Abstract
Improvements in living standards have led to non-alcoholic fatty liver disease (NAFLD), one of the most common chronic liver diseases worldwide. Recent studies have shown that N6-methyladenosine (m6A), a type of RNA modification, is strongly associated with many important biological processes. However, the relationship between m6A methylation modifications and NAFLD remains poorly understood. In the present study, through methylated RNA immunoprecipitation sequencing and RNA transcriptome sequencing in high fructose diet-induced NAFLD mice, we found that hypermethylation-encoding genes were mainly enriched in lipid metabolism processes. We identified 266 overlapping and differentially expressed genes (DEGs) that changed at both the mRNA expression level and m6A modification level. Among them, 193 genes displayed increased expression and m6A modification, indicating that m6A RNA modifications tend to be positively correlated with NAFLD. We further compared the high fructose diet-induced NAFLD mouse model with leptin receptor-deficient mice and found that DEGs enriched in the lipid metabolism pathway were up-regulated in both groups. In contrast, DEGs associated with the immune inflammatory response were up-regulated in the high fructose diet group, but down-regulated in leptin receptor-deficient mice. Taken together, our results demonstrate that m6A methylation modifications may play an important role in the development of NAFLD.
Highlights
Rapid changes in lifestyles have led to an increased prevalence of metabolic syndrome
We found that in the high-fructose diet (HFrD) mouse model, genes associated with m6A methylation were significantly involved in lipid metabolism-related pathways, and that the up-regulation of gene expression was often accompanied by up-regulation of m6A methylation
FTO deficiency inhibits the expression of autophagy related 5 and autophagy related 7 by increasing mRNA m6A levels, leading to inactivation of autophagy and inhibiting adipogenesis [32]. m6A is involved in the biological functions of pancreatic b-cells
Summary
Rapid changes in lifestyles have led to an increased prevalence of metabolic syndrome. The manifestation of metabolic syndrome in the liver, non-alcoholic fatty liver disease (NAFLD), has become the most common chronic liver disease worldwide. NAFLD includes a series of clinical features, from simple liver steatosis and non-alcoholic steatohepatitis (NASH) to liver fibrosis, cirrhosis and hepatocellular carcinoma [1]. DNL is a complex metabolic reaction that enables the liver to synthesize new fatty acids from acetyl-CoA. In this process, the two key transcription factors are sterol regulatory element binding protein 1c (SREBP-1c) and carbohydrate response element binding protein (ChREBP). Most of the fatty acid synthesis rate-limiting enzymes, including fatty acid synthase (FASN), acetyl CoA carboxylase 1 (ACC1) and stearoyl-CoAdesaturase (SCD1), are transcriptionally activated by these two transcription factors [4]. Very low-density lipoprotein transport is a complex lipoprotein particle that converts insoluble TG into a water-soluble form, which is exported from the liver and transported to peripheral tissues [3]
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