Microbiology and Immunology Graduate Program, Graduate School of Biomedical Sciences and Professional Studies, Drexel University College of Medicine, Philadelphia, PA, 19102, USA.
Molecular and Cellular Biology and Genetics Graduate Program, Graduate School of Biomedical Sciences and Professional Studies, Drexel University College of Medicine, Philadelphia, PA, 19102, USA.
Metabolism. 2018 Jun;83:50-59. doi: 10.1016/j.metabol.2018.01.007. Epub 2018 Feb 2.
As the leading risk factor for the development of liver cancer, chronic infection with hepatitis B virus (HBV) represents a significant global health concern. Although an effective HBV vaccine exists, at least 240 million people are chronically infected with HBV worldwide. Therapeutic options for the treatment of chronic HBV remain limited, and none achieve an absolute cure. To develop novel therapeutic targets, a better understanding of the complex network of virus-host interactions is needed. Because of the central metabolic role of the liver, we assessed the metabolic impact of HBV infection as a means to identify viral dependency factors and metabolic pathways that could serve as novel points of therapeutic intervention.
Primary rat hepatocytes were infected with a control adenovirus, an adenovirus expressing a greater-than-unit-length copy of the HBV genome, or an adenovirus expressing the HBV X protein (HBx). A panel of 369 metabolites was analyzed for HBV- or HBx-induced changes 24 and 48 h post infection. Pathway analysis was used to identify key metabolic pathways altered in the presence of HBV or HBx expression, and these findings were further supported through integration of publically available gene expression data.
We observed distinct changes to multiple metabolites in the context of HBV replication or HBx expression. Interestingly, a panel of 7 metabolites (maltotriose, maltose, myristate [14:0], arachidate [20:0], 3-hydroxybutyrate [BHBA], myo-inositol, and 2-palmitoylglycerol [16,0]) were altered by both HBV and HBx at both time points. In addition, incorporation of data from a transcriptome-based dataset allowed us to identify metabolic pathways, including long chain fatty acid metabolism, glycolysis, and glycogen metabolism, that were significantly altered by HBV and HBx.
Because the liver is a central regulator of metabolic processes, it is important to understand how HBV replication and HBV protein expression affects the metabolic function of hepatocytes. Through analysis of a broad panel of metabolites we investigated this metabolic impact. The results of these studies have defined metabolic consequences of an HBV infection of hepatocytes and will help to lay the groundwork for novel research directions and, potentially, development of novel anti-HBV therapeutics.
慢性乙型肝炎病毒（HBV）感染是肝癌发展的主要危险因素，这是一个全球性的健康问题。虽然存在有效的 HBV 疫苗，但全球仍有至少 2.4 亿人慢性感染 HBV。慢性 HBV 的治疗选择仍然有限，没有一种方法可以实现绝对治愈。为了开发新的治疗靶点，需要更好地了解病毒-宿主相互作用的复杂网络。由于肝脏具有重要的代谢作用，我们评估了 HBV 感染对代谢的影响，以确定病毒依赖性因素和代谢途径，这些因素和途径可以作为新的治疗干预点。
原代大鼠肝细胞分别感染对照腺病毒、表达 HBV 基因组全长拷贝的腺病毒或表达 HBV X 蛋白（HBx）的腺病毒。在感染后 24 小时和 48 小时，用 369 种代谢物分析 HBV 或 HBx 诱导的变化。采用通路分析识别在 HBV 或 HBx 表达存在时发生改变的关键代谢通路，并通过整合公共基因表达数据进一步支持这些发现。
我们观察到在 HBV 复制或 HBx 表达的情况下，多种代谢物发生了明显变化。有趣的是，一组 7 种代谢物（麦芽三糖、麦芽糖、肉豆蔻酸[14:0]、花生四烯酸[20:0]、β-羟丁酸[BHBA]、肌醇和 16,0-二棕榈酰甘油[16,0]）在两个时间点均被 HBV 和 HBx 同时改变。此外，纳入基于转录组数据集的数据使我们能够识别代谢途径，包括长链脂肪酸代谢、糖酵解和糖原代谢，这些途径在 HBV 和 HBx 作用下显著改变。
由于肝脏是代谢过程的中央调节者，因此了解 HBV 复制和 HBV 蛋白表达如何影响肝细胞的代谢功能非常重要。通过分析广泛的代谢物面板，我们研究了这种代谢影响。这些研究的结果定义了 HBV 感染肝细胞的代谢后果，并为新的研究方向奠定了基础，并可能开发出新的抗 HBV 治疗方法。
