱导的细胞死亡在代谢疾病的发病机理中起有害作用。阿魏酸广泛存在于植物性食品中，是一种具有多种生物活性的自由基清除剂。但是，阿魏酸抗肝脂质毒性的益处在很大程度上尚不清楚。在这里，我们调查了阿魏酸对棕榈酸酯诱导的脂毒性的保护作用，并阐明了其在AML-12肝细胞中的潜在机制。将AML-12小鼠肝细胞暴露于棕榈酸酯以模拟脂毒性。棕榈酸酯处理前2小时，添加不同剂量（25、50和100μM）的阿魏酸。通过测量乳酸脱氢酶的释放，核染色和裂解的caspase-3的表达来检测细胞活力。用荧光探针分析细胞内活性氧的含量和线粒体膜电位。通过分子生物学方法（包括蛋白质印迹和定量实时PCR）探索了潜在的机制，并通过siRNA干扰进行了进一步验证。我们的数据表明，阿魏酸能显着抑制棕榈酸酯诱导的细胞死亡，挽救线粒体膜电位，减少活性氧的积累，并减少包括IL-6和IL-1beta在内的炎症因子的活化。阿魏酸显着刺激肝细胞中的自噬，而自噬抑制则阻止了阿魏酸抗脂毒性的保护作用。SIRT1上调触发的阿魏酸激活自噬从机械上参与了其抗脂毒性作用。SIRT1沉默阻止了阿魏酸引起的最有益的变化。我们证明了在植物性食品中发现的植物化学阿魏酸可通过SIRT1 /自噬途径保护免受肝脂毒性。富含阿魏酸的食物摄入量增加是预防和/或改善以脂毒性为典型病理特征的代谢疾病的潜在策略。