Docosahexaenoic acid inhibits hepatic stellate cell activation to attenuate liver fibrosis in a PPARγ-dependent manner
Docosahexaenoic acid inhibits hepatic stellate cell activation to attenuate liver fibrosis in a PPARγ-dependent manner
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二十二碳六烯酸通过 PPAR γ 依赖性方式抑制肝星状细胞活化，从而减轻肝纤维化
DOI：
10.1016/j.intimp.2019.105816
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发表时间：
2019-10-01
影响因子：
5.6
通讯作者：
Zheng, Shizhong
中科院分区：
文献类型：
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作者：
He, Jianlin;Hong, Bihong;Zheng, Shizhong
二十二碳六烯酸(DHA)已被发现具有保护肝脏的作用。在这项研究中，我们研究了过氧化体增殖物激活受体γ(PPARγ)在DHA调节肝纤维化中的作用。DHA可抑制肝星状细胞(HSC)-Lx2细胞的活性，下调HSC活化的标志蛋白。DHA诱导HSCs细胞周期停滞于G1期。GW9662拮抗PPAR-γ可阻断DHA对HSCs的作用。计算机辅助分子对接预测DHA通过与Ser289、His323、Tyr473和His499残基的氢键与PPAR伽马结合。我们在HSC-Lx2细胞中过表达了Ser289突变体PPARγ，并研究了纤维化标志物的调节，发现DHA对HSC的作用减弱。因此，与Ser289残基的结合可能是DHA激活PPAR-γ对激活的HSC发挥抑制作用所必需的。最后，来自CCl4处理的小鼠模型的数据证实，DHA需要PPAR伽马激活来减轻肝纤维化。
Docosahexaenoic acid (DHA) has been found to have a hepatoprotective effect. In this study, we investigated the role of peroxisome proliferator-activated receptor gamma (PPAR gamma) in DHA regulation of liver fibrosis. DHA was found to inhibit hepatic stellate cell (HSC)-LX2 cell viability and downregulate marker proteins of HSC activation. Furthermore, DHA induced cell cycle arrest at G1 phase in HSCs. Antagonism of PPAR gamma by GW9662 abrogated the effects of DHA on HSCs. Computer-aided molecular docking predicted that DHA bound to PPAR gamma via hydrogen bonding with residues Ser289, His323, Tyr473, and His499. We overexpressed Ser289 mutant PPAR gamma in HSC-LX2 cells and investigated fibrotic marker modulation, and found that DHA effects on HSCs were diminished. Thus, bonding with the Ser289 residue might be indispensable for DHA to activate PPAR gamma to exert its inhibiting effect on activated HSCs. Last, data from a CCl4-treated mouse model confirmed that PPAR gamma activation was required for DHA to attenuate liver fibrosis.