Zhao Jianjian, Peng Lei, Cui Ruibing, Guo Xiaolan, Yan Ming
Department of Geriatric Gastroenterology, Qilu Hospital of Shandong University, Jinan, 250012, China.
Department of Geriatric Gastroenterology, Qilu Hospital of Shandong University, Jinan, 250012, China.
Biochem Biophys Res Commun. 2016 Dec 2;481(1-2):90-96. doi: 10.1016/j.bbrc.2016.11.010. Epub 2016 Nov 5.
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 CCl-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.
肝星状细胞（HSCs）的持续激活会导致肝纤维化。自噬通过产生ATP促进HSCs的激活。我们之前的研究证明了α-酮戊二酸二甲酯（DMKG）在体外对HSCs激活具有抑制作用。在本研究中，我们证明了DMKG可减轻Wistar大鼠由四氯化碳诱导的肝纤维化。然后，通过使用HSC-T6细胞系以及对肝组织切片进行双重免疫荧光染色，我们发现抗纤维化作用是通过抑制HSCs的自噬而发生的。两项实验均表明，DMKG可抑制HSCs的自噬和激活，并且随着自噬作用，HSCs的激活被下调。此外，我们还表明，DMKG可导致HSCs中脂滴积累并降低细胞ATP含量。此外，我们在体外使用c646（一种与乙酰转移酶EP300结合的乙酰辅酶A竞争性抑制剂）和硫辛酸（一种可替代DMKG补充乙酰辅酶A的试剂）探索了DMKG抑制HSCs自噬的机制，结果表明乙酰辅酶A和EP300均参与其中。总的来说，我们的研究探讨了DMKG在预防肝纤维化和HSCs激活中的可能作用。我们表明，DMKG可能是一种治疗肝纤维化的潜在治疗药物。
