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New messengers in the intreactome between hepatic and extra-hepatic cells in non' alcoholic fatty liver disease with diagnostic value

19th national competition for scientific and technical research

Intercellular Dialogue and Interactome: Pathological Implications

Senior Researcher : Ángela María Martínez Valverde

Research Centre or Institution : Instituto de Investigaciones Biomédicas "Alberto Sols". CSIC-Universidad Autónoma de Madrid.


Background and Aims: Extracellular vesicles (EVs) have emerged as key mediators in non-alcoholic fatty liver disease (NAFLD). As part of this project we aimed to analyze the specific role of lipotoxic hepatocyte-derived EVs inflammation and insulin resistance in the liver, as well as in extra-hepatic tissues with a major focus in the pancreas.

Methods: C57BL/6J male mice were fed a chow (CHD) or high-fat diet (HFD) for 12-14 weeks. EVs were isolated from: 1) primary hepatocytes (PH) from chow diet-fed mice without (EVC) or with palmitic acid treatment (EVPA), 2) hepatocytes from HFD-fed mice (EVHFD). To study inflammatory responses in the liver, in vivo injections of hepatocyte-derived EVs were conducted in lean mice in the absence or presence of a Toll-like receptor 4 (TLR4) inhibitor. The crosstalk between macrophages and hepatocytes was also evaluated using circulating EVs from lean (Circ-EVC) or obese (Circ-EVHFD) mice and humans without (h-EVC) or with NAFLD (h-EVNAFLD). Moreover, EVs were used to treat pancreatic islets to analyze EVs internalization in intra- and peri- islet macrophages and their effect in glucose-stimulated insulin secretion (GSIS).

Results: The release of PH-EV, Circ-EV and h-EV was increased under NAFLD conditions. In vivo injection of hepatocyte-derived lipotoxic EVs identified Kupffer cells as early targets leading to increased JNK phosphorylation, infiltration of inflammatory monocytes, NF-kB nuclear translocation in both immune cells and hepatocytes, and pro-inflammatory cytokine expression in the liver. Importantly, these effects were attenuated by TLR4 inhibition. Likewise, circulating EVs from obese mice and NAFLD patients (Circ-EVHFD and h-EVNAFLD, respectively) triggered macrophage inflammation that resulted in impaired insulin signaling in hepatocytes. Regarding extra-hepatic effects, EVs released by lipotoxic hepatocytes were able to trigger NF-kB nuclear translocation in intra- and peri- islet macrophages in parallel with an impairment in GSIS.

Conclusion: At the molecular level, we have identified: i) Hepatocyte-derived EVs as potent inducers of TLR4/NFκB-mediated liver inflammation. Ii) The macrophage-hepatocyte interactome mediated by lipotoxic circulating EVs involvement in mice and patients with NAFLD. iii) The pancreatic islet as another target of hepatocyte-derived lipotoxic EVs-mediated inflammation.


Scientific Production
Magazine Articles 2
Communications at national conferences 2
Communications at international conferences 1


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