Hepatocyte-derived exosomal miR-27a activateshepatic stellate cells through the inhibitionof PINK1-mediated mitophagy in MAFLD

Molecular Therapy: Nucleic Acids

Zi-Xin Xu¹  Sheng-Zheng Luo¹  Xin Luo²  Jun-Cheng Wu²  Ming-Yi Xu³ 

[1] Department of Gastroenterology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080 China;Department of Gastroenterology, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai 200092, China;Departments of Gastroenterology, The Third Affiliated Hospital of Soochow University, Changzhou, 213000 Jiangsu Province, China;

关键词: metabolic-associated fatty liver disease;    MAFLD;    mitophagy;    exosomes;    microRNA-27a;    miR27a;   

DOI  :  

来源: DOAJ

【 摘 要 】

The role of exosome-mediated mitophagy in the crosstalk between hepatocytes (HCs) and hepatic stellate cells (HSCs) in metabolic-associated fatty liver disease (MAFLD) remains unknown. Serum exosomal miR-27a levels were markedly increased and positively correlated with liver fibrosis in MAFLD patients and mice. Exosomal miR-27a was released from lipotoxic HCs and specifically transmitted to recipient-activated HSCs. PINK1, the key target of miR-27a, primarily mediates mitophagy. Overexpression of miR-27a or knockdown of PINK1 or lipotoxic HC-exosomal miR-27a impaired mitochondria (inhibiting mitophagy, respiration, membrane potential, and transcription while promoting reactive oxygen species production) in activated HSCs and stimulated HSC-derived fibroblasts (promoting activation and proliferation while inhibiting autophagy). High exosomal miR-27a serum levels and a lack of hepatic PINK1-mediated mitophagy were directly related to liver fibrosis in MAFLD mice. Lipotoxic HC exosome transplantation aggravated the degree of PINK1-mediated mitophagy suppression, steatohepatitis, lipidosis, and fibrosis in the livers of MAFLD mice with cirrhosis. Both in vitro and in vivo, exosomes derived from miR-27a-knockdown HCs could not facilitate the abovementioned deteriorating effects. In conclusion, lipotoxic HC-exosomal miR-27a plays a pivotal role in inhibiting mitophagy and in promoting MAFLD-related liver fibrosis by negatively regulating PINK1 expression.

【 授权许可】

Unknown