Exosomes regulate SIRT3-related autophagy by delivering miR-421 to regulate macrophage polarization and participate in OSA-related NAFLD

• Published in: Journal of translational medicine 2024-05, Vol.22 (1), p.475-475, Article 475
• Main Authors: Yang, Li, Liu, Shijie, He, Yan, Gan, Lulu, Ni, Qing, Dai, Anni, Mu, Changhuan, Liu, Qian, Chen, Hongyan, Lu, Hongying, Sun, Ruixue
• Format: Article
• Language: English
• Subjects: AMP-Activated Protein Kinases - metabolism; Analysis; Animals; Autophagy; Base Sequence; Care and treatment; Cell Polarity; Complications and side effects; Diagnosis; Exosomes; Exosomes - metabolism; Fatty liver; Hepatocytes - metabolism; Hepatocytes - pathology; Humans; Inflammasomes - metabolism; Liver - metabolism; Liver - pathology; Macrophages; Macrophages - metabolism; Male; Mice; Mice, Inbred C57BL; MicroRNAs - genetics; MicroRNAs - metabolism; miR-421; NLR Family, Pyrin Domain-Containing 3 Protein - metabolism; Non-alcoholic fatty liver; Non-alcoholic Fatty Liver Disease - complications; Non-alcoholic Fatty Liver Disease - metabolism; Non-alcoholic Fatty Liver Disease - pathology; Obstructive sleep apnea; Protein kinases; SIRT3/AMPK; Sirtuin 3 - genetics; Sirtuin 3 - metabolism; Sleep apnea syndromes; Sleep Apnea, Obstructive - complications; Sleep Apnea, Obstructive - metabolism
• ISSN: 1479-5876; 1479-5876
• DOI: 10.1186/s12967-024-05283-8

To analyze the role of and mechanism underlying obstructive sleep apnea (OSA)-derived exosomes in inducing non-alcoholic fatty liver (NAFLD). The role of OSA-derived exosomes was analyzed in inducing hepatocyte fat accumulation in mice models both in vivo and in vitro. OSA-derived exosomes caused fat accumulation and macrophage activation in the liver tissue. These exosomes promoted fat accumulation; steatosis was more noticeable in the presence of macrophages. Macrophages could internalize OSA-derived exosomes, which promoted macrophage polarization to the M1 type. Moreover, it inhibited sirtuin-3 (SIRT3)/AMP-activated protein kinase (AMPK) and autophagy and promoted the activation of nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-3 (NLRP3) inflammasomes. The use of 3-methyladenine (3-MA) to inhibit autophagy blocked NLRP3 inflammasome activation and inhibited the M1 polarization of macrophages. miR-421 targeting inhibited SIRT3 protein expression in the macrophages. miR-421 was significantly increased in OSA-derived exosomes. Additionally, miR-421 levels were increased in OSA + NAFLD mice- and patient-derived exosomes. In the liver tissues of OSA and OSA + NAFLD mice, miR-421 displayed similar co-localization with the macrophages. Intermittent hypoxia-induced hepatocytes deliver miR-421 to the macrophages via exosomes to inhibit SIRT3, thereby participating in macrophage M1 polarization. After OSA and NAFLD modeling in miR-421 mice, liver steatosis and M1 polarization were significantly reduced. Additionally, in the case of miR-421 knockout, the inhibitory effects of OSA-derived exosomes on SIRT3 and autophagy were significantly alleviated. Furthermore, their effects on liver steatosis and macrophage M1 polarization were significantly reduced. OSA promotes the delivery of miR-421 from the hepatocytes to macrophages. Additionally, it promotes M1 polarization by regulating the SIRT3/AMPK-autophagy pathway, thereby causing NAFLD.