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Finding fibroblast growth factor 19 during cholestasis: Does x mark the spot?

  • Lianne R. de Haan
    Affiliations
    Department of Surgery, Surgical Laboratory, Academic Medical Center, Amsterdam, the Netherlands
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  • Rowan F. van Golen
    Correspondence
    Corresponding author. Address: Leiden University Medical Center, Leiden University, Albinusdreef 2, 2333 ZA Leiden, the Netherlands.
    Affiliations
    Department of Surgery, Surgical Laboratory, Academic Medical Center, Amsterdam, the Netherlands

    Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, the Netherlands
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Published:October 04, 2018DOI:https://doi.org/10.1016/j.jhep.2018.09.008

      Linked Article

      To the Editor:
      Reducing hepatocyte bile salt levels under cholestatic conditions is crucial to avoid the deterioration of liver function through bile salt toxicity. Hepatocyte bile salt production is largely controlled by fibroblast growth factor 19 (FGF19), normally produced by ileal enterocytes in response to activation of the intestinal bile salt receptor FXR.
      • De Haan L.R.
      • Van der Lely S.
      • Warps A.
      • Hofsink Q.
      • Olthof P.B.
      • De Keijzer M.J.
      • et al.
      Post-hepatectomy liver regeneration in the context of bile acid homeostasis and the gut-liver signaling axis.
      Enterohepatic cycling of FGF19 prevents hepatic bile salt toxicity by downregulating hepatocyte bile salt production by CYP7A1. Although undetectable in native livers, the compensatory induction of hepatic FGF19 expression has been noted in patients with extrahepatic cholestasis.
      • Schaap F.G.
      • van der Gaag N.A.
      • Gouma D.J.
      • Jansen P.L.
      High expression of the bile salt-homeostatic hormone fibroblast growth factor 19 in the liver of patients with extrahepatic cholestasis.
      Using alcoholic hepatitis (AH) as a template disease, the InTeam consortium
      • Brandl K.
      • Hartmann P.
      • Jih L.J.
      • Pizzo D.P.
      • Argemi J.
      • Ventura-Cots M.
      • et al.
      Dysregulation of serum bile acids and FGF19 in alcoholic hepatitis.
      reveals several striking parallels between intrahepatic and extrahepatic cholestasis. In severe AH, hepatocyte bile salt synthesis by CYP7A1 was suppressed, while hepatic bile salt loading was reduced through the induction of bile salt export and suppression of bile salt uptake. More importantly, severe AH triggered hepatic FGF19 expression and an increase in plasma FGF19. As was previously reported for primary biliary cholangitis,
      • Wunsch E.
      • Milkiewicz M.
      • Wasik U.
      • Trottier J.
      • Kempińska-Podhorodecka A.
      • Elias E.
      • et al.
      Expression of hepatic fibroblast growth factor 19 is enhanced in primary biliary cirrhosis and correlates with severity of the disease.
      circulating FGF19 correlated with markers of AH disease severity. This supports the paradigm that the induction of hepatic FGF19 during cholestasis is a cytoprotective response that aims to limit bile salt toxicity when intestinal FGF19 production is compromised.
      Little is known about how and where FGF19 is produced when hepatic bile salt load increases, owing to the fact that, with the exception of Gold Syrian hamsters,
      • van Golen R.F.
      • Olthof P.B.
      • de Haan L.R.
      • Coelen R.J.
      • Pechlivanis A.
      • de Keijzer M.J.
      • et al.
      The pathophysiology of human obstructive cholestasis is mimicked in cholestatic gold syrian hamsters.
      no animal models are available to study this mechanism. Whereas some studies show that hepatocytes can produce FGF19 in an FXR-linked fashion
      • Wunsch E.
      • Milkiewicz M.
      • Wasik U.
      • Trottier J.
      • Kempińska-Podhorodecka A.
      • Elias E.
      • et al.
      Expression of hepatic fibroblast growth factor 19 is enhanced in primary biliary cirrhosis and correlates with severity of the disease.
      • Ijssennagger N.
      • Janssen A.W.
      • Milona A.
      • Ramos Pittol J.M.
      • Hollman D.A.
      • Mokry M.
      • et al.
      Gene expression profiling in human precision cut liver slices upon treatment with the FXR agonist obeticholic acid.
      • Song K.H.
      • Li T.
      • Owsley E.
      • Strom S.
      • Chiang J.Y.
      Bile acids activate fibroblast growth factor 19 signaling in human hepatocytes to inhibit cholesterol 7alpha-hydroxylase gene expression.
      others have claimed that FGF19 actually derives from the non-parenchymal hepatic cell fraction.
      • Naugler W.E.
      • Tarlow B.D.
      • Fedorov L.M.
      • Taylor M.
      • Pelz C.
      • Li B.
      • et al.
      Fibroblast growth factor signaling controls liver size in mice with humanized livers.
      Using immunohistochemistry, Brandl et al. propose that FGF19 expression in severe AH is confined to biliary epithelium and, possibly, some endothelial cells. As the expression of FGF19 was characterized as ‘very low’, it is questionable whether the observed FGF19-positive cells account for the noted steep rise in hepatic FGF19 mRNA expression. With respect to the immunohistochemistry, large intrahepatic bile ducts were also FGF19-positive in negative controls, which is in line with earlier findings.
      • Zweers S.J.
      • Booij K.A.
      • Komuta M.
      • Roskams T.
      • Gouma D.J.
      • Jansen P.L.
      • et al.
      The human gallbladder secretes fibroblast growth factor 19 into bile: Towards defining the role of fibroblast growth factor 19 in the enterobiliary tract.
      The pattern of FGF19 staining in AH also differed considerably from patients with primary biliary cholangitis,
      • Wunsch E.
      • Milkiewicz M.
      • Wasik U.
      • Trottier J.
      • Kempińska-Podhorodecka A.
      • Elias E.
      • et al.
      Expression of hepatic fibroblast growth factor 19 is enhanced in primary biliary cirrhosis and correlates with severity of the disease.
      which is analogous to AH in terms of intrahepatic cholestasis. Beyond immunohistochemistry, no experiments were performed to characterize the FGF19-positive cells. As a control group with proven hepatic FGF19 induction was lacking (i.e., patients with obstructive cholestasis), it is uncertain whether the presented data allow firm conclusions about the cell type(s) that express (or produce) FGF19 during AH. The latter is also supported by the fact that, inherent to the study population, no ileal biopsies were available to monitor the endogenous site of FGF19 production during AH and juxtapose this to systemic FGF19 dynamics. This is particularly interesting considering that intestinal bile salt delivery and, hence, ileal FGF19 production should not be fully compromised in AH, which differs from extrahepatic cholestasis. Direct effects of alcohol use on intestinal FGF19 production have also been noted. Lastly, these findings call into question how portal hypertension typically seen in severe AH and the consequent effects on intestinal barrier function affect ileal bile salt metabolism and FGF19 production.
      Until hepatic FGF19 expression is mapped on a single-cell resolution, the cellular source of FGF19 during cholestasis remains uncertain. That notwithstanding, the data collected by the InTeam consortium show that adaptive changes in bile salt signaling are conserved between extrahepatic and intrahepatic cholestasis. Supported by early preclinical findings,
      • Hartmann P.
      • Hochrath K.
      • Horvath A.
      • Chen P.
      • Seebauer C.T.
      • Llorente C.
      • et al.
      Modulation of the intestinal bile acid/farnesoid X receptor/fibroblast growth factor 15 axis improves alcoholic liver disease in mice.
      it reaffirms that therapeutic options beyond steroids may become available for AH.

      Conflict of interest

      The authors who have taken part in this study declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.
      Please refer to the accompanying ICMJE disclosure forms for further details.

      Supplementary data

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