New mechanisms involving the EGFR and FGF15/19 systems in liver regeneration and carcinogenesis

Excerpt

In response to tissue injury the liver mounts a robust protective and regenerative response aimed at the restoration of the lost or damaged parenchyma. Different molecules have been identified to play important roles in the coordination of the reparative process after liver damage. These can be of varied molecular nature, including inflammatory mediators like cytokines, growth factors such as epidermal growth factor receptor (EGFR) ligands, and metabolites like bile acids (BAs) [1]. These molecules establish complex crosstalks involving different liver cell types, and in some instances also extrahepatic tissues, ultimately leading to the survival and proliferation of hepatocytes and non-parenchymal cells. The identification of biologically relevant and potent effectors of liver tissue repair may provide new therapeutic tools to treat acute liver failure, allow more extensive hepatic resection in oncologic surgery, and utilize smaller or marginal liver grafts. BAs are emerging as key metabolites involved in liver regeneration after partial hepatectomy (PH). Their intrahepatic and serum levels transiently increase after liver tissue resection, and the preservation of the enterohepatic circulation of BAs seems to be essential for liver regeneration [2, 3]. BAs can interact with the cell surface receptor TGR5 and also with the nuclear receptor FXR, and both interactions are important for liver regeneration to proceed normally. BAs are taken up from the gut lumen in the distal ileum, and return to the liver through the portal circulation. It has been known for many years that portal blood containes essential components for liver regeneration after PH, and BAs could be one of these components that promote hepatic growth [1]. Importantly, during their passage through the ileal enterocytes BAs also bind and activate their FXR receptor. One of the FXR target genes in the ileal enterocytes is fibroblast growth factor 19 (FGF19, FGF15 in rodents). FGF15/19 has been recently characterized as an important hormone with effects similar to those of insulin, and a potent inhibitory action on liver BA synthesis. We have identified a new role for FGF15/19 in liver regeneration after PH. FGF15/19 deficient mice showed reduced survival after liver tissue resection, attributable to their inability to downregulate BA synthesis after PH and the consequent toxic cholestasis [3]. Importantly, we could also demonstrate that FGF15/19 was also essential for the growth-promoting effects of BAs on liver parenchymal cells and cholangiocytes. Indeed, the proliferative effects of a cholate-supplemented diet observed in wild type mice were markedly attenuated in FGF15/19 deficient animals [3] ( Figure 1 ). These findings attest to the importance of FGF15/19 in liver regeneration, and led us to test the efficacy of exogenously administered FGF15 in mice subjected to extensive liver resection (85% PH), a clinically relevant model of the small-for-size syndrome. Overexpression of FGF15 in the liver of wild type mice, by means of an adenoviral vector encompassing FGF15 cDNA, significantly enhanced mouse survival. While all mice infected with a control adenovirus died 24 h after 85% PH, almost 50% of mice infected with the FGF15 expressing adenoviral vector survived the intervention. These findings support the potential application of FGF15/19 as a liver pro-regenerative strategy in the acute setting.

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