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  • br The active role of liver microenvironment in


    The active role of liver microenvironment in HCC development on a dysmetabolic background The initial “two-hit hypothesis” of NASH pathogenesis considering steatosis as the first step followed by a “second hit” of injury due to inflammation and oxidative stress has been gradually replaced by the “multiple-hits hypothesis”, according to which the described above events occur in parallel. Therefore, the triglycerides storage may be an early adaptive and protective stress response to hepatocytes injuries [11]. Interestingly, more recent evidence shows the key role of liver microenvironment in NAFLD progression. In fact, liver microenvironment is considered a proinflammatory milieu, based on the wide variety of immunologically active cells, such as Kupffer cells, T Mocetinostat (MGCD0103, MG0103) and several antigen presenting cells, hepatic stellate cells (HSCs) and endothelial cells. For example, HSCs express Toll like receptor 4 (TLR4), activate IKB Kinase/NF-kB and JNK pathways and release proinflammatory cytokines (i.e. IL6, TGFβ1 and MCP1) with consequent T cells recruitment upon activation by a liver injury [24]. Hedgehog signaling, involved in modulation of myofibroblast transdifferentiation by recruitment of NKT cells, has been related to fibrosis stage in NASH patients [25]. As a consequence of this complex proinflammatory and fibrogenic background, cell death of liver cells occur, thus amplifying these processes. Also, cellular senescence may have a relevant role in steatosis to HCC transition. In fact, the increased ability of senescent cells (i.e. HSCs) to secrete cytokines, chemokines, matrix remodeling factors and growth factors known as senescence-associated secretory phenotype (SASP) has been related to fibrosis progression [26]. In summary, the proinflammatory and fibrogenic liver microenvironment plays a determinant role in NAFLD progression in addition to a persistent external injury. Several pathobiological factors and mechanisms interact with the liver microenvironment in a bidirectional crosstalk creating, in the long term, potential pro-oncogenic substrates that increase the probability of HCC development (Fig. 2). Among these substrates, the interactions with the gut microbiota, the obesity-inflammatory phenotype, the insulin resistance, the lipid and metabolism of bile acids are the main investigated fields and therefore hereafter reviewed.
    Microbiota and the crosstalk with the liver microenvironment The discovery of fatal NASH complicating jejunoileal bypass in bariatric surgery and the reversal of trend after metronidazol therapy was the basis for the scientific interest on the role of gut microbiota in NAFLD progression [27]. As reviewed in detail, a higher prevalence of small intestinal bacterial overgrowth (SIBO) has been observed in patients with NASH [28]. Also, specific microflora changes may have a role in steatosis progression, particularly in obese patients. For example, NASH patients showed reduced Bacteroides and increased alcohol-producing species [29], [30]. The following main mechanisms implicated in the progression of gut microbiota-related NAFLD to NASH and HCC have been described: i) alteration of intestine permeability; ii) persistent activation of innate immune system with consequent inflammation; iii) changes in dietary choline and bile acid metabolism [31]. i) Patients with NAFLD show increased gut permeability with altered tight junctions, and these alterations may be induced by high fat diet. Therefore, dysbiosis may induce intestinal inflammation, bacterial and TLR4/TLR9 agonist traslocation to the liver, activation of inflammatory pathways (i.e. TNFα) and eventually progression of steatosis [31]. ii) Innate immunity has a crucial role in modulation of the crosstalk between the gut and the liver and its persistent activation has been implicated in HCC development. In this field of investigation, many observations show a crucial role of lipopolysaccharide (LPS), a known innate immune system activator. In fact, a higher prevalence of gram-negative bacteria in microbiota known to produce LPS was involved in liver fibrosis progression in a mouse model [32]. The key role of LPS was also well described by Cani et al. in mouse models. These authors described increased LPS levels after high fat diet, NASH development after subcutaneous LPS infusion and beneficial metabolic effects on glucose intolerance and fat mass after antibiotics treatments [33]. These findings were confirmed in human study wherein increased LPS-binding protein (LBP) levels were reported in NAFLD obese patients and even more in NASH obese patients, correlating with liver TNFα expression [34]. In mouse models of hepatocarcinogenesis, the gut microbiota was found to be involved in HCC progression, rather than initiation, through activation of TLR4 signaling in HSCs [35]. Another important mediator of the liver-gut interaction is Toll Like Receptor 5 (TLR5), expressed in gut mucosa. In fact, in TLR5-deficient mice, features of microbiome-mediated metabolic syndrome can be transferred to wild type mice by microflora transmittion [36]. Also, inflammasomes sensors of exogenous PAMPs and DAMPs (pathogen- and damaged-associated molecular patterns), regulating maturation of IL1β and IL18, may play a key role in the gut-liver crosstalk. In fact, changes in inflammasome-deficiency-related microbioma have been related to NAFLD progression and metabolic features, both transferred to wild-type cohabitating Mocetinostat (MGCD0103, MG0103) mice. Interestingly, antibiotics reduced NASH severity in inflammasome-deficient mice and prevented NASH phenotype transmission [37]. All these findings emphasize how changes in the microbiome, in combination with loss of innate immune sensors, may induce metabolic liver disorders.