fig1
Figure 1. Multifactorial pathogenesis of NAFLD-related HCC. Single nucleotide polymorphism (GCKR, MBOAT7, PNPLA3, and TM6SF2) have been associated to the development of both NAFLD and HCC and the NASH-HCC mutational profiling (TERT promoter, CTNNB1, TP53, and ACVR2A) and signature (MutSig-NASH-HCC) have been recently described. Hyperinsulinemia and obesity favor chronic liver inflammation and DNA damage through ROS production, ER stress and inhibition of fatty free acid oxidation. The higher levels of IL-6 and TNF-α promote the activation of STAT-3, a transcription factor which is involved in HCC development. Hyperinsulinemia induced IGF1 expression that phosphorylates insulin receptor substrates 1 leading to the activation of mTOR and MAPK pathways and therefore to cell proliferation, inhibition of apoptosis and HCC development. A role for the immune system has also been described, involving the intratumor CD8+ PD1+ cells, platelet (PLT) and IgA plasma cells and the circulating NET. In addition, dysbiosis and gut hyperpermeability expose the liver to bacterial metabolites and MAMPs promoting HCC development. EC: Enterocyte cell; ER: endoplasmic reticulum; FFA: free fatty acid; GCKR: glucokinase regulator; HCC: hepatocellular carcinoma; HSC: hepatic stellate cell; HSD17B13: 17β-hydroxysteroid dehydrogenase 13; IgA: immunoglobulin A; IGF: insulin-like growth factor; IGFBP: insulin-like growth-factor binding protein; IGFR: insulin-like growth-factor receptor; IL: interleukin; IRS: insulin receptor substrate; MAMPS: microbe-associated molecular pattern; MAPK: mitogen-activated protein kinase; MBOAT7: membrane-bound O-acyltransferase domain containing 7; mTOR: mammalian target of rapamycin; NAFLD: non-alcoholic fatty liver disease; NET: neutrophil extracellular traps;
