Fatty acid synthase is up-regulated during hepatitis C virus infection and regulates hepatitis C virus entry and production.
Fatty acid synthase is up-regulated during hepatitis C virus infection and regulates hepatitis C virus entry and production.
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DOI：
10.1002/hep.22508
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发表时间：
2008-11
期刊：
影响因子：
--
通讯作者：
Wang T
中科院分区：
文献类型：
--
作者：
Yang W;Hood BL;Chadwick SL;Liu S;Watkins SC;Luo G;Conrads TP;Wang T
丙型肝炎病毒（HCV）是一种主要的人类病原体，可引起严重疾病，包括急性和慢性肝炎、肝硬化和肝细胞癌。利用基于质谱的蛋白质组学方法，我们从含有HCV JFH1病毒的细胞培养上清部分中鉴定出175种蛋白质，其中脂肪酸合成酶（FASN）是一种催化脂肪酸从头合成的多功能酶，被证实是高度富集的。随后的研究表明，HCV感染后，FASN在人肝癌细胞系Huh7或其衍生物中的表达增加。药理学抑制剂C75阻断FASN活性导致HCV产生减少。通过RNA干扰（RNAi）减少FASN抑制复制子和感染系统中的病毒复制。值得注意的是，FASN似乎是claudin-1 （CLDN1）的选择性表达所必需的，CLDN1是一种紧密连接（TJ）蛋白，最近被鉴定为HCV的一种进入共受体，但不用于另一种HCV共受体CD81的表达。由于FASN抑制导致的CLDN1表达降低伴随着Huh7细胞的经上皮电阻（TER）的降低，这意味着细胞单层的相对紧密性降低。因此，在C75处理的Huh7细胞中，HIV-HCV假型（HCVpp）的进入被显著抑制。结论：据我们所知，这是第一个证明HCV感染直接诱导FASN表达的证据，从而提示了HCV感染改变细胞脂质谱并导致脂肪变性等疾病的可能机制。
Hepatitis C virus (HCV) is a major human pathogen that causes serious illness including acute and chronic hepatitis, cirrhosis, and hepatocellular carcinoma. Using a mass spectrometry-based proteomics approach, we have identified 175 proteins from a cell culture supernatant fraction containing HCV JFH1 virus, among which fatty acid synthase (FASN), the multifunctional enzyme catalyzing the de novo synthesis of fatty acids, was confirmed to be highly enriched. Subsequent studies showed that FASN expression increased in the human hepatoma cell line, Huh7 or its derivative, upon HCV infection. Blocking FASN activity by a pharmacological inhibitor C75 led to decreased HCV production. Reduction of FASN by RNA interference (RNAi) suppressed viral replication in both replicon and infection systems. Remarkably, FASN appeared to be selectively required for the expression of claudin-1 (CLDN1), a tight junction (TJ) protein that was recently identified as an entry co-receptor for HCV, but not for the expression of another HCV co-receptor, CD81. The decrease in CLDN1 expression resulting from FASN inhibition was accompanied by a decrease in transepithelial electric resistance (TER) of Huh7 cells, implying a reduction in the relative tightness of the cell monolayer. Consequently, the entry of HIV-HCV pseudotypes (HCVpp) was significantly inhibited in C75 treated Huh7 cells. Conclusion: As far as we know, this is the first line of evidence that demonstrates that HCV infection directly induces FASN expression, and thus suggests a possible mechanism by which HCV infection alters the cellular lipid profile and causes diseases such as steatosis.
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影响因子：
3.7
作者：
Shi, ST;Polyak, SJ;Lai, MMC
通讯作者：
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DOI：
10.1073/pnas.202608199
发表时间：
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影响因子：
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