Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, Western New England University, Springfield, MA 01119, USA.
Hepatology Research Group, Department of BioMedical Research, University of Bern, CH-3008 Bern, Switzerland.
Int J Mol Sci. 2023 Jan 11;24(2):1407. doi: 10.3390/ijms24021407.
A mass spectrometry-based lipidomic investigation of 30 patients with chronic hepatitis C virus (HCV) infection and 30 age- and sex-matched healthy blood donor controls was undertaken. The clustering and complete separation of these two groups was found by both unsupervised and supervised multivariate data analyses. Three patients who had spontaneously cleared the virus and three who were successfully treated with direct-acting antiviral drugs remained within the HCV-positive metabotype, suggesting that the metabolic effects of HCV may be longer-lived. We identified 21 metabolites that were upregulated in plasma and 34 that were downregulated ( < 1 × 10 to 0.0002). Eleven members of the endocannabinoidome were elevated, including anandamide and eight fatty acid amides (FAAs). These likely activated the cannabinoid receptor GPR55, which is a pivotal host factor for HCV replication. FAAH1, which catabolizes FAAs, reduced mRNA expression. Four phosphosphingolipids, d16:1, d18:1, d19:1 sphingosine 1-phosphate, and d18:0 sphinganine 1-phosphate, were increased, together with the mRNA expression for their synthetic enzyme SPHK1. Among the most profoundly downregulated plasma lipids were several lysophosphatidylinositols (LPIs) from 3- to 3000-fold. LPIs are required for the synthesis of phosphatidylinositol 4-phosphate (PI4P) pools that are required for HCV replication, and LPIs can also activate the GPR55 receptor. Our plasma lipidomic findings shed new light on the pathobiology of HCV infection and show that a subset of bioactive lipids that may contribute to liver pathology is altered by HCV infection.
对 30 名慢性丙型肝炎病毒（HCV）感染患者和 30 名年龄和性别匹配的健康献血者对照进行了基于质谱的脂质组学研究。通过无监督和有监督的多变量数据分析发现，这两组能够聚类和完全分离。三名自发清除病毒的患者和三名成功接受直接作用抗病毒药物治疗的患者仍处于 HCV 阳性代谢型内，这表明 HCV 的代谢影响可能更持久。我们鉴定出 21 种在血浆中上调的代谢物和 34 种下调的代谢物（<1×10 至 0.0002）。内源性大麻素组的 11 个成员升高，包括大麻素和 8 种脂肪酸酰胺（FAAs）。这些可能激活了大麻素受体 GPR55，这是 HCV 复制的关键宿主因素。分解 FAA 的 FAAH1 的 mRNA 表达降低。四种磷酸鞘脂，d16:1、d18:1、d19:1 鞘氨醇 1-磷酸和 d18:0 鞘氨醇 1-磷酸，以及它们的合成酶 SPHK1 的 mRNA 表达增加。血浆脂质中下调最明显的是几种溶血磷脂酰肌醇（LPIs），下调幅度为 3 到 3000 倍。LPIs 是合成磷脂酰肌醇 4-磷酸（PI4P）池所必需的，PI4P 池是 HCV 复制所必需的，LPIs 也可以激活 GPR55 受体。我们的血浆脂质组学发现为 HCV 感染的病理生物学提供了新的见解，并表明可能有助于肝脏病理学的一组生物活性脂质发生改变。
