Figure 2.

Signaling events mediated by extracellular vesicles during hepatocyte lipotoxicity. Hepatocyte injury induced by lipotoxicity triggers the release of EVs (Hep-EVs) that drive the response of surrounding cells playing an important role during NAFLD progression to NASH such as hepatic inflammation, dysregulated angiogenesis, and fibrosis. Recent in vitro and in vivo studies have defined multiple Hep-EV cargos responsible of different phenotypic effects in the target cells. CXCL10 and ceramide-enriched EVs mediate monocyte/macrophage chemotaxis to the liver, whereas TRAIL-enriched EVs and miR192-5p contribute to macrophage activation. ITGβ-enriched EVs regulate monocyte adhesion to LSECs, and Hep-EVs can also activate NLRP3 inflammasome. VNN1-1–bearing EVs mediate endothelial cell migration and tube formation and neovascularization, whereas miR-128-3p–laden EVs induce HSC proliferation and activation. EV, extracellular vesicles; CXCL10, C-X-C motif chemokine ligand 10; Cer, ceramide; S1P, sphingosine 1-phosphate; TRAIL, tumor necrosis factor–like apoptosis inducing ligand; ITGβ1, integrin β1, LSEC, liver sinusoidal endothelial cells; NLRP3, nucleotide-binding oligomerization domain-like receptor protein 3; VNN1, vanin-1; EC, endothelial cells; HSCs, hepatic stellate cells; NAFLD, nonalcoholic fatty liver; NASH, nonalcoholic steatohepatitis.