Hepatitis B virus X protein induces lipogenic transcription factor SREBP1 and fatty acid synthase through the activation of nuclear receptor LXRα
Hepatitis B virus X protein induces lipogenic transcription factor SREBP1 and fatty acid synthase through the activation of nuclear receptor LXRα
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DOI：
10.1042/bj20081336
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发表时间：
2008-12-01
影响因子：
4.1
通讯作者：
Cheong, JaeHun
中科院分区：
文献类型：
--
作者：
Kim, KyeongJin;Kim, Kook Hwan;Cheong, JaeHun
HBV（乙型肝炎病毒）是慢性肝病的主要病因，经常导致肝炎、肝硬化并最终导致HCC（肝细胞癌）。最近，我们发现HBx （HBV蛋白X）表达通过诱导SREBP1（甾醇调节元件结合蛋白1）介导的肝细胞脂质积累，SREBP1是肝脏脂肪生成基因的关键调节因子。然而，HBx增加SREBP1表达和转激活的分子机制仍有待明确阐明。在本研究中，我们证明了HBx与LXR α（肝X受体α）相互作用，增强了LXR α与LXR反应元件LXRE的结合，从而导致肝细胞和HBx转基因小鼠在存在或不存在LXR激动剂T0901317的情况下上调SREBP1和FAS（脂肪酸合成酶）。此外，HBx还增强了通过LXR α向LXRE募集ASC2（激活信号协积子2）的能力，ASC2是一种控制肝脏脂质代谢途径的转录共激活因子。这些研究表明LXR α在hbx诱导的脂肪生成途径中处于关键位置，并提出了HBV感染可以刺激srebp1介导的肝脏脂质积累控制的分子机制。
HBV (hepatitis B virus) is a primary cause of chronic liver disease, which frequently results in hepatitis, cirrhosis and ultimately HCC (hepatocellular carcinoma). Recently, we showed that HBx (HBV protein X) expression induces lipid accumulation in hepatic cells mediated by the induction of SREBP1 (sterol-regulatory-element-binding protein 1), a key regulator of lipogenic genes in the liver. However, the molecular mechanisms by which HBx increases SREBP1 expression and transactivation remain to be clearly elucidated. In the present study, we demonstrated that HBx interacts with LXR alpha (liver X receptor alpha) and enhances the binding of LXR alpha to LXRE (LXR-response element), thereby resulting in the up-regulation of SREBP1 and FAS (fatty acid synthase) in the presence or absence of the LXR agonist T0901317 in the hepatic cells and HBx-transgenic mice. Furthermore, HBx also augments the ability to recruit ASC2 (activating signal cointegrator 2), a transcriptional co-activator that controls liver lipid metabolic pathways, to the LXRE with LXR alpha. These studies place LXR alpha in a key position within the HBx-induced lipogenic pathways, and Suggest a molecular mechanism through which HBV infection can stimulate the SREBP1-mediated control of hepatic lipid accumulation.