• 2019-07
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  • 2019-11
  • 2020-03
  • 2020-08
  • iii Gut microbiota influences bile


    iii) Gut microbiota influences bile ABT-888 (Veliparib) metabolisms mainly through the stimulation of the bile-acid-activated nuclear receptor, farnesoid X receptor (FXR). On the contrary, altered bile acid composition, induced by dietary fats, may result in dysbiosis [31]. Furthemore, high-fat diet has been shown to alter the gut microbiota and increase levels of the gut metabolite deoxycholic acid (DCA). The enterohepatic circulation of DCA causes senescence-associated secretory phenotype (SASP) phenotype in HSCs, which in turn secretes inflammatory and tumor-promoting factors in the liver, thus facilitating HCC development in mice [38]. Another mechanism involved in the gut-liver crosstalk is the diet-induced microbiome changes concerning choline intake. Choline is a phospolipid component of cell membrane and has a relevant role in liver fat metabolism, very-low-lipoprotein assembly and induction of lipids transport from the liver. Therefore, choline deficiency may be involved in the development of hepatic steatosis. As previously reviewed by Aron-Wisnewsky et al., high-fat diet increases microbiota-mediated conversion of dietary choline into toxic methylamines (dimethylamine and trimethylamine). In addition, the dysfunctional liver metabolism of these toxic amines produces trimethylamine-N-oxide, which promote liver inflammation [31].
    Obesity-related inflammatory phenothype and the crosstalk with liver microenvironment Adipose tissue expansion occurring in obesity involves tissue remodeling which is characterized by recruitment of pre-adipocytes, endothelial precursors, and macrophages, in a complex cell-cell interaction. This results in adipocyte differentiation, connective tissue proliferation and angiogenesis. Also, adipose tissue remodeling induces a relevant alteration in the adipokine secretion pattern of adipocytes and recruited macrophages. Dysregulation of hormonal and inflammatory pathways induced by visceral obesity causes a chronic low-grade inflammatory state, which is a favorable condition for HCC development [4]. The main factors involved in the obese-related inflammation as well as in liver cancer include the release of cytokines (i.e. IL-6, TNF╬▒) by expanded visceral adipose tissue, the adipokines imbalance and the cell senescence.
    Insulin resistance and the crosstalk with liver microenvironment The strong link between visceral obesity and insulin resistance (IR) is well known. However, IR may be not only adipose tissue-related. In fact, liver accumulation of fatty acid metabolites induces hepatic IR. One of the main fatty acid metabolite involved in hepatic IR is diacylglycerol (DAG). DAG hepatocyte content observed in liver steatosis has been proposed as a strong predictor of hepatic IR [41]. The consequent hyperinsulinemia downregulates hepatocytes expression of IRS2 and enhances hepatic IR. In addition, although unable to suppress gluconeogenesis, insulin may chronically stimulate lipogenesis through activation of SREBP-1c, inducing further fat deposition and hepatic IR in a vicious circle [11]. Interestingly, the liver microenvironment may induce IR in nonhepatic tissues. In fact, an increase in liver fat content may be considered as the strongest predictor of skeletal muscle, hepatic and adipose tissue IR, regardless of adiposity. In other words, liver fat content may predict development of metabolic syndrome, diabetes or prediabetic conditions. For example, low levels of hepatic fats predict metabolically healthy obesity, a condition characterized by lower IR and lower cardiovascular risk [42]. The underlying mechanism may be the altered gene expression and protein synthesis and secretion observed in NAFLD. In fact, hepatocytes secrete a class of proteins named hepatokines, including fetuin A, fetuin B, retinol-binding protein 4 (RBP4) and selenoprotein P, which have been correlated with higher risk of IR and development of DMII [42]. It is known that an increase in insulin secretion into the blood (hyperinsulinemia) occurs to overcome IR. Hyperinsulinemia is considered a risk factor for liver fibrosis and HCC development. In fact, hyperinsulinemia may induce liver fibrosis progression by activation of HSCs, dysregulate the proliferation-apoptosis balance in hepatic cells, and stimulate angiogenesis. The most studied pathway involved in insulin-mediated HCC development (particularly in NAFLD-related HCC) is the IGF signaling axis, which exerts a growth factor-like activity on hepatocytes and a pro-angiogenic activity on the hepatic vascular system [43]. Insulin receptors (IRS) bind to insulin or IGF and share the same pro-oncogenic pathways with IGF1 receptor (IGF1R), including the activation of P13K/Akt and MAPK. A reduced expression of IGF-binding proteins (IGFBPs), along with an increased protease activity on these proteins (e.g. cathepsin D), which determines an augmented IGFs bioavailability, has been reported in mouse and human HCC cells. In addition, the overexpression of IGF1R in HCC and the increase of IGF2R circulating levels in cirrhotic patients have been observed [43]. Interestingly, IGF-1 expression in hepatic tissue adjacent to tumor was related to survival after HCC resection, suggesting an IGF-1 paracrine effect of adjacent tissue on tumor cells, which result in a more aggressive phenotype [44].