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

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 patien...

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Autores principales:	Xin Luo, Zi-Xin Xu, Jun-Cheng Wu, Sheng-Zheng Luo, Ming-Yi Xu
Formato:	article
Lenguaje:	EN
Publicado:	Elsevier 2021
Materias:	metabolic-associated fatty liver disease MAFLD mitophagy exosomes microRNA-27a miR27a Therapeutics. Pharmacology RM1-950
Acceso en línea:	https://doaj.org/article/cbd16e2f695b429f9a8bc38683761f6d
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spelling	oai:doaj.org-article:cbd16e2f695b429f9a8bc38683761f6d2021-11-20T05:05:33ZHepatocyte-derived exosomal miR-27a activateshepatic stellate cells through the inhibitionof PINK1-mediated mitophagy in MAFLD2162-253110.1016/j.omtn.2021.10.022https://doaj.org/article/cbd16e2f695b429f9a8bc38683761f6d2021-12-01T00:00:00Zhttp://www.sciencedirect.com/science/article/pii/S2162253121002651https://doaj.org/toc/2162-2531The 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.Xin LuoZi-Xin XuJun-Cheng WuSheng-Zheng LuoMing-Yi XuElsevierarticlemetabolic-associated fatty liver diseaseMAFLDmitophagyexosomesmicroRNA-27amiR27aTherapeutics. PharmacologyRM1-950ENMolecular Therapy: Nucleic Acids, Vol 26, Iss , Pp 1241-1254 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	metabolic-associated fatty liver disease MAFLD mitophagy exosomes microRNA-27a miR27a Therapeutics. Pharmacology RM1-950
spellingShingle	metabolic-associated fatty liver disease MAFLD mitophagy exosomes microRNA-27a miR27a Therapeutics. Pharmacology RM1-950 Xin Luo Zi-Xin Xu Jun-Cheng Wu Sheng-Zheng Luo Ming-Yi Xu Hepatocyte-derived exosomal miR-27a activateshepatic stellate cells through the inhibitionof PINK1-mediated mitophagy in MAFLD
description	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.
format	article
author	Xin Luo Zi-Xin Xu Jun-Cheng Wu Sheng-Zheng Luo Ming-Yi Xu
author_facet	Xin Luo Zi-Xin Xu Jun-Cheng Wu Sheng-Zheng Luo Ming-Yi Xu
author_sort	Xin Luo
title	Hepatocyte-derived exosomal miR-27a activateshepatic stellate cells through the inhibitionof PINK1-mediated mitophagy in MAFLD
title_short	Hepatocyte-derived exosomal miR-27a activateshepatic stellate cells through the inhibitionof PINK1-mediated mitophagy in MAFLD
title_full	Hepatocyte-derived exosomal miR-27a activateshepatic stellate cells through the inhibitionof PINK1-mediated mitophagy in MAFLD
title_fullStr	Hepatocyte-derived exosomal miR-27a activateshepatic stellate cells through the inhibitionof PINK1-mediated mitophagy in MAFLD
title_full_unstemmed	Hepatocyte-derived exosomal miR-27a activateshepatic stellate cells through the inhibitionof PINK1-mediated mitophagy in MAFLD
title_sort	hepatocyte-derived exosomal mir-27a activateshepatic stellate cells through the inhibitionof pink1-mediated mitophagy in mafld
publisher	Elsevier
publishDate	2021
url	https://doaj.org/article/cbd16e2f695b429f9a8bc38683761f6d
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Hepatocyte-derived exosomal miR-27a activateshepatic stellate cells through the inhibitionof PINK1-mediated mitophagy in MAFLD

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