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首页> 外文期刊>Hepatology: Official Journal of the American Association for the Study of Liver Diseases >The adenosine monophosphate–activated protein kinase—vacuolar adenosine triphosphatase–pH axis: A key regulator of the profibrogenic phenotype of human hepatic stellate cells
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The adenosine monophosphate–activated protein kinase—vacuolar adenosine triphosphatase–pH axis: A key regulator of the profibrogenic phenotype of human hepatic stellate cells

机译：腺苷一磷酸氨磷酸活性蛋白激酶 - 真空腺苷腺苷三磷酸酶-PH轴：人肝星状细胞的抗原表型的关键调节器

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摘要

Liver fibrosis and cirrhosis are characterized by activation of hepatic stellate cells (HSCs), which is associated with higher intracellular pH (pHi). The vacuolar H + adenosine‐triphosphatase (v‐ATPase) multisubunit complex is a key regulator of pHi homeostasis. The present work investigated the functional role of v‐ATPase in primary human HSC (hHSC) activation and its modulation by specific adenosine monophosphate–activated protein kinase (AMPK) subunits. We demonstrate that the expression of different v‐ATPase subunits was increased in in vivo and in vitro activated hHSCs compared to nonactivated hHSCs. Specific inhibition of v‐ATPase with bafilomycin and KM91104 induced a down‐regulation of the HSC fibrogenic gene profile, which coincided with increased lysosomal pH, decreased pHi, activation of AMPK, reduced proliferation, and lower metabolic activity. Similarly, pharmacological activation of AMPK by treatment with diflunisal, A769662, and ZLN024 reduced the expression of v‐ATPase subunits and profibrogenic markers. v‐ATPase expression was differently regulated by the AMPK α1 subunit (AMPKα1) and AMPKα2, as demonstrated in mouse embryo fibroblasts specifically deficient for AMPK α subunits. In addition, activation of v‐ATPase in hHSCs was shown to be AMPKα1‐dependent. Accordingly, pharmacological activation of AMPK in AMPKα1‐depleted hHSCs prevented v‐ATPase down‐regulation. Finally, we showed that v‐ATPase expression was increased in fibrotic livers from bile duct–ligated mice and in human cirrhotic livers. Conclusion: The down‐regulation of v‐ATPase might represent a promising target for the development of antifibrotic strategies. (H epatology 2018).
机译：肝纤维化和肝硬化的特征在于激活肝星状细胞（HSC），其与更高的细胞内pH（PHI）相关。真空H +腺苷 - 三磷酸酶（V-ATP酶）MultiSubinit Complex是Phi Hoosostasis的关键调节剂。本作者研究了V-ATP酶在原发性人HSC（HHSC）活化中的功能作用及其通过特异性腺苷的单磷酸酯活化蛋白激酶（AMPK）亚基的调节。我们证明，与非活动的HHSC相比，体内和体外活化HHSC中的不同V-ATP酶亚单位的表达增加。与BafiLomycin和KM91104的V-ATP酶对V-ATP酶的特异性抑制诱导了HSC纤维原基因谱的下调，这与增加的溶酶体pH值增加，降低，AMPK的激活，降低增殖和降低代谢活性。类似地，通过用不同的不同性A769662和ZLN024处理AMPK的药理活化，降低了V-ATP酶亚基和抗纤维发生标记的表达。 V-ATP酶表达由AMPKα1亚基（AMPKα1）和AMPKα2不同，如特异性缺乏AMPKα亚基的小鼠胚胎成纤维细胞中所示。此外，HHSC中的V-ATP酶的激活显示为依赖于AMPKα1。因此，在AMPKα1耗尽的HHSC中的AMPK药理活化防止了V-ATP酶的下调。最后，我们表明V-ATP酶表达从胆管切断的小鼠和人肝肝脏肝脏中的纤维化肝脏增加。结论：V-ATPase的下调可能代表了开发抗纤维化策略的有希望的目标。 （2018年Hopatology）。

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