BACKGROUND While the impact of metformin in hepatocytes leads to fatty acid (FA) oxidation and decreased lipogenesis, hepatic microRNAs (miRNAs) have been associated with fat overload and impaired metabolism, contributing to the pathogenesis of non-alcoholic fatty liver disease (NAFLD). METHODS We investigated the expression of hundreds of miRNAs in primary hepatocytes challenged by compounds modulating steatosis, palmitic acid and compound C (as inducers), and metformin (as an inhibitor). Then, additional hepatocyte and rodent models were evaluated, together with transient mimic miRNAs transfection, lipid droplet staining, thin-layer chromatography, quantitative lipidomes, and mitochondrial activity, while human samples outlined the translational significance of this work. FINDINGS Our results show that treatments triggering fat accumulation and AMPK disruption may compromise the biosynthesis of hepatic miRNAs, while the knockdown of the miRNA-processing enzyme DICER in human hepatocytes exhibited increased lipid deposition. In this context, the ectopic recovery of miR-30b and miR-30c led to significant changes in genes related to FA metabolism, consistent reduction of ceramides, higher mitochondrial activity, and enabled β-oxidation, redirecting FA metabolism from energy storage to expenditure. INTERPRETATION Current findings unravel the biosynthesis of hepatic miR-30b and miR-30c in tackling inadequate FA accumulation, offering a potential avenue for the treatment of NAFLD. FUNDING Instituto de Salud Carlos III (ISCIII), Govern de la Generalitat (PERIS2016), Associació Catalana de Diabetis (ACD), Sociedad Española de Diabetes (SED), Fondo Europeo de Desarrollo Regional (FEDER), Xunta de Galicia, Ministerio de Economía y Competitividad (MINECO), "La Caixa" Foundation, and CIBER de la Fisiopatología de la Obesidad y Nutrición (CIBEROBN).

中文翻译：

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调节AMPK活性和肝脂肪变性的化合物会影响维持肝细胞脂质稳态所需的microRNA的生物合成。

背景技术虽然二甲双胍在肝细胞中的作用导致脂肪酸（FA）氧化和脂肪生成减少，但肝微小RNA（miRNA）与脂肪超载和代谢受损有关，从而导致了非酒精性脂肪肝疾病（NAFLD）的发病机理。方法我们研究了原代肝细胞中数百种miRNA的表达，这些化合物受到调节脂肪变性，棕榈酸和化合物C（作为诱导剂）和二甲双胍（作为抑制剂）的化合物的挑战。然后，评估了其他肝细胞和啮齿动物模型，以及瞬时模拟miRNA转染，脂质滴染色，薄层色谱，定量脂质组和线粒体活性，而人类样品则概述了这项工作的翻译意义。结果我们的结果表明，触发脂肪堆积和AMPK破坏的治疗方法可能会损害肝miRNA的生物合成，而在人肝细胞中miRNA处理酶DICER的敲低表现出脂质沉积增加。在这种情况下，miR-30b和miR-30c的异位恢复导致与FA代谢相关的基因发生显着变化，神经酰胺含量持续降低，线粒体活性更高，并且能够进行β氧化，从而将FA代谢从能量存储转移到支出。解释目前的发现揭示了肝miR-30b和miR-30c在解决FA积累不足方面的生物合成，为NAFLD的治疗提供了潜在途径。萨洛德·卡洛斯三世基金会（ISCIII），日内瓦政府（PERIS2016），加泰罗尼亚糖尿病联盟（ACD），