dc.contributor.author | Garcia-Martinez, Irma | |
dc.contributor.author | Alen, Rosa | |
dc.contributor.author | Pereira, Laura | |
dc.contributor.author | Povo-Retana, Adrián | |
dc.contributor.author | Astudillo, Alma M | |
dc.contributor.author | Hitos, Ana B | |
dc.contributor.author | Gomez-Hurtado, Isabel | |
dc.contributor.author | Lopez-Collazo, Eduardo | |
dc.contributor.author | Boscá, Lisardo | |
dc.contributor.author | Francés, Rubén | |
dc.contributor.author | Lizasoain, Ignacio | |
dc.contributor.author | Moro, María Ángeles | |
dc.contributor.author | Balsinde, Jesús | |
dc.contributor.author | Izquierdo, Manuel | |
dc.contributor.author | Valverde, Ángela M | |
dc.date.accessioned | 2024-02-19T10:07:01Z | |
dc.date.available | 2024-02-19T10:07:01Z | |
dc.date.issued | 2023-08 | |
dc.identifier.citation | JHEP Rep. 2023 Apr 7;5(8):100756. | es_ES |
dc.identifier.uri | http://hdl.handle.net/20.500.12105/18216 | |
dc.description.abstract | BACKGROUND & AIMS
Lipotoxicity triggers non-alcoholic fatty liver disease (NAFLD) progression owing to the accumulation of toxic lipids in hepatocytes including saturated fatty acids (SFAs), which activate pro-inflammatory pathways. We investigated the impact of hepatocyte- or circulating-derived small extracellular vesicles (sEV) secreted under NAFLD conditions on liver inflammation and hepatocyte insulin signalling.
METHODS
sEV released by primary mouse hepatocytes, characterised and analysed by lipidomics, were added to mouse macrophages/Kupffer cells (KC) to monitor internalisation and inflammatory responses. Insulin signalling was analysed in hepatocytes exposed to conditioned media from sEV-loaded macrophages/KC. Mice were i.v. injected sEV to study liver inflammation and insulin signalling. Circulating sEV from mice and humans with NAFLD were used to evaluate macrophage-hepatocyte crosstalk.
RESULTS
Numbers of sEV released by hepatocytes increased under NAFLD conditions. Lipotoxic sEV were internalised by macrophages through the endosomal pathway and induced pro-inflammatory responses that were ameliorated by pharmacological inhibition or deletion of Toll-like receptor-4 (TLR4). Hepatocyte insulin signalling was impaired upon treatment with conditioned media from macrophages/KC loaded with lipotoxic sEV. Both hepatocyte-released lipotoxic sEV and the recipient macrophages/KC were enriched in palmitic (C16:0) and stearic (C18:0) SFAs, well-known TLR4 activators. Upon injection, lipotoxic sEV rapidly reached KC, triggering a pro-inflammatory response in the liver monitored by Jun N-terminal kinase (JNK) phosphorylation, NF-κB nuclear translocation, pro-inflammatory cytokine expression, and infiltration of immune cells into the liver parenchyma. sEV-mediated liver inflammation was attenuated by pharmacological inhibition or deletion of TLR4 in myeloid cells. Macrophage inflammation and subsequent hepatocyte insulin resistance were also induced by circulating sEV from mice and humans with NAFLD.
CONCLUSIONS
We identified hepatocyte-derived sEV as SFA transporters targeting macrophages/KC and activating a TLR4-mediated pro-inflammatory response enough to induce hepatocyte insulin resistance.
IMPACT AND IMPLICATIONS
Small extracellular vesicles (sEV) released by the hepatocytes under non-alcoholic fatty liver disease (NAFLD) conditions cause liver inflammation and insulin resistance in hepatocytes via paracrine hepatocyte-macrophage-hepatocyte crosstalk. We identified sEV as transporters of saturated fatty acids (SFAs) and potent lipotoxic inducers of liver inflammation. TLR4 deficiency or its pharmacological inhibition ameliorated liver inflammation induced by hepatocyte-derived lipotoxic sEV. Evidence of this macrophage-hepatocyte interactome was also found in patients with NAFLD, pointing to the relevance of sEV in SFA-mediated lipotoxicity in NAFLD. | es_ES |
dc.description.sponsorship | This work was supported by grants PID2021-122766OB-I00 (AMV),
PID2019-105989RB-I00 (JB), PID2020-113238RB-I00 (LB), PID2019-
106581RB-I00 (MAM), PID2020-114148RB-I00 (MI), PID2019-107036RBI00 (RF), and RD21/0006/0001 (ISCIII) (IL) funded by Ministerio de
Ciencia e Innovación/Agencia Estatal de Investigación/10.13039/
501100011033 and ERDF ‘A way of making Europe’ by the European Union (MICINN/AEI/FEDER, EU), grant EFSD/Boehringer Ingelheim European
Research Programme on ‘Multi-System Challenges in Diabetes’ from the
European Foundation for the Study of Diabetes (AMV), P2022/BMD-7227
(Comunidad de Madrid, Spain) (AMV), Fundación Ramón Areces (Spain)
(AMV), CIBERdem (AMV and JB), CIBERhed (RF), and CIBERcv (LB) (ISCIII,
Spain). LB and AMV belong to the Spanish National Research Council’s
(CSIC’s) Cancer Hub. We also acknowledge the Spanish Ministry of
Economy and Competitiveness (MINECO) postdoctoral contract IJCI-2015-
24758 to IGM and the Spanish Ministry of Education, Culture and Sport
(MECD) FPU17/02786 grant to RA. | es_ES |
dc.language.iso | eng | es_ES |
dc.publisher | Elsevier | es_ES |
dc.type.hasVersion | VoR | es_ES |
dc.rights.uri | http://creativecommons.org/licenses/by-nc-nd/4.0/ | * |
dc.title | Saturated fatty acid-enriched small extracellular vesicles mediate a crosstalk inducing liver inflammation and hepatocyte insulin resistance. | es_ES |
dc.type | journal article | es_ES |
dc.rights.license | Attribution-NonCommercial-NoDerivatives 4.0 Internacional | * |
dc.identifier.pubmedID | 37360906 | es_ES |
dc.format.volume | 5 | es_ES |
dc.format.number | 8 | es_ES |
dc.format.page | 100756 | es_ES |
dc.identifier.doi | 10.1016/j.jhepr.2023.100756 | es_ES |
dc.contributor.funder | Ministerio de Ciencia e Innovación (España) | es_ES |
dc.contributor.funder | European Foundation for the Study of Diabetes | es_ES |
dc.contributor.funder | Comunidad de Madrid (España) | es_ES |
dc.contributor.funder | Fundación Ramón Areces | es_ES |
dc.contributor.funder | Instituto de Salud Carlos III | es_ES |
dc.contributor.funder | Ministerio de Educación, Cultura y Deporte (España) | es_ES |
dc.description.peerreviewed | Sí | es_ES |
dc.identifier.e-issn | 2589-5559 | es_ES |
dc.relation.publisherversion | 10.1016/j.jhepr.2023.100756 | es_ES |
dc.identifier.journal | JHEP reports : innovation in hepatology | es_ES |
dc.repisalud.orgCNIC | CNIC::Grupos de investigación::Fisiopatología Neurovascular | es_ES |
dc.repisalud.institucion | CNIC | es_ES |
dc.rights.accessRights | open access | es_ES |
dc.relation.projectFECYT | info:eu-repo/grantAgreement/ES/PID2021-122766OB-I00 | es_ES |
dc.relation.projectFECYT | info:eu-repo/grantAgreement/ES/PID2019-105989RB-I00 | es_ES |
dc.relation.projectFECYT | info:eu-repo/grantAgreement/ES/PID2020-113238RB-I00 | es_ES |
dc.relation.projectFECYT | info:eu-repo/grantAgreement/ES/PID2019-106581RB-I00 | es_ES |
dc.relation.projectFECYT | info:eu-repo/grantAgreement/ES/PID2020-114148RB-I00 | es_ES |
dc.relation.projectFECYT | info:eu-repo/grantAgreement/ES/PID2019-107036RBI00 | es_ES |
dc.relation.projectFECYT | info:eu-repo/grantAgreement/ES/RD21/0006/0001 | es_ES |
dc.relation.projectFECYT | info:eu-repo/grantAgreement/ES/P2022/BMD-7227 | es_ES |
dc.relation.projectFECYT | info:eu-repo/grantAgreement/ES/FPU17/02786 | es_ES |