Inhibition of liver fibrosis by solubilized coenzyme Q10: Role of Nrf2 activation in inhibiting transforming growth factor-β1 expression
Inhibition of liver fibrosis by solubilized coenzyme Q10: Role of Nrf2 activation in inhibiting transforming growth factor-β1 expression
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DOI：
10.1016/j.taap.2009.07.030
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发表时间：
2009-11-01
影响因子：
3.8
通讯作者：
Kang, Keon Wook
中科院分区：
文献类型：
--
作者：
Choi, Hoo-Kyun;Pokharel, Yuba Raj;Kang, Keon Wook
辅酶Q10（CoQ 10）是一种内源性抗氧化剂，在线粒体氧化磷酸化中起重要作用。它具有抗糖尿病和抗心血管疾病的作用，但其防止肝纤维化的能力尚未研究。在这里，我们评估了溶解辅酶Q10改善二甲基亚硝胺（DMN）诱导的小鼠肝纤维化的能力。DMN治疗3周产生了明显的肝纤维化，通过组织病理学检查和组织4-羟脯氨酸含量进行评估。可溶性辅酶Q10（10和30 mg/kg）显著抑制DMN诱导的纤维化评分和4-羟脯氨酸含量的增加。逆转录-聚合酶链反应和蛋白质印迹分析表明，溶解辅酶Q10抑制增加转化生长因子-β 1（TGF-β 1）mRNA和α-平滑肌肌动蛋白（α-SMA）蛋白的DMN。有趣的是，肝脏谷氨酸-半胱氨酸连接酶（GCL）和谷胱甘肽S-转移酶A2（GSTA 2）在用辅酶Q10治疗的小鼠中上调。可溶性辅酶Q10还通过激活H4 IIE肝癌细胞中的NF-E2相关因子2（Nrf 2）/抗氧化反应元件（ARE）上调抗氧化酶如GCL和GSTA 2的催化亚基。此外，辅酶Q10对α-SMA和TGF-β 1表达的抑制在Nrf 2缺失的MEF细胞中消失。相反，Nrf 2过表达显著降低了Nrf 2缺失的MEF细胞中α-SMA和TGF-β 1的基础表达水平。这些结果表明，溶解的辅酶Q10抑制DMN诱导的肝纤维化通过抑制TGF-β 1的表达，通过Nrf 2/ARE激活。(C)2009 Elsevier Inc. All rights reserved.
Coenzyme Q10 (CoQ10), an endogenous antioxidant, is important in oxidative phosphorylation in mitochondria. It has anti-diabetic and anti-cardiovascular disease effects, but its ability to protect against liver fibrosis has not been studied. Here, we assessed the ability of solubilized CoQ10 to improve dimethylnitrosamine (DMN)-induced liver fibrogenesis in mice. DMN treatments for 3 weeks produced a marked liver fibrosis as assessed by histopathological examination and tissue 4-hydroxyproline content. Solubilized CoQ10 (10 and 30 mg/kg) significantly inhibited both the increases in fibrosis score and 4-hydroxyproline content induced by DMN. Reverse transcription-polymerase chain reaction and Western blot analyses revealed that solubilized CoQ10 inhibited increases in the transforming growth factor-beta 1 (TGF-beta 1) mRNA and alpha-smooth muscle actin (alpha-SMA) protein by DMN. Interestingly, hepatic glutamate-cysteine ligase (GCL) and glutathione S-transferase A2 (GSTA2) were up-regulated in mice treated with CoQ10. Solubilized CoQ10 also up-regulated antioxidant enzymes such as catalytic subunits of GCL and GSTA2 via activating NF-E2 related factor2 (Nrf2)/antioxidant response element (ARE) in H4IIE hepatoma cells. Moreover, CoQ10's inhibition of alpha-SMA and TGF-beta 1 expressions disappeared in Nrf2-null MEF cells. In contrast, Nrf2 overexpression significantly decreased the basal expression levels of alpha-SMA and TGF-beta 1 in Nrf2-null MEF cells. These results demonstrated that solubilized CoQ10 inhibited DMN-induced liver fibrosis through suppression of TGF-beta 1 expression via Nrf2/ARE activation. (C) 2009 Elsevier Inc. All rights reserved.