PURPOSE: To analyze the role of and mechanism underlying obstructive sleep apnea (OSA)-derived exosomes in inducing non-alcoholic fatty liver (NAFLD). METHODS: The role of OSA-derived exosomes was analyzed in inducing hepatocyte fat accumulation in mice models both in vivo and in vitro. RESULTS: 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. CONCLUSIONS: 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.
Autophagy , Cell Polarity , Exosomes , Macrophages , Mice, Inbred C57BL , MicroRNAs , Non-alcoholic Fatty Liver Disease , Sirtuin 3 , Sleep Apnea, Obstructive , Exosomes/metabolism , Animals , Sirtuin 3/metabolism , Sirtuin 3/genetics , MicroRNAs/metabolism , MicroRNAs/genetics , Macrophages/metabolism , Non-alcoholic Fatty Liver Disease/complications , Non-alcoholic Fatty Liver Disease/metabolism , Non-alcoholic Fatty Liver Disease/pathology , Humans , Sleep Apnea, Obstructive/complications , Sleep Apnea, Obstructive/metabolism , Male , Mice , Hepatocytes/metabolism , Hepatocytes/pathology , Inflammasomes/metabolism , Base Sequence , Liver/pathology , Liver/metabolism , AMP-Activated Protein Kinases/metabolism , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism
A correlation exists between obstructive sleep apnoea (OSA) and the severity of metabolic dysfunction-associated steatotic liver disease (MASLD), OSA can induce more severe MASLD. However, the underlying regulatory mechanism between the two is unclear. To this end, this study explored the role and possible molecular mechanisms of adipocyte-derived exosomes under OSA in aggravating MASLD. Through sequencing technology, miR-455-3p was identified as a co-differentially expressed miRNA between the MASLD + OSA and Control groups and between the MASLD + OSA and MASLD groups. Upregulation of TCONS-00039830 and Smad2 and downregulation of miR-455-3p in the MASLD and MASLD + OSA groups were validated in vivo and in vitro. TCONS-00039830, as a differentially expressed LncRNA in exosomes found in the sequencing results, transfection notably downregulated miR-455-3p and upregulated Smad2 in hepatocytes. TCONS_00039830 overexpression increased fat, triglyceride and cholesterol levels, while miR-455-3p overexpression decreased these levels. Furthermore, exosome administration promoted the accumulation of fat, triglyceride and cholesterol, upregulated TCONS_00039830 and Smad2, and downregulated miR-455-3p. Overexpression of miR-455-3p reversed the increased fat accumulation and upregulated TCONS_00039830 and Smad2. In conclusion, OSA-derived exosomes promoted hepatocyte steatosis by regulating TCONS_00039830/miR-455-3p/Smad2 axis, thereby aggravating liver damage in MASLD.
Exosomes , MicroRNAs , Sleep Apnea, Obstructive , Smad2 Protein , Animals , Exosomes/metabolism , Exosomes/genetics , MicroRNAs/genetics , MicroRNAs/metabolism , Smad2 Protein/metabolism , Smad2 Protein/genetics , Sleep Apnea, Obstructive/metabolism , Sleep Apnea, Obstructive/genetics , Sleep Apnea, Obstructive/complications , Male , Rats , Adipocytes/metabolism , RNA, Long Noncoding/genetics , RNA, Long Noncoding/metabolism , Fatty Liver/metabolism , Fatty Liver/genetics , Fatty Liver/pathology , Rats, Sprague-Dawley , Humans , Hepatocytes/metabolism , Disease Models, Animal
Interactions between angiotensin-converting enzyme-2 (ACE2) gene polymorphisms and high salt intake increase the risk of hypertension (HTN); however, this association is not well-established in the Chinese Wa population. In this study, we investigated the prevalence and associated factors of HTN in the Chinese Wa ethnic minority in Yunnan Province, China. In addition, we assessed the associations of single nucleotide polymorphisms (SNPs) in ACE2 with blood pressure and environmental factors. Among a total of 838 Wa individuals, the overall prevalence, awareness, treatment and control rates of HTN were 31.03%, 32.81%, 10.77%, and 0.70%, respectively. In addition, 260 hypertensive patients and 290 normotensive individuals were randomly selected for investigations of salt intake and ACE2 SNPs. The levels of e24-h salt intake in female hypertensive patients were significantly higher that those in normotensive individuals. The ACE2 rs2285666 T allele or TT genotype and rs714205 G allele or GG genotype were identified as risk factors for the development of HTN in female Wa individuals. The CGTG haplotype was a risk factor in hypertensive patients. Moreover, high salt intake increased the occurrence of hypertension among ACE2 rs2285666 TT and rs714205 GG individuals. In this study, we not only identified an association between ACE2 gene polymorphism and HTN in the Chinese Wa population, but also a possible link interaction between ACE2 polymorphism type and high salt intake in increasing the risk of HTN in this population.
