Involvement of cholesterol in hepatitis B virus X protein-induced abnormal lipid metabolism of hepatoma cells via up-regulating miR-205-targeted ACSL4
Involvement of cholesterol in hepatitis B virus X protein-induced abnormal lipid metabolism of hepatoma cells via up-regulating miR-205-targeted ACSL4
复制标题
胆固醇通过上调miR-205靶向ACSL4参与乙型肝炎病毒X蛋白诱导肝癌细胞脂质代谢异常
DOI：
10.1016/j.bbrc.2014.02.068
复制
发表时间：
2014-03-14
影响因子：
3.1
通讯作者：
Zhang, XiaoDong
中科院分区：
文献类型：
--
作者：
Cui, Ming;Xiao, ZeLin;Zhang, XiaoDong
乙型肝炎病毒 X 蛋白 (HBx) 在肝细胞癌 (HCC) 的发展中起着至关重要的作用。脂质代谢异常参与肝癌的发生。我们之前报道过 HBx 抑制肝癌细胞中的 miR-205。在本研究中，根据生物信息学分析，我们推测HBx减少的miR-205可能导致脂质代谢异常。有趣的是，我们发现临床HCC组织中酰基辅酶A合成酶长链家族成员4（ACSL4）的表达水平与miR-205的表达水平呈负相关。然后，我们验证了miR-205能够通过靶向ACSL4的3'UTR在mRNA和蛋白质水平抑制ACSL4的表达。引人注目的是，我们发现 HBx 能够增加肝癌细胞中细胞胆固醇（ACSL4 的一种代谢产物）的水平，而这种水平可以被 miR-205（或 ACSL4 的抑制剂 Triacsin C）阻断。然而，抗 miR-205 可能会增加细胞中的胆固醇水平。此外，我们证明HBx转基因小鼠肝脏中的胆固醇水平随时间推移而增加。从功能上来说，油红 0 染色显示 HBx 促进 HepG2 细胞中的脂肪生成，而这种作用可以被 miR-205（或 Triacsin C）消除。然而，抗 miR-205 能够加速细胞中的脂肪生成。有趣的是，Triacsin C 治疗可以显着阻断抗 miR-205 在该事件中的作用。因此，我们得出结论，miR-205 能够靶向 ACSL4 mRNA。 HBx 抑制的 miR-205 通过在肝癌细胞中积累胆固醇而导致脂质代谢异常。 (C) 2014 Elsevier Inc. 保留所有权利。
Hepatitis B virus X protein (HBx) plays crucial roles in the development of hepatocellular carcinoma (HCC). The abnormal lipid metabolism is involved in the hepatocarcinogenesis. We previously reported that HBx suppressed miR-205 in hepatoma cells. In this study, we supposed that HBx-decreased miR-205 might contribute to the abnormal lipid metabolism according to the bioinformatics analysis. Interestingly, we showed that the expression levels of acyl-CoA synthetase long-chain family member 4 (ACSL4) were negatively associated with those of miR-205 in clinical HCC tissues. Then, we validated that miR-205 was able to inhibit the expression of ACSL4 at the levels of mRNA and protein through targeting its 3'UTR. Strikingly, we found that HBx was able to increase the levels of cellular cholesterol, a metabolite of ACSL4, in hepatoma cells, which could be blocked by miR-205 (or Triacsin C, an inhibitor of ACSL4). However, anti-miR-205 could increase the levels of cholesterol in the cells. Moreover, we demonstrated that the levels of cholesterol were increased in the liver of HBx transgenic mice in a time course manner. Functionally, oil red 0 staining revealed that HBx promoted lipogenesis in HepG2 cells, which could be abolished by miR-205 (or Triacsin C). However, anti-miR-205 was able to accelerate lipogenesis in the cells. Interestingly, the treatment with Triacsin C could remarkably block the role of anti-miR-205 in the event. Thus, we conclude that miR-205 is able to target ACSL4 mRNA. The HBx-depressed miR-205 is responsible for the abnormal lipid metabolism through accumulating cholesterol in hepatoma cells. (C) 2014 Elsevier Inc. All rights reserved.