Background

Upon liver injury, quiescent hepatic stellate cells (qHSCs), reside in the perisinusoidal space, phenotypically transdifferentiate into myofibroblast-like cells (MFBs). The qHSCs in the normal liver are less fibrogenic, migratory, and also have less proliferative potential. However, activated HSCs (aHSCs) are more fibrogenic and have a high migratory and proliferative MFBs phenotype. HSCs activation is a highly energetic process that needs abundant intracellular energy in the form of adenosine triphosphate (ATP) for the synthesis of extracellular matrix (ECM) in the injured liver to substantiate the injury.

Data sources

The articles were collected through PubMed and EMBASE using search terms “mitochondria and hepatic stellate cells”, “mitochondria and HSCs”, “mitochondria and hepatic fibrosis”, “mitochondria and liver diseases”, and “mitochondria and chronic liver disease”, and relevant publications published before September 31, 2020 were included in this review.

Results

Mitochondria homeostasis is affected during HSCs activation. Mitochondria in aHSCs are highly energetic and are in a high metabolically active state exhibiting increased activity such as glycolysis and respiration. aHSCs have high glycolytic enzymes expression and glycolytic activity induced by Hedgehog (Hh) signaling from injured hepatocytes. Increased glycolysis and aerobic glycolysis (Warburg effect) end-products in aHSCs consequently activate the ECM-related gene expressions. Increased Hh signaling from injured hepatocytes downregulates peroxisome proliferator-activated receptor-γ expression and decreases lipogenesis in aHSCs. Glutaminolysis and tricarboxylic acid cycle liberate ATPs that fuel HSCs to proliferate and produce ECM during their activation.

Conclusions

Available studies suggest that mitochondria functions can increase in parallel with HSCs activation. Therefore, mitochondrial modulators should be tested in an elaborate manner to control or prevent the HSCs activation during liver injury to subsequently regress hepatic fibrosis.

中文翻译：

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线粒体：慢性肝病期间肝星状细胞活化的关键枢纽

背景

肝损伤后，静止的肝星状细胞 (qHSCs) 位于窦周间隙，在表型上转分化为肌成纤维细胞样细胞 (MFBs)。正常肝脏中的 qHSC 纤维化、迁移性较低，并且增殖潜力也较小。然而，活化的 HSC (aHSC) 纤维化程度更高，并且具有高度迁移和增殖的 MFB 表型。HSCs 激活是一个高能过程，需要以三磷酸腺苷 (ATP) 形式提供的丰富细胞内能量来合成受损肝脏中的细胞外基质 (ECM) 以证实损伤。

数据源

这些文章是通过 PubMed 和 EMBASE 使用搜索词“线粒体和肝星状细胞”、“线粒体和 HSCs”、“线粒体和肝纤维化”、“线粒体和肝病”和“线粒体和慢性肝病”进行收集的，以及相关的2020 年 9 月 31 日之前发表的出版物被纳入本次审查。

结果

在 HSC 激活期间，线粒体稳态受到影响。aHSC 中的线粒体具有高能量并且处于高代谢活性状态，表现出增加的活性，例如糖酵解和呼吸。aHSC 具有高糖酵解酶表达和由受损肝细胞的刺猬 (Hh) 信号诱导的糖酵解活性。因此，aHSC 中增加的糖酵解和有氧糖酵解（Warburg 效应）终产物会激活 ECM 相关基因表达。来自受损肝细胞的 Hh 信号增加会下调过氧化物酶体增殖物激活受体-γ 的表达并减少 aHSC 中的脂肪生成。谷氨酰胺分解和三羧酸循环释放 ATP，这些 ATP 为 HSC 提供燃料，使其在活化过程中增殖并产生 ECM。

结论

现有研究表明，线粒体功能可以与 HSC 激活同时增加。因此，线粒体调节剂应以精细的方式进行测试，以控制或防止肝损伤期间 HSCs 的活化，从而缓解肝纤维化。