title: Hepatocyte-secreted extracellular vesicles modify blood metabolome and endothelial function by an arginase-dependent mechanism.
abstract: Hepatocytes release extracellular vesicles (EVs) loaded with signaling molecules and enzymes into the bloodstream. Although the importance of EVs in the intercellular communication is already recognized, the metabolic impact of the enzymes carried by these vesicles is still unclear. We evaluated the global effect of the enzymatic activities of EVs by performing untargeted metabolomic profiling of serum samples after their exposure to EVs. This approach revealed a significant change in the abundance of 94 serum metabolic signals. Our study shows that these vesicles modify the concentration of metabolites of different chemical nature including metabolites related to arginine metabolism, which regulates vascular function. To assess the functional relevance of this finding, we examined the levels of arginase-1 protein and its activity in the hepatic EVs carrying the exosomal markers CD81 and CD63. Remarkably, the arginase activity was also detected in EVs isolated from the serum in vivo, and this vesicular activity significantly increased under liver-damaging conditions. Finally, we demonstrated that EVs secreted by hepatocytes inhibited the acetylcholine-induced relaxation in isolated pulmonary arteries, via an arginase-dependent mechanism. In summary, our study demonstrates that the hepatocyte-released EVs are metabolically active, affecting a number of serum metabolites involved in oxidative stress metabolism and the endothelial function.
authors.affiliation: Exosomes Laboratory. CIC bioGUNE, CIBEREHD, Derio 48160 Bizkaia, Spain.
authors.forename: Felix
authors.initials: F
authors.lastname: Royo
authors.affiliation: Department of Pharmacology, School of Medicine, University Complutense of Madrid, CIBERES. Instituto de Investigación Sanitaria Gregorio Marañón (IISGM), 28040 Madrid, Spain.
authors.forename: Laura
authors.initials: L
authors.lastname: Moreno
authors.affiliation: Exosomes Laboratory. CIC bioGUNE, CIBEREHD, Derio 48160 Bizkaia, Spain.
authors.forename: Justyna
authors.initials: J
authors.lastname: Mleczko
authors.affiliation: Exosomes Laboratory. CIC bioGUNE, CIBEREHD, Derio 48160 Bizkaia, Spain.
authors.forename: Laura
authors.initials: L
authors.lastname: Palomo
authors.affiliation: Exosomes Laboratory. CIC bioGUNE, CIBEREHD, Derio 48160 Bizkaia, Spain.
authors.forename: Esperanza
authors.initials: E
authors.lastname: Gonzalez
authors.affiliation: Metabolomics platform, CIC bioGUNE, CIBERehd, Derio 48160 Bizkaia, Spain.
authors.forename: Diana
authors.initials: D
authors.lastname: Cabrera
authors.affiliation: Department of Pharmacology, School of Medicine, University Complutense of Madrid, CIBERES. Instituto de Investigación Sanitaria Gregorio Marañón (IISGM), 28040 Madrid, Spain.
authors.forename: Angel
authors.initials: A
authors.lastname: Cogolludo
authors.affiliation: Department of Pharmacology, School of Medicine, University Complutense of Madrid, CIBERES. Instituto de Investigación Sanitaria Gregorio Marañón (IISGM), 28040 Madrid, Spain.
authors.forename: Francisco Perez
authors.initials: FP
authors.lastname: Vizcaino
authors.affiliation: Metabolomics platform, CIC bioGUNE, CIBERehd, Derio 48160 Bizkaia, Spain.
authors.forename: Sebastiaan
authors.initials: S
authors.lastname: van-Liempd
authors.affiliation: Exosomes Laboratory. CIC bioGUNE, CIBEREHD, Derio 48160 Bizkaia, Spain.|Metabolomics platform, CIC bioGUNE, CIBERehd, Derio 48160 Bizkaia, Spain.|IKERBASKE Basque Foundation for science, Bilbao, 48013 Bizkaia, Spain.
authors.forename: Juan M
authors.initials: JM
authors.lastname: Falcon-Perez
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D001119:Arginase / Q000378:metabolism*; D001769:Blood / Q000378:metabolism*; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000187:drug effects / Q000502:physiology*; D000067128:Extracellular Vesicles / Q000201:enzymology*; D022781:Hepatocytes / Q000166:cytology* / Q000378:metabolism; D008297:Male; D055432:Metabolomics / Q000379:methods*; D051381:Rats; D060225:Tetraspanin 28 / Q000378:metabolism; D060149:Tetraspanin 30 / Q000378:metabolism
chemical_list: C554588:Cd63 protein, rat; C554797:Cd81 protein, rat; D060225:Tetraspanin 28; D060149:Tetraspanin 30; D001119:Arginase; D000109:Acetylcholine