fig4

Figure 4. Main mechanisms involved in the development of HCC. A: chronic alcohol consumption increases the production of its main toxic metabolite acetaldehyde, favoring mitochondrial dysfunction and oxidative stress perpetuating liver injury. In the long run, this will generate a decreased function of TJ and AJ, interfering with the protective barrier of the intestine, developing a leaky gut. B: we can see how the bacterial overgrowth and translocation of its metabolites to the liver will increase liver injury and the recognition of PAMPs by specific TLRs such as TLR-4 binding with its ligand MYD88 and with the final activation of NF-κβ pathway with important repercussion for systemic inflammation and HCC development. ADH: alcohol dehydrogenase; MEOS: microsomal ethanol oxidizing system; ALDH: aldehyde dehydrogenase; DRP1: dynamin-related protein 1; CYP2E1: cytochrome P450 2E1; ROS: reactive oxygen species; TJ: tight junction proteins; AJ: adhesion junction proteins; PAMPs: pathogen-associated molecular patterns; TLR4: toll-like receptor-4; KCs: kupffer cells; HSCs: hepatic stellate cells; MYD88: myeloid differentiation primary response 88; JNK: c-Jun N-terminal kinase; MAPK: mitogen-activated protein kinase; IKK2: inhibitor of nuclear factor kappa-B kinase 2; NF-κβ: nuclear-factor κβ; TNF: tumor necrosis factor; TRAF-1: TNF receptor associated factor-1; TRAF-2: TNF receptor associated factor-2; HCC: hepatocellular carcinoma