肝星状细胞
自噬
四氯化碳
细胞生物学
化学
纤维化
体外
肝纤维化
辅酶A
生物
生物化学
癌症研究
细胞凋亡
酶
内分泌学
内科学
医学
有机化学
还原酶
四氯化碳
作者
Jianjian Zhao,Lei Peng,Ruibing Cui,Xiaolan Guo,Mingxia Yan
标识
DOI:10.1016/j.bbrc.2016.11.010
摘要
Sustained activation of hepatic stellate cells (HSCs) leads to liver fibrosis. Autophagy fuels the activation of HSCs by generation of ATP. Our previous research demonstrated an inhibitory effect of dimethyl α-ketoglutarate (DMKG) on HSCs activation in vitro. In the current study, we demonstrated that DMKG reduced CCl4-induced liver fibrosis in Wistar rats. Then, with the use of the HSC-T6 cell lines and double immunofluorescent staining of liver sections, we showed that the anti-fibrotic effect occurred through the inhibition of the autophagy of HSCs. Both experiments showed that DMKG could inhibit autophagy and activation of HSCs, and that the activation of HSCs was down-regulated with autophagy. In addition, we showed that DMKG could lead to lipid droplet accumulation and decrease cellular ATP content in HSCs. Furthermore, the mechanism of how DMKG inhibited autophagy of HSCs was explored in vitro with the use of c646 (a competitive inhibitor of acetyl-coenzyme A which binds to the acetyltransferase EP300) and lipoic acid (an alternative acetyl-coenzyme A -replenishing agent to DMKG), and showed that both acetyl-coenzyme A and EP300 were involved. Collectively, our study investigated the possible role of DMKG in preventing liver fibrosis and HSCs activation. We showed that DMKG may be a potential therapeutic agent for the treatment of liver fibrosis.
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