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

May 20, 2024

Experts: Li Yang,Shijie Liu,Yan He,Lulu Gan,Qing Ni,Anni Dai,Changhuan Mu,Qian Liu,Hongyan Chen,Hongying Lu,Ruixue Sun

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.

© 2024. The Author(s).

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ABOUT THE EXPERTS

Li Yang,Shijie Liu,Yan He,Lulu Gan,Qing Ni,Anni Dai,Changhuan Mu,Qian Liu,Hongyan Chen,Hongying Lu,Ruixue Sun

Li Yang

Hypertension Center, Yan ‘an Hospital of Kunming Medical University, 245 Renmin East Road, Panlong District, Kunming City, 650000, Yunnan Province, China. yl13330466619@163.com.

Kunming Technical Diagnosis and Treatment Center for Refractory Hypertension, Kunming Medical University, 245 Renmin East Road, Panlong District, Kunming City, 650000, Yunnan Province, China. yl13330466619@163.com.

Shijie Liu

Hypertension Center, Yan ‘an Hospital of Kunming Medical University, 245 Renmin East Road, Panlong District, Kunming City, 650000, Yunnan Province, China.

Kunming Technical Diagnosis and Treatment Center for Refractory Hypertension, Kunming Medical University, 245 Renmin East Road, Panlong District, Kunming City, 650000, Yunnan Province, China.

Yan He

Hypertension Center, Yan ‘an Hospital of Kunming Medical University, 245 Renmin East Road, Panlong District, Kunming City, 650000, Yunnan Province, China.

Kunming Technical Diagnosis and Treatment Center for Refractory Hypertension, Kunming Medical University, 245 Renmin East Road, Panlong District, Kunming City, 650000, Yunnan Province, China.

Lulu Gan

Hypertension Center, Yan ‘an Hospital of Kunming Medical University, 245 Renmin East Road, Panlong District, Kunming City, 650000, Yunnan Province, China.

Kunming Technical Diagnosis and Treatment Center for Refractory Hypertension, Kunming Medical University, 245 Renmin East Road, Panlong District, Kunming City, 650000, Yunnan Province, China.

Qing Ni

Hypertension Center, Yan ‘an Hospital of Kunming Medical University, 245 Renmin East Road, Panlong District, Kunming City, 650000, Yunnan Province, China.

Kunming Technical Diagnosis and Treatment Center for Refractory Hypertension, Kunming Medical University, 245 Renmin East Road, Panlong District, Kunming City, 650000, Yunnan Province, China.

Anni Dai

Hypertension Center, Yan ‘an Hospital of Kunming Medical University, 245 Renmin East Road, Panlong District, Kunming City, 650000, Yunnan Province, China.

Kunming Technical Diagnosis and Treatment Center for Refractory Hypertension, Kunming Medical University, 245 Renmin East Road, Panlong District, Kunming City, 650000, Yunnan Province, China.

Changhuan Mu

Hypertension Center, Yan ‘an Hospital of Kunming Medical University, 245 Renmin East Road, Panlong District, Kunming City, 650000, Yunnan Province, China.

Kunming Technical Diagnosis and Treatment Center for Refractory Hypertension, Kunming Medical University, 245 Renmin East Road, Panlong District, Kunming City, 650000, Yunnan Province, China.

Qian Liu

Hypertension Center, Yan ‘an Hospital of Kunming Medical University, 245 Renmin East Road, Panlong District, Kunming City, 650000, Yunnan Province, China.

Kunming Technical Diagnosis and Treatment Center for Refractory Hypertension, Kunming Medical University, 245 Renmin East Road, Panlong District, Kunming City, 650000, Yunnan Province, China.

Hongyan Chen

Hypertension Center, Yan ‘an Hospital of Kunming Medical University, 245 Renmin East Road, Panlong District, Kunming City, 650000, Yunnan Province, China.

Kunming Technical Diagnosis and Treatment Center for Refractory Hypertension, Kunming Medical University, 245 Renmin East Road, Panlong District, Kunming City, 650000, Yunnan Province, China.

Hongying Lu

Hypertension Center, Yan ‘an Hospital of Kunming Medical University, 245 Renmin East Road, Panlong District, Kunming City, 650000, Yunnan Province, China.

Kunming Technical Diagnosis and Treatment Center for Refractory Hypertension, Kunming Medical University, 245 Renmin East Road, Panlong District, Kunming City, 650000, Yunnan Province, China.

Ruixue Sun

Hypertension Center, Yan ‘an Hospital of Kunming Medical University, 245 Renmin East Road, Panlong District, Kunming City, 650000, Yunnan Province, China.

Kunming Technical Diagnosis and Treatment Center for Refractory Hypertension, Kunming Medical University, 245 Renmin East Road, Panlong District, Kunming City, 650000, Yunnan Province, China.