Downregulation of microRNA-145a-5p promotes steatosis-to-NASH progression through upregulation of Nr4a2

Bo Li; Ziyi Yang; Fei Mao; Wei Gong; Qing Su; Jialin Yang; Bin Liu; Yuping Song; Jie Jin; Yan Lu

doi:10.1016/j.jhep.2023.06.019

Downregulation of microRNA-145a-5p promotes steatosis-to-NASH progression through upregulation of Nr4a2

J Hepatol. 2023 Nov;79(5):1096-1109. doi: 10.1016/j.jhep.2023.06.019. Epub 2023 Jul 16.

Authors

Bo Li¹, Ziyi Yang², Fei Mao³, Wei Gong⁴, Qing Su¹, Jialin Yang⁵, Bin Liu⁶, Yuping Song⁷, Jie Jin⁸, Yan Lu⁹

Affiliations

¹ Department of Endocrinology, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China.
² Department of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China; Institute of Metabolism and Regenerative Medicine, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200235, China.
³ Department of Endocrinology and Metabolism, Zhongshan Hospital, Fudan University, Shanghai 230032, China.
⁴ Department of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China.
⁵ Department of Endocrinology and Metabolism, Minhang Hospital, Fudan University, Shanghai 201100, China.
⁶ Jiangsu Key Laboratory of Marine Pharmaceutical Compound Screening, College of Pharmacy, Jiangsu Ocean University, Lianyungang 222005, China.
⁷ Department of Endocrinology and Metabolism, Minhang Hospital, Fudan University, Shanghai 201100, China. Electronic address: ellie_song@fudan.edu.cn.
⁸ Department of Endocrinology, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China. Electronic address: jinjie@xinhuamed.com.cn.
⁹ Institute of Metabolism and Regenerative Medicine, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200235, China. Electronic address: luyan5011@shsmu.edu.cn.

PMID: 37463623
DOI: 10.1016/j.jhep.2023.06.019

Abstract

Background & aims: The molecular mechanisms underlying the progression of simple steatosis to non-alcoholic steatohepatitis (NASH) remain incompletely understood, though the potential role of epigenetic regulation by microRNA (miRNAs) is an area of increasing interest. In the present study, we aimed to investigate the role of miRNAs during steatosis-to-NASH progression, as well as underlying mechanisms.

Methods: miR-145a-5p was identified as an important checkpoint in steatosis-to-NASH progression. 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 targets of miR-145a-5p.

Results: Suppression of miR-145a-5p in the liver aggravated lipid accumulation and 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 and thus 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. This role of the miR-145a-5p/Nr4a2 regulatory axis was also confirmed in primary human hepatocytes. Furthermore, the expression of miR-145a-5p was reduced and the expression of Nr4a2 was increased in the livers of patients with NASH, while their expression levels significantly negatively and positively correlated with features of liver pathology, respectively.

Conclusions: Our findings highlight the role of the 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 the treatment of NASH.

Impact and implications: Non-alcoholic fatty liver disease (NAFLD) is a dynamic spectrum of chronic liver diseases ranging from simple steatosis to non-alcoholic 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 differential 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.

Keywords: MicroRNA; Nonalcoholic fatty liver disease; Nonalcoholic steatohepatitis; Nuclear receptor; Simple steatosis.