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.
J Transl Med. 2024 May 19;22(1):475. 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.
分析阻塞性睡眠呼吸暂停（OSA）衍生外泌体在诱导非酒精性脂肪性肝病（NAFLD）中的作用和机制。
在体内和体外小鼠模型中分析了 OSA 衍生外泌体在诱导肝细胞脂肪积累中的作用。
OSA 衍生的外泌体导致肝组织中脂肪积累和巨噬细胞活化。这些外泌体促进脂肪积累；在存在巨噬细胞的情况下，脂肪变性更加明显。巨噬细胞可以内化 OSA 衍生的外泌体，促进巨噬细胞向 M1 型极化。此外，它抑制了沉默调节蛋白 3（SIRT3）/AMP 激活蛋白激酶（AMPK）和自噬，并促进核苷酸结合域，富含亮氨酸的家族，吡咯啉域-3（NLRP3）炎性小体的激活。使用 3-甲基腺嘌呤（3-MA）抑制自噬阻断了 NLRP3 炎性小体的激活，并抑制了巨噬细胞的 M1 极化。miR-421 靶向抑制了巨噬细胞中的 SIRT3 蛋白表达。miR-421 在 OSA 衍生的外泌体中显著增加。此外，在 OSA+NAFLD 小鼠和患者衍生的外泌体中，miR-421 水平增加。在 OSA 和 OSA+NAFLD 小鼠的肝组织中，miR-421 与巨噬细胞显示出相似的共定位。间歇性缺氧诱导的肝细胞通过外泌体将 miR-421 递送到巨噬细胞中，从而抑制 SIRT3，参与巨噬细胞 M1 极化。在 miR-421 小鼠中进行 OSA 和 NAFLD 建模后，肝脂肪变性和 M1 极化明显减少。此外，在 miR-421 敲除的情况下，OSA 衍生的外泌体对 SIRT3 和自噬的抑制作用明显减轻。此外，它们对肝脂肪变性和巨噬细胞 M1 极化的影响明显降低。
OSA 促进 miR-421 从肝细胞向巨噬细胞的传递。此外，它通过调节 SIRT3/AMPK-自噬途径促进 M1 极化，从而导致 NAFLD。
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