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• W2150191954 abstract "See “Fibroblast growth factor signaling controls liver size in mice with humanized livers,” by Naugler WE, Tarlow BD, Fedorov LM, et al, on page 728. See “Fibroblast growth factor signaling controls liver size in mice with humanized livers,” by Naugler WE, Tarlow BD, Fedorov LM, et al, on page 728. The liver possesses an extraordinary regenerative capacity that is triggered upon death of parenchymal cells or after partial liver resection. This fundamental response likely evolved to protect the organ and the organism from endogenous and exogenous toxins and thus preserve systemic metabolic homeostasis.1Michalopoulos G.K. Liver regeneration after partial hepatectomy: critical analysis of mechanistic dilemmas.Am J Pathol. 2010; 176: 2-13Abstract Full Text Full Text PDF PubMed Scopus (555) Google Scholar A number of mediators involved in the onset and termination of liver regeneration have been identified over the years, and these where categorized by the late Nelson Fausto into 3 types of interconnected pathways known as the cytokine, growth factor, and metabolic networks.2Fausto N. Campbell J.S. Riehle K.J. Liver regeneration.Hepatology. 2006; 43: S45-53Crossref PubMed Scopus (1262) Google Scholar Most of this knowledge has been acquired from partial hepatectomy (PH), hepatocyte transplantation, and liver transplantation experiments performed in animal models.3Michalopoulos G.K. DeFrances M.C. Liver regeneration.Science. 1997; 276: 60-66Crossref PubMed Scopus (2884) Google Scholar These studies revealed the tremendous proliferative ability of the hepatocyte, with an almost unlimited clonogenic potential. However, they also demonstrated that the regenerative response was proportional to the liver mass removed in the case of PHs, and that the size of the transplanted liver adapts (ie, grows or shrinks) in relation to the size of the recipient body.3Michalopoulos G.K. DeFrances M.C. Liver regeneration.Science. 1997; 276: 60-66Crossref PubMed Scopus (2884) Google Scholar Such findings indicate the existence of mechanisms that tightly control the onset and termination of adult liver growth, namely, a “hepatostat,” or specific sensors that maintain the proper liver size.1Michalopoulos G.K. Liver regeneration after partial hepatectomy: critical analysis of mechanistic dilemmas.Am J Pathol. 2010; 176: 2-13Abstract Full Text Full Text PDF PubMed Scopus (555) Google Scholar Given the fundamental role of the liver in systemic metabolism, it was likely that this hepatostat would reside at least in part within the metabolic network. In this context, bile acids (BA) are increasingly recognized as key players in the regulation of liver regeneration and constitute attractive candidates to modulate the hepatostat. Indeed, systemic and intrahepatic BA levels increase shortly after PH both in rodents and humans, and the modulation of BA enterohepatic circulation strongly influences liver regeneration.4Gilgenkrantz H. Tordjmann T. Bile acids and FGF receptors: orchestrators of optimal liver regeneration.Gut. 2015 Feb 5; ([Epub ahead or print])PubMed Google Scholar Early experimental reports also showed that feeding BA-enriched diets elicited hepatocyte proliferation and liver growth.4Gilgenkrantz H. Tordjmann T. Bile acids and FGF receptors: orchestrators of optimal liver regeneration.Gut. 2015 Feb 5; ([Epub ahead or print])PubMed Google Scholar, 5Fan M. Wang X. Xu G. et al.Bile acid signaling and liver regeneration.Biochim Biophys Acta. 2015; 1849: 196-200Crossref PubMed Scopus (69) Google Scholar In contrast, BA levels need to be finely tuned to avoid their excess and hepatic toxicity. The nuclear receptor farnesoid X receptor (FXR) is a central transcriptional sensor of BA metabolic cascades, as was originally demonstrated in FXR-null mice undergoing PH.6Huang W. Ma K. Zhang J. et al.Nuclear receptor-dependent bile acid signaling is required for normal liver regeneration.Science. 2006; 312: 233-236Crossref PubMed Scopus (525) Google Scholar FXR is highly expressed in the liver and in the enterocytes.7Modica S. Gadaleta R.M. Moschetta A. Deciphering the nuclear bile acid receptor FXR paradigm.Nucl Recept Signal. 2010; 8: e005Google Scholar The main FXR target gene in the gut is fibroblast growth factor 15 (FGF15; FGF19 in humans), which is an enterokine secreted into the portal blood upon BA stimulation. FGF15/19 reaches the liver where it activates the duo FGF receptor 4 (FGFR4)/beta KLOTHO on the hepatocyte basolateral membrane triggering intracellular pathways that repress cholesterol 7-α-hydroxylase (CYP7A1), which is the rate limiting enzyme in BA synthesis.8Inagaki T. Choi M. Moschetta A. et al.Fibroblast growth factor 15 functions as an enterohepatic signal to regulate bile acid homeostasis.Cell Metab. 2005; 2: 217-225Abstract Full Text Full Text PDF PubMed Scopus (1325) Google Scholar The down-regulation of BA synthesis via intestinal FXR/FGF15 activation is known to protect from cholestatic injury even when FXR is ablated in the liver.9Modica S. Petruzzelli M. Bellafante E. et al.Selective activation of nuclear bile acid receptor FXR in the intestine protects mice against cholestasis.Gastroenterology. 2012; 142 (e1–4): 355-365Abstract Full Text Full Text PDF PubMed Scopus (213) Google Scholar Indeed, FGF15/19 inhibits hepatocellular CYP7A1 expression in a complex and not completely understood manner. As occurs for FXR, FGF15/19 action also depends on the transcriptional repressor small heterodimer partner (SHP). However, FGF15/19 does not change SHP protein levels or the position of this repressor on the CYP7A1 promoter, suggesting the involvement of additional factors that interact with the SHP complex.10Kliewer S.A. Mangelsdorf D.J. Bile Acids as Hormones: The FXR-FGF15/19 pathway.Dig Dis. 2015; 33: 327-331Crossref PubMed Scopus (237) Google Scholar In the liver, FXR seems to promote directly hepatocellular proliferation by the induction of the transcription factor FoxM1b.6Huang W. Ma K. Zhang J. et al.Nuclear receptor-dependent bile acid signaling is required for normal liver regeneration.Science. 2006; 312: 233-236Crossref PubMed Scopus (525) Google Scholar In contrast, when FGF15 binds to the FGFR4/beta KLOTHO complex, there is a net reduction of BA overload and injury after PH, and a putative contribution to liver regeneration through the up-regulation of FoxM1b, among other proliferative genes, suggesting that FoxM1b can be also activated in an FXR-independent manner.11Uriarte I. Fernández-Barrena M.G. Monte M.J. et al.Identification of fibroblast growth factor 15 as a novel mediator of liver regeneration and its application in the prevention of post-resection liver failure in mice.Gut. 2013; 62: 899-910Crossref PubMed Scopus (136) Google Scholar, 12Padrissa-Altés S. Bachofner M. Bogorad R.L. et al.Control of hepatocyte proliferation and survival by Fgf receptors is essential for liver regeneration in mice.Gut. 2014 Nov 21; ([Epub ahead of print])PubMed Google Scholar Together, these findings point to an important role for the BA–FXR–FGF15 axis in the regulation of liver growth. Interestingly, FXR expression is down-regulated upon acute BA accumulation in the liver,11Uriarte I. Fernández-Barrena M.G. Monte M.J. et al.Identification of fibroblast growth factor 15 as a novel mediator of liver regeneration and its application in the prevention of post-resection liver failure in mice.Gut. 2013; 62: 899-910Crossref PubMed Scopus (136) Google Scholar as well as in certain cholestatic conditions,13Schaap F.G. van der Gaag N.A. Gouma D.J. et al.High expression of the bile salt-homeostatic hormone fibroblast growth factor 19 in the liver of patients with extrahepatic cholestasis.Hepatology. 2009; 49: 1228-1235Crossref PubMed Scopus (211) Google Scholar and this response may represent an adaptive mechanism evolved to prevent excessive liver growth. In this issue of Gastroenterology, Naugler et al,14Naugler W.E. Tarlow B.D. Fedorov L.M. et al.Fibroblast growth factor signaling controls liver size in mice with humanized livers.Gastroenterology. 2015; 149: 728-740Abstract Full Text Full Text PDF PubMed Scopus (73) Google Scholar working in an elegant experimental model of mice with humanized livers, make a strong case for BAs as key players in the regulation of the hepatostat. Mice with humanized livers are chimeric models in which the recipient animals are transplanted with human hepatocytes that extensively repopulate the liver parenchyma.15Grompe M. Strom S. Mice with human livers.Gastroenterology. 2013; 145: 1209-1214Abstract Full Text Full Text PDF PubMed Scopus (95) Google Scholar In one of these models, the immune deficient Fah-/-, Rag2-/-, Il2r-/-, NOD mice, or FRGN mice, in which human hepatocyte repopulation is favored by an inducible murine suicidal hepatocyte genetic defect, Markus Grompe and his team16Ellis E.C.S. Nauglers S. Parini P. et al.Mice with chimeric livers are an improved model for human lipoprotein metabolism.PLoS ONE. 2013; 8: e78550Crossref PubMed Scopus (39) Google Scholar previously described the overexpression of CYP7A1 in the transplanted, proliferating human hepatocytes along with a marked elevation in the BA pool. This situation was reversed upon administration of recombinant FGF19, suggesting that transplanted human hepatocytes were not sensitive to murine FGF15 (which is elevated in this model), but retained the ability to respond to the human enterokine.16Ellis E.C.S. Nauglers S. Parini P. et al.Mice with chimeric livers are an improved model for human lipoprotein metabolism.PLoS ONE. 2013; 8: e78550Crossref PubMed Scopus (39) Google Scholar These findings, together with the increased liver size observed in these chimeric mice, provided Naugler et al with an excellent model in which to further test the role of BA in liver growth, in the absence of the potentially confounding signals elicited during PH. The authors then restored the physiologic regulation of the BA pool in these mice by generating a transgenic strain of FRGN mice in which the FGF19 gene, along with its regulatory region, was introduced.14Naugler W.E. Tarlow B.D. Fedorov L.M. et al.Fibroblast growth factor signaling controls liver size in mice with humanized livers.Gastroenterology. 2015; 149: 728-740Abstract Full Text Full Text PDF PubMed Scopus (73) Google Scholar Human hepatocytes were then transplanted into these FRGN19+ mice and the control FRGN animals, and 4 months later liver repopulation by human hepatocytes was complete. FRGN19+ mice showed very low levels of FGF19 messenger RNA in the intestine and FGF19 protein was undetectable in sera under normal conditions. However, BA infusion led to marked elevations in FGF19 expression, indicating that these mice responded to BA signaling as expected. It was shown previously that in patients with cholestasis hepatic specific expression of FGF19 was up-regulated,13Schaap F.G. van der Gaag N.A. Gouma D.J. et al.High expression of the bile salt-homeostatic hormone fibroblast growth factor 19 in the liver of patients with extrahepatic cholestasis.Hepatology. 2009; 49: 1228-1235Crossref PubMed Scopus (211) Google Scholar whereas under normal conditions FGF19 is expressed only in the intestine. In the present study, the authors performed bile duct ligation and induced cholestasis. Intriguingly, the humanized FRGN19+ mice began transcribing FGF19 in the liver. Notably, the immunolocalization revealed a nonparenchymal expression pattern of the enterokine, indicating that human hepatocytes do not express FGF19, even in cholestatic conditions. In agreement with previous findings in FGF19–treated FRGN mice,16Ellis E.C.S. Nauglers S. Parini P. et al.Mice with chimeric livers are an improved model for human lipoprotein metabolism.PLoS ONE. 2013; 8: e78550Crossref PubMed Scopus (39) Google Scholar hyperexpression of hepatic CYP7A1 was corrected in FRGN19+ animals, and this response was accompanied by the restoration of a normal (decreased) total BA pool size. This finding is consistent with observations in other mouse models demonstrating that FGF19 or FGF15 administration decreased hepatic CYP7A1 expression and BA levels, and confirms the central role played by this enterokine in the regulation of BA metabolism.9Modica S. Petruzzelli M. Bellafante E. et al.Selective activation of nuclear bile acid receptor FXR in the intestine protects mice against cholestasis.Gastroenterology. 2012; 142 (e1–4): 355-365Abstract Full Text Full Text PDF PubMed Scopus (213) Google Scholar, 11Uriarte I. Fernández-Barrena M.G. Monte M.J. et al.Identification of fibroblast growth factor 15 as a novel mediator of liver regeneration and its application in the prevention of post-resection liver failure in mice.Gut. 2013; 62: 899-910Crossref PubMed Scopus (136) Google Scholar Interestingly, the size of the livers repopulated with human hepatocytes in FRGN19+ mice was almost 3 times smaller than that found in FRGN animals, and this was not owing to differences in the percentage of repopulation between the 2 strains. Taken together, these findings provide additional support to the hypothesis of liver growth being regulated by the size of the BA pool (Figure 1). Nevertheless, to further substantiate the conclusions drawn in this experimental model, it will be interesting to test the effect on liver growth of reducing the BA pool in transplanted FRGN mice by an alternative method, such as feeding these animals a BA-sequestering resin.11Uriarte I. Fernández-Barrena M.G. Monte M.J. et al.Identification of fibroblast growth factor 15 as a novel mediator of liver regeneration and its application in the prevention of post-resection liver failure in mice.Gut. 2013; 62: 899-910Crossref PubMed Scopus (136) Google Scholar In accordance with their increased size, livers from transplanted FRGN mice showed a significantly higher hepatocyte proliferation than those of FRGN19+ mice. Consistently, transcriptome analyses revealed enhanced expression of genes involved in DNA synthesis and cell cycle in repopulated FRGN livers. One critical regulator of liver growth is the Hippo-YAP pathway.17Avruch J. Zhou D. Fitamant J. et al.Mst1/2 signalling to Yap: gatekeeper for liver size and tumour development.Br J Cancer. 2011; 104: 24-32Crossref PubMed Scopus (92) Google Scholar In the quiescent liver, the transcriptional coactivator YAP is phosphorylated and retained in the cytosol unable to drive cell proliferation. Upstream signals activating this pathway may emanate from a decreased cell density and alterations in the extracellular milieu, but their nature has not been fully established yet.18Moroishi T. Hansen C.G. Guan K.-L. The emerging roles of YAP and TAZ in cancer.Nat Rev Cancer. 2015; 15: 73-79Crossref PubMed Scopus (790) Google Scholar Interestingly, in their study Naugler et al14Naugler W.E. Tarlow B.D. Fedorov L.M. et al.Fibroblast growth factor signaling controls liver size in mice with humanized livers.Gastroenterology. 2015; 149: 728-740Abstract Full Text Full Text PDF PubMed Scopus (73) Google Scholar also identified a gene signature consistent with the activation of the Hippo-YAP pathway in transplanted FRGN livers. This remarkable finding is in agreement with the recently reported activation of YAP in response to elevated BA levels in the liver,19Anakk S. Bhosale M. Schmidt V.A. et al.Bile acids activate YAP to promote liver carcinogenesis.Cell Rep. 2013; 5: 1060-1069Abstract Full Text Full Text PDF PubMed Scopus (126) Google Scholar and highlights the interaction between a metabolic signal and a critical growth regulatory pathway that may work in concert in the regulation of the hepatostat. In line with these findings, it has been shown recently that the reactivation of the enterohepatic FXR-FGF15 axis reduces circulating BA levels to normal and prevents spontaneous proliferation and hepatocarcinoma of FXR-null mice.20Degirolamo C. Modica S. Vacca M. et al.Prevention of spontaneous hepatocarcinogenesis in farnesoid X receptor-null mice by intestinal-specific farnesoid X receptor reactivation.Hepatology. 2015; 61: 161-170Crossref PubMed Scopus (85) Google Scholar Thus, the present study highlights the FXR-FGF19 gut–liver axis as a novel hepatostat and opens new therapeutic avenues based on the physiologic regulators of this hormonal gut–liver axis. Fibroblast Growth Factor Signaling Controls Liver Size in Mice With Humanized LiversGastroenterologyVol. 149Issue 3PreviewThe ratio of liver size to body weight (hepatostat) is tightly controlled, but little is known about how the physiologic functions of the liver help determine its size. Livers of mice repopulated with human hepatocytes (humanized livers) grow to larger than normal; the human hepatocytes do not recognize the fibroblast growth factor (FGF)-15 produced by mouse intestine. This results in up-regulation of bile acid synthesis in the human hepatocytes and enlargement of the bile acid pool. We investigated whether abnormal bile acid signaling affects the hepatostat in mice. Full-Text PDF" @default.
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• W2150191954 title "The FXR-FGF19 Gut–Liver Axis as a Novel “Hepatostat”" @default.
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