Fig. 3.

Multicellular cross-talks during NAFLD progression 1) insulin resistance is a potential nexus between T2DM and NAFLD that leads to glucolipotoxicity, which stimulates ROS generation and increases endoplasmic reticulum stress resulting in cell death e.g., apoptosis and necroptosis 2) dead cells activate HSC and Kupffer cells by various mechanisms including apoptotic bodies engulfment and DAMP release 3) “find me” signals released by dead cells stimulate inflammatory cells infiltration to the liver 4) lipid stressed HC could secrete EV that stimulate fibrogenic gene expression in HSC 5) free cholesterol and FFA could also directly activate HSC 6) intestine-derived LPS activate both HSC and KC 7) microbiota-derived ethanol precipitates in increased ROS generation 8) activated KC secrete TGF-β resulting in activation of HSC 9) defenestrated LSEC (LSEC capillarization) support HSC activation and acquire inflammatory phenotype that induces liver inflammation. As a result of HSC activation, ECM production increases, leading to liver fibrosis, which could progress further to cirrhosis or liver cancer [179]. DAMP, damage-associated molecular patterns; ECM, extracellular matrix; ER, endoplasmic reticulum; EV, extracellular vesicle; FFA, free fatty acids; HC, hepatocyte; HSC, hepatic stellate cells; KC, Kupffer cells; LPS, lipopolysaccharide; LSEC, liver sinusoidal endothelial cells; MC, monocytes; ROS, reactive oxygen species; TGF, tumor growth factor.