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• W4384470742 abstract "Background & aims Nonalcoholic fatty liver disease (NAFLD) is a dynamic spectrum of chronic metabolic liver disease and ranges from simple steatosis to nonalcoholic steatohepatitis (NASH). However, the molecular mechanisms underlying steatosis-to-NASH progression remain incompletely understood. Methods In the present study, we investigated the profiling changes of MicroRNAs and identified miR-145a-5p as an important checkpoint in this process. In vivo loss-of-function and gain-of-function studies were performed to explore the role of miR-145a-5p and Nr4a2 in NASH progression. RNA-Sequencing and bioinformatic analysis were used to investigate the target of miR-145a-5p. Results Suppression of miR-145a-5p in the liver activated hepatic inflammation, liver injury and fibrosis in steatotic mice, whereas its restoration markedly attenuated diet-induced NASH pathogenesis. Mechanistically, miR-145a-5p was able to downregulate the nuclear receptor Nr4a2 to inhibit the expression of NASH-associated genes. Similarly, Nr4a2 overexpression promoted steatosis-to-NASH progression while liver-specific Nr4a2 knockout mice were protected from diet-induced NASH. Of potential clinical significance, the miR-145a-5p/Nr4a2 regulatory axis was also confirmed in human primary hepatocytes. Besides, expression level of miR-145a-5p was reduced and Nr4a2 was increased in the livers of NASH patients. Their expression levels were significantly correlated with hepatic pathological features. Conclusions Our findings highlight the role of miR-145a-5p/Nr4a2 regulatory axis in steatosis-to-NASH progression, suggesting that either supplementation of miR-145a-5p or pharmacological inhibition of Nr4a2 in hepatocytes may provide a promising therapeutic approach for treating NASH. Impact and implications Nonalcoholic fatty liver disease (NAFLD) is a dynamic spectrum of chronic liver disease ranging from simple steatosis to nonalcoholic steatohepatitis (NASH). Unfortunately, there are currently no approved drugs for NASH. Our current study identified miR-145a-5p as a novel regulator that inhibits steatosis-to-NASH progression. We found that miR-145a-5p was able to downregulate the nuclear receptor Nr4a2 to suppress the expression of NASH-associated genes. The differentially expression of miR-145a-5p and Nr4a2 was further confirmed in patients with NASH, raising the possibility that supplementation of miR-145a-5p or suppression of Nr4a2 in hepatocytes might provide novel strategies for treating NASH." @default.
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• W4384470742 date "2023-07-01" @default.
• W4384470742 modified "2023-09-27" @default.
• W4384470742 title "Downregulation of microRNA-145a-5p promotes steatosis-to-NASH progression through upregulation of Nr4a2" @default.
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• W4384470742 doi "https://doi.org/10.1016/j.jhep.2023.06.019" @default.
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