Abstract
BackgroundHyperuricemia 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.MethodsMicroarray 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.ResultsMicroarray 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.ConclusionsUric 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.
Highlights
Hyperuricemia is a major risk for non-alcoholic fatty liver disease
Male C57BL/6 mice, 8 weeks of age, weighing 22–23 g, were randomly divided into three groups, consisting of 6 animals per group and fed with standard chow diet (SCD), high fat diet (HFD), or HFD combined with allopurinol in drinking water (HFD + A), respectively
We found that the serum uric acid levels were significantly increased about 1.5-fold in HFD-fed mice, while the serum uric acid levels are reduced by about 90% in HFD + A mice than of HFD-mice (Fig. 1c)
Summary
Hyperuricemia is a major risk for non-alcoholic fatty liver disease. This study aimed to investigate whether microRNAs mediated the pathogenic effects of uric acid on non-alcoholic fatty liver disease. Nonalcoholic fatty liver disease (NAFLD) is a group of liver disease characterized by excessive hepatic lipid accumulation without excess alcohol intake [1]. We previously identified that high serum uric acid level is a major risk factor of NAFLD [8, 9], and uric acid induced hepatic lipid accumulation by activating NLRP3 inflammasome [10]. Uric acid may induce hepatic lipid accumulation by inducing endoplasmic reticulum stress and mitochondrial oxidative stress [11, 12]. Increasing researches have emerged to explore the mechanism by which uric acid induced hepatic lipid accumulation, its underlying molecular mechanisms remains not fully clarified. A better understanding of the mechanisms may help for developing novel therapeutic strategy for NAFLD
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