Hyperuricemia is a major risk for non-alcoholic fatty liver disease. However, the mechanisms for this phenomenon are not fully understood. This study aimed to investigate whether microRNAs mediated the pathogenic effects of uric acid on non-alcoholic fatty liver disease. Microarray was used to determine the hepatic miRNA expression profiles of male C57BL/6 mice fed on standard chow diet, high fat diet (HFD), and HFD combined with uric acid-lowering therapy by allopurinol. We validated the expression of the most significant differentially expressed microRNAs and explored its role and downstream target in uric acid-induced hepatocytes lipid accumulation. Microarray analysis and subsequent validation showed that miR-149-5p was significantly up-regulated in the livers of HFD-fed mice, while the expression was down-regulated by allopurinol therapy. MiR-149-5p expression was also significantly up-regulated in uric acid-stimulated hepatocytes. Over-expression of miR-149-5p significantly aggregated uric acid-induced triglyceride accumulation in hepatocytes, while inhibiting miR-149-5p ameliorated the triglyceride accumulation. Luciferase report assay confirmed that FGF21 is a target gene of miR-149-5p. Silencing FGF21 abolished the ameliorative effects of miR-149-5p inhibitor on uric acid-induced hepatocytes lipid accumulation, while overexpression of FGF21 prevented the lipid accumulation induced by miR-149-5p mimics. Uric acid significantly up-regulated the expression of miR-149-5p in hepatocytes and induced hepatocytes lipid accumulation via regulation of miR-149-5p/FGF21 axis.

中文翻译：

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尿酸通过调节miR-149-5p / FGF21轴诱导肝细胞脂质蓄积

高尿酸血症是非酒精性脂肪肝疾病的主要风险。但是，这种现象的机制尚未完全了解。这项研究旨在调查microRNA是否介导尿酸对非酒精性脂肪肝的致病作用。使用微阵列测定以标准食物，高脂饮食（HFD）和HFD结合别嘌呤醇降低尿酸的疗法喂养的雄性C57BL / 6小鼠的肝miRNA表达谱。我们验证了最显着差异表达的microRNA的表达，并探讨了其在尿酸诱导的肝细胞脂质积累中的作用和下游靶标。微阵列分析和随后的验证表明，在喂食HFD的小鼠肝脏中miR-149-5p明显上调，而别嘌呤醇治疗则下调了其表达。在尿酸刺激的肝细胞中，MiR-149-5p表达也显着上调。miR-149-5p的过表达显着聚集了尿酸诱导的肝细胞甘油三酸酯积累，而抑制miR-149-5p则改善了甘油三酸酯积累。萤光素酶报告检测证实FGF21是miR-149-5p的靶基因。沉默FGF21消除了miR-149-5p抑制剂对尿酸诱导的肝细胞脂质蓄积的改善作用，而FGF21的过表达阻止了miR-149-5p模拟物诱导的脂质蓄积。尿酸通过上调miR-149-5p / FGF21轴显着上调miR-149-5p在肝细胞中的表达并诱导肝细胞脂质蓄积。miR-149-5p的过表达显着聚集了尿酸诱导的肝细胞甘油三酸酯积累，而抑制miR-149-5p则改善了甘油三酸酯积累。萤光素酶报告检测证实FGF21是miR-149-5p的靶基因。沉默FGF21消除了miR-149-5p抑制剂对尿酸诱导的肝细胞脂质蓄积的改善作用，而FGF21的过表达阻止了miR-149-5p模拟物诱导的脂质蓄积。尿酸通过上调miR-149-5p / FGF21轴显着上调miR-149-5p在肝细胞中的表达并诱导肝细胞脂质蓄积。miR-149-5p的过表达显着聚集了尿酸诱导的肝细胞甘油三酸酯积累，而抑制miR-149-5p则改善了甘油三酸酯积累。萤光素酶报告检测证实FGF21是miR-149-5p的靶基因。沉默FGF21消除了miR-149-5p抑制剂对尿酸诱导的肝细胞脂质蓄积的改善作用，而FGF21的过表达阻止了miR-149-5p模拟物诱导的脂质蓄积。尿酸通过上调miR-149-5p / FGF21轴显着上调miR-149-5p在肝细胞中的表达并诱导肝细胞脂质蓄积。萤光素酶报告检测证实FGF21是miR-149-5p的靶基因。沉默FGF21消除了miR-149-5p抑制剂对尿酸诱导的肝细胞脂质蓄积的改善作用，而FGF21的过表达阻止了miR-149-5p模拟物诱导的脂质蓄积。尿酸通过上调miR-149-5p / FGF21轴显着上调miR-149-5p在肝细胞中的表达并诱导肝细胞脂质蓄积。萤光素酶报告检测证实FGF21是miR-149-5p的靶基因。沉默FGF21消除了miR-149-5p抑制剂对尿酸诱导的肝细胞脂质蓄积的改善作用，而FGF21的过表达阻止了miR-149-5p模拟物诱导的脂质蓄积。尿酸通过上调miR-149-5p / FGF21轴显着上调miR-149-5p在肝细胞中的表达并诱导肝细胞脂质蓄积。