Department of Pharmacology, the Blue Lab, Molecular Medicine and Toxicology Division, Saveetha Dental College, Saveetha Institute of Medical and Technical Sciences (SIMATS), Chennai 600077, Tamil Nadu, India.
Hepatobiliary Pancreat Dis Int. 2021 Aug;20(4):315-322. doi: 10.1016/j.hbpd.2021.04.010. Epub 2021 Apr 28.
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.
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.
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.
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.
在肝损伤时，静息状态的肝星状细胞（qHSCs）位于窦周间隙，表型转化为肌成纤维细胞样细胞（MFBs）。正常肝脏中的 qHSCs 纤维生成能力较弱、迁移能力较弱且增殖潜能较低。然而，激活的 HSCs（aHSCs）具有更强的纤维生成能力和高迁移及增殖的 MFBs 表型。HSCs 的激活是一个高度耗能的过程，需要大量的细胞内能量，以三磷酸腺苷（ATP）的形式为受损肝脏中细胞外基质（ECM）的合成提供能量，以维持损伤。
通过 PubMed 和 EMBASE 数据库使用“线粒体和肝星状细胞”、“线粒体和 HSCs”、“线粒体和肝纤维化”、“线粒体和肝脏疾病”和“线粒体和慢性肝病”等检索词收集文章，纳入本综述的相关出版物均发表于 2020 年 9 月 31 日之前。
HSCs 激活时，线粒体的稳态受到影响。aHSCs 中的线粒体能量丰富，处于高代谢活跃状态，表现出增加的活性，如糖酵解和呼吸作用。Hh 信号从受损的肝细胞传递给 aHSCs，诱导其高表达糖酵解酶并增加糖酵解活性。aHSCs 中增加的糖酵解和有氧糖酵解（Warburg 效应）终产物激活 ECM 相关基因表达。Hh 信号从受损的肝细胞传递给 aHSCs，还会下调过氧化物酶体增殖物激活受体-γ的表达，减少其脂生成。谷氨酰胺分解和三羧酸循环释放 ATP，为 aHSCs 在激活过程中增殖和产生 ECM 提供燃料。
现有研究表明，线粒体功能可以随着 HSCs 的激活而增加。因此，应该以精细的方式测试线粒体调节剂，以控制或预防肝损伤过程中 HSCs 的激活，从而使肝纤维化逆转。
