Hepatitis B Virus X Protein Induces Hepatic Steatosis by Enhancing the Expression of Liver Fatty Acid Binding Protein
Hepatitis B Virus X Protein Induces Hepatic Steatosis by Enhancing the Expression of Liver Fatty Acid Binding Protein
复制标题
乙型肝炎病毒X蛋白通过增强肝脏脂肪酸结合蛋白的表达诱导肝脂肪变性。
DOI：
10.1128/jvi.02604-15
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发表时间：
2016-02-01
影响因子：
5.4
通讯作者：
Lin, Xu
中科院分区：
文献类型：
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作者：
Wu, Yun-li;Peng, Xian-e;Lin, Xu
B型肝炎病毒（HBV）是肝脂肪变性的潜在触发因素，但HBV相关肝脂肪变性发病机制的分子机制仍不清楚。我们先前的工作已经揭示了肝脏脂肪酸结合蛋白1（FABP 1）的表达水平，肝脏脂质代谢的关键调节因子，在产生HBV的肝癌细胞中升高。在这项研究中，HBV X蛋白（HBx）介导的FABP 1调节对肝脂肪变性的影响和潜在的机制进行了确定。通过定量RT-PCR（qPCR）和Western blotting检测FABP 1的mRNA和蛋白水平。HBx介导的FABP 1调节通过荧光素酶测定、免疫共沉淀和染色质免疫沉淀进行评价。采用油红O染色法检测肝脏脂质蓄积和甘油三酯水平。发现FABP 1在HBV产生的肝癌细胞、HBV感染患者的血清、HBV转基因小鼠的血清和肝组织中表达增加。在HBx表达的肝癌细胞中，HBx的异位过表达导致FABP 1的上调，而HBx的废除降低了FABP 1的表达。从机制上讲，HBx以HNF 3 β、C/EBP α和PPAR α依赖性方式激活FABP 1启动子，其中HBx增加HNF 3 β的基因表达，并与C/EBP α和PPAR α发生物理相互作用。另一方面，FABP 1的敲除显着阻止了长链游离脂肪酸处理的表达HBx的HepG 2细胞和高脂饮食喂养的HBx转基因小鼠中的脂质积聚。因此，FABP 1是通过调节HNF 3 β、C/EBP α和PPAR α而在HBx诱导的肝脏脂质蓄积中的关键驱动基因。FABP 1可能是治疗HBV相关性肝脂肪变性的新靶点。
Hepatitis B virus (HBV) has been implicated as a potential trigger of hepatic steatosis although molecular mechanisms involved in the pathogenesis of HBV-associated hepatic steatosis still remain elusive. Our prior work has revealed that the expression level of liver fatty acid binding protein 1 (FABP1), a key regulator of hepatic lipid metabolism, was elevated in HBV-producing hepatoma cells. In this study, the effects of HBV X protein (HBx) mediated FABP1 regulation on hepatic steatosis and the underlying mechanism were determined. mRNA and protein levels of FABP1 were measured by quantitative RT-PCR (qPCR) and Western blotting. HBx-mediated FABP1 regulation was evaluated by luciferase assay, coimmunoprecipitation, and chromatin immunoprecipitation. Hepatic lipid accumulation was measured by using Oil-Red-O staining and the triglyceride level. It was found that expression of FABP1 was increased in HBV-producing hepatoma cells, the sera of HBV-infected patients, and the sera and liver tissues of HBV-transgenic mice. Ectopic overexpression of HBx resulted in upregulation of FABP1 in HBx-expressing hepatoma cells, whereas HBx abolishment reduced FABP1 expression. Mechanistically, HBx activated the FABP1 promoter in an HNF3 beta-, C/EBP alpha-, and PPAR alpha-dependent manner, in which HBx increased the gene expression of HNF3 beta and physically interacted with C/EBP alpha and PPAR alpha. On the other hand, knockdown of FABP1 remarkably blocked lipid accumulation both in long-chain free fatty acids treated HBx-expressing HepG2 cells and in a high-fat diet-fed HBx-transgenic mice. Therefore, FABP1 is a key driver gene in HBx-induced hepatic lipid accumulation via regulation of HNF3 beta, C/EBP alpha, and PPAR alpha. FABP1 may represent a novel target for treatment of HBV-associated hepatic steatosis.