title: Metabolically active extracellular vesicles released from hepatocytes under drug-induced liver-damaging conditions modify serum metabolome and might affect different pathophysiological processes.
abstract: Hepatocytes are involved in the endogenous and drug metabolism; many of the enzymes involved in those processes are incorporated into extracellular vesicles and secreted into the bloodstream. Liver-damaging conditions modify the molecular cargo of those vesicles significantly. However, no information about the effect of these hepatic vesicles on the extracellular environment is available. Drug-induced liver damage increases the number of circulating extracellular vesicles and affects the release and content of hepatocyte-derived vesicles. In this work, we evaluated the metabolic effect of these vesicles on the composition of the serum. We performed a targeted ultra-high performance liquid chromatography-mass spectrometry (UHPLC-MS) metabolomics analysis of serum samples. The samples had been first incubated with hepatic extracellular vesicles from hepatocytes challenged with acetaminophen or diclofenac. The incubation affected the serum levels of 67 metabolites, such as amino acids and different species of lipids. The metabolites included various species of phosphatidylcholines and phosphatidylethanolamines. These compounds are the components of biological membranes; our observations suggest that the vesicles might take part in remodelling and maintenance of the membranes. Alterations in the levels of some other serum metabolites might have deleterious consequences, for example, the tetracosanoic acid with its cardiovascular effects. However, some of the metabolites whose levels were increased, including alpha-linoleic and tauroursodeoxycholic acids, have been reported to have a protective effect. Our targeted metabolomics analysis indicated that the hepatic extracellular vesicles act as nano-metabolic machines supplying the extracellular environment with the means to integrate diverse tissue responses. In conclusion, we show that the hepatic extracellular vesicles are metabolically active and might play a role in the physiopathological response to hepatic insults, including drug-induced liver injury.
authors: Exosomes Lab, CIC bioGUNE, CIBERehd, Derio 48160, Bizkaia, Spain. Electronic address: froyo.ciberehd@cicbiogune.es.
authors: Felix
authors: F
authors: Royo
authors: Exosomes Lab, CIC bioGUNE, CIBERehd, Derio 48160, Bizkaia, Spain.
authors: Laura
authors: L
authors: Palomo
authors: Exosomes Lab, CIC bioGUNE, CIBERehd, Derio 48160, Bizkaia, Spain.
authors: Justyna
authors: J
authors: Mleczko
authors: Exosomes Lab, CIC bioGUNE, CIBERehd, Derio 48160, Bizkaia, Spain.
authors: Esperanza
authors: E
authors: Gonzalez
authors: OWL, Parque Tecnológico de Bizkaia, Derio 48160, Bizkaia, Spain.
authors: Cristina
authors: C
authors: Alonso
authors: OWL, Parque Tecnológico de Bizkaia, Derio 48160, Bizkaia, Spain.
authors: Ibon
authors: I
authors: Martínez
authors: OWL, Parque Tecnológico de Bizkaia, Derio 48160, Bizkaia, Spain.
authors: Miriam
authors: M
authors: Pérez-Cormenzana
authors: OWL, Parque Tecnológico de Bizkaia, Derio 48160, Bizkaia, Spain.
authors: Azucena
authors: A
authors: Castro
authors: Exosomes Lab, CIC bioGUNE, CIBERehd, Derio 48160, Bizkaia, Spain; Metabolomics Platform, CIC bioGUNE, CIBERehd, Derio 48160, Bizkaia, Spain; IKERBASQUE Basque Foundation for Science, Bilbao, 48013, Bizkaia, Spain. Electronic address: jfalcon@cicbiogune.es.
authors: Juan M
authors: JM
authors: Falcon-Perez
mesh_terms: D000082:Acetaminophen; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal; D056486:Chemical and Drug Induced Liver Injury / Q000378:metabolism*; D004008:Diclofenac; D000067128:Extracellular Vesicles / Q000378:metabolism*; D022781:Hepatocytes / Q000378:metabolism*; D008297:Male; D055442:Metabolome; D017208:Rats, Wistar; D044967:Serum / Q000378:metabolism
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D004008:Diclofenac; D000082:Acetaminophen
keywords: Acetaminophen; Diclofenac; Drug-induced liver injury; Exosomes; Extracellular vesicles; Metabolomics; Serum