Autophagic degradation of MVBs in LSECs promotes Aldosterone induced-HSCs activation

被引：3

作者：

Chen, Tingting ^{[1
,2
]}

Zhang, Yan ^{[1
,2
]}

Zhang, Yijie ^{[1
,2
]}

Ning, Zuowei ^{[2
]}

Xu, Qihan ^{[1
,2
]}

Lin, Ying ^{[1
,2
]}

Gong, Jiacheng ^{[1
,2
]}

Li, Jierui ^{[1
,2
]}

Chen, Zhuoer ^{[1
,2
]}

Meng, Ying ^{[3
]}

Li, Yang ^{[1
]}

Li, Xu ^{[1
]}

机构：

[1] Southern Med Univ, Nanfang Hosp, Dept Emergency Med, 1838,North Guangzhou Ave, Guangzhou 510515, Guangdong, Peoples R China

[2] Southern Med Univ, Nanfang Hosp, Dept Gastroenterol, Guangdong Prov Key Lab Gastroenterol, Guangzhou 510515, Peoples R China

[3] Southern Med Univ, Nanfang Hosp, Dept Resp Dis, Guangzhou 510515, Peoples R China

来源：

HEPATOLOGY INTERNATIONAL | 2023年 / 18卷 / 1期

基金：

中国博士后科学基金; 中国国家自然科学基金;

关键词：

Liver fibrosis; Aldosterone; Autophagy; LSECs; HSCs; Extracellular vesicles; SINUSOIDAL ENDOTHELIAL-CELLS; OXIDATIVE STRESS; LIVER; FIBROSIS; VESICLES; DISEASE;

D O I：

10.1007/s12072-023-10559-0

中图分类号：

R57 [消化系及腹部疾病];

学科分类号：

摘要：

Background and aims The important role of extracellular vesicles (EVs) in liver fibrosis has been confirmed. However, EVs derived from liver sinusoidal endothelial cells (LSECs) in the activation of hepatic stellate cells (HSCs) and liver fibrosis is still unclear. Our previous work demonstrated that Aldosterone (Aldo) may have the potential to regulate EVs from LSECs via autophagy pathway. Thus, we aim to investigate the role of Aldo in the regulation of EVs derived from LSECs. Approach and results Using an Aldo-continuous pumping rat model, we observed that Aldo-induced liver fibrosis and capillarization of LSECs. In vitro, transmission electron microscopy (TEM) revealed that stimulation of Aldo led to the upregulation of autophagy and degradation of multivesicular bodies (MVBs) in LSECs. Mechanistically, Aldo upregulated ATP6V0A2, which promoted lysosomal acidification and subsequent autophagy in LSECs. Inhibiting autophagy with siATG5 adeno-associated virus ( AAV) in LSECs effectively mitigated Aldo-induced liver fibrosis in rats. RNA sequencing and nanoparticle tracking (NTA) analyses of EVs derived from LSECs indicated that Aldo result in a decrease in both the quantity and quality of EVs. We also observed a reduction in the protective miRNA- 342-5P in EVs derived from Aldotreated LSECs, which may play a critical role in HSCs activation. Target knockdown of EV secretion with si-RAB27a AAV in LSECs led to the development of liver fibrosis and HSC activation in rats. Conclusion Aldo-induced Autophagic degradation of MVBs in LSECs promotes a decrease in the quantity and quality of EVs derived from LSECs, resulting in the activation of HSCs and liver fibrosis under hyperaldosteronism. Modulating the autophagy level of LSECs and their EV secretion may represent a promising therapeutic approach for treating liver fibrosis. In a physiological state, LSECs transmit inhibitory signals to HSCs via the secretion of EVs that are rich in miR-342-5p. However, in pathological conditions, the elevated levels of serum aldosterone induce capillarization and excessive autophagy in LSECs. This autophagy leads to the degradation of MVBs in LSECs, resulting in a reduction of the number of EVs and miR- 342-5p content within EVs. This reduction ultimately leads to a diminished inhibitory signal transmitted to HSCs, thereby activating HSCs and promoting the development of liver fibrosis.

引用

页码：273 / 288

页数：16

共 32 条

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