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首页> 外文期刊>Hepatology communications. >Ribavirin suppresses hepatic lipogenesis through inosine monophosphate dehydrogenase inhibition: Involvement of adenosine monophosphate‐activated protein kinase‐related kinases and retinoid X receptor α
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Ribavirin suppresses hepatic lipogenesis through inosine monophosphate dehydrogenase inhibition: Involvement of adenosine monophosphate‐activated protein kinase‐related kinases and retinoid X receptor α

机译：利巴韦林通过抑制肌苷单磷酸脱氢酶抑制肝脂肪生成：参与腺苷单磷酸激活的蛋白激酶相关激酶和类维生素A X受体α的参与

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Ribavirin (RBV) has been widely used as an antiviral reagent, specifically for patients with chronic hepatitis C. We previously demonstrated that adenosine kinase, which monophosphorylates RBV into the metabolically active form, is a key determinant for RBV sensitivity against hepatitis C virus RNA replication. However, the precise mechanism of RBV action and whether RBV affects cellular metabolism remain unclear. Analysis of liver gene expression profiles obtained from patients with advanced chronic hepatitis C treated with the combination of pegylated interferon and RBV showed that the adenosine kinase expression level tends to be lower in patients who are overweight and significantly decreases with progression to advanced fibrosis stages. In our effort to investigate whether RBV affects cellular metabolism, we found that RBV treatment under clinically achievable concentrations suppressed lipogenesis in hepatic cells. In this process, guanosine triphosphate depletion through inosine monophosphate dehydrogenase inhibition by RBV and adenosine monophosphate‐activated protein kinase‐related kinases, especially microtubule affinity regulating kinase 4, were required. In addition, RBV treatment led to the down‐regulation of retinoid X receptor α (RXRα), a key nuclear receptor in various metabolic processes, including lipogenesis. Moreover, we found that guanosine triphosphate depletion in cells induced the down‐regulation of RXRα, which was mediated by microtubule affinity regulating kinase 4. Overexpression of RXRα attenuated the RBV action for suppression of lipogenic genes and intracellular neutral lipids, suggesting that down‐regulation of RXRα was required for the suppression of lipogenesis in RBV action. Conclusion : We provide novel insights about RBV action in lipogenesis and its mechanisms involving inosine monophosphate dehydrogenase inhibition, adenosine monophosphate‐activated protein kinase‐related kinases, and down‐regulation of RXRα. RBV may be a potential reagent for anticancer therapy against the active lipogenesis involved in hepatocarcinogenesis. ( Hepatology Communications 2017;1:550–563)
机译：利巴韦林（RBV）已被广泛用作抗病毒剂，特别是针对慢性丙型肝炎患者。我们先前证明，腺苷激酶将RBV单磷酸化为代谢活性形式，是决定RBV对丙型肝炎病毒RNA复制敏感性的关键决定因素。 。但是，RBV作用的确切机制以及RBV是否影响细胞代谢仍不清楚。对由聚乙二醇干扰素和RBV联合治疗的晚期慢性丙型肝炎患者获得的肝基因表达谱的分析表明，超重患者的腺苷激酶表达水平趋于降低，并且随着进展至晚期纤维化阶段而显着降低。在研究RBV是否影响细胞代谢的努力中，我们发现在临床上可达到的浓度下进行RBV治疗抑制了肝细胞的脂肪生成。在此过程中，需要通过RBV抑制肌苷单磷酸脱氢酶和三磷酸腺苷活化的蛋白激酶相关激酶（特别是微管亲和力调节激酶4）来消耗鸟苷三磷酸。此外，RBV治疗导致类视色素X受体α（RXRα）的下调，该受体是包括脂肪生成在内的各种代谢过程中的关键核受体。此外，我们发现细胞中三磷酸鸟苷的消耗诱导了RXRα的下调，这是由微管亲和力调节激酶4介导的。RXRα的过表达减弱了RBV抑制脂生性基因和细胞内中性脂质的作用，表明这种下调抑制RBV作用中的脂肪生成需要RXRα的抑制。结论：我们提供了有关RBV在脂肪形成中的作用及其机制的新见解，涉及肌苷单磷酸脱氢酶抑制，单磷酸腺苷活化的蛋白激酶相关激酶以及RXRα的下调。 RBV可能是针对涉及肝癌发生的活动性脂肪生成的抗癌治疗的潜在试剂。 （肝病通讯2017; 1：550–563）

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