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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 (p &lt; 1 \u00d7 10\u221216 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.<\/jats:p>","DOI":"10.3390\/ijms24021407","type":"journal-article","created":{"date-parts":[[2023,1,11]],"date-time":"2023-01-11T02:59:54Z","timestamp":1673405994000},"page":"1407","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Hepatitis C Virus Infection Upregulates Plasma Phosphosphingolipids and Endocannabinoids and Downregulates Lysophosphoinositols"],"prefix":"10.3390","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9882-5841","authenticated-orcid":false,"given":"Diren","family":"Beyo\u011flu","sequence":"first","affiliation":[{"name":"Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, Western New England University, Springfield, MA 01119, USA"},{"name":"Hepatology Research Group, Department of BioMedical Research, University of Bern, CH-3008 Bern, Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stephanie","family":"Schwalm","sequence":"additional","affiliation":[{"name":"Pharmazentrum Frankfurt\/ZAFES, Institute of General Pharmacology and Toxicology, University Hospital, Goethe University Frankfurt am Main, D-60590 Frankfurt am Main, Germany"},{"name":"Institute of Pharmacology, Inselspital, INO-F, University of Bern, CH-3010 Bern, Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nasser","family":"Semmo","sequence":"additional","affiliation":[{"name":"Hepatology Research Group, Department of BioMedical Research, University of Bern, CH-3008 Bern, Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1615-5691","authenticated-orcid":false,"given":"Andrea","family":"Huwiler","sequence":"additional","affiliation":[{"name":"Institute of Pharmacology, Inselspital, INO-F, University of Bern, CH-3010 Bern, Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6143-1520","authenticated-orcid":false,"given":"Jeffrey R.","family":"Idle","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, Western New England University, Springfield, MA 01119, USA"},{"name":"Hepatology Research Group, Department of BioMedical Research, University of Bern, CH-3008 Bern, Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2023,1,11]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Bley, H., Schobel, A., and Herker, E. 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