FGF19 in Obstructive Cholestasis: "Unveil the Signal"

Because bile salts are biological emulsifiers, they play an essential role in digestion and absorption of dietary lipids and fat soluble vitamins. Bile salts also act as potent signaling molecules targeting bile salt sensing nuclear and plasma cell membrane bound receptors. Several metabolic and biological processes are influenced by activation of these receptors, including bile salt and glucose homeostasis, thermogenesis, intestinal barrier function and liver regeneration.

Bile salts are synthesized in the liver, and efficiently returned to the liver via the intestinal lumen and portal blood (enterohepatic circulation = EHC). Hepatic bile salt content is tightly regulated at multiple levels to maintain non-toxic levels. The transcription factor Farnesoid X Receptor (FXR) plays a key role in bile salt homeostasis by regulating synthesis, biliary excretion, intestinal reuptake and metabolism of bile salts. Genetic deficiency of FXR in mice results in impaired gut barrier function, dysregulated hepatic metabolism and impaired recovery from cholestatic liver injury. Bile salts repress their own biosynthesis, and this encompasses activation of FXR by bile salts in the enterohepatic tissue and controlling the transcription of Cyp7a1 in the liver (rate limiting enzyme of bile salt synthesis). Activated hepatic FXR represses the bile salt synthetic enzyme Cyp7a1 by inducing the expression of Shp. On the other hand, activated FXR in the ileum induces the expression of FGF19 which signals to the liver to repress the expression of Cyp7a1. The liver is considered to be the primary target of FGF19 as it expresses both components of the FGF19 -receptor complex (FGFR4-βklotho). Animal experiments demonstrated a crucial role of intestinal FXR in preventing bacterial overgrowth and maintaining intestinal integrity in a mouse model of obstructive cholestasis. Moreover, intestinal FXR activation ameliorated cholestatic liver injury in bile duct-ligated mice. This emphasizes that an intact EHC is crucial to maintain tissue homeostasis in the small intestine and the liver.

Intraluminal bacterial overgrowth, translocation of microbial endotoxins, increased intestinal permeability, activation of intestinal and hepatic inflammatory cascades and endotoxemia occurs frequently in patients with obstructive cholestasis (e.g. pancreatic cancer and cholangiocarcinoma). Absence of bile in the intestinal tract is associated with these anomalies. The investigators postulate that normal bile flow in patients with obstructive cholestasis is impaired and therefore bile salt signaling is impaired leading to dysregulation in enterohepatic tissues. To further improve our understanding of bile salt-FGF19 signaling across different abdominal organs, the investigators will obtain blood samples not only from the radial artery, the portal and the hepatic vein, but also from the superior mesenteric vein, inferior mesenteric vein, the splenic vein and the renal vein. By including these blood vessels, the investigators will be able to obtain information about the contribution of the small intestine, the colon, the spleen and the kidneys, separately in the production or extraction of FGF19 in humans. Namely, arteriovenous differences (ΔAV) and net organ fluxes (flow x ΔAV) serve as a quantitative measure of metabolite exchange across the portal drained viscera (PDV), the splanchnic area and the small intestine, colon, spleen and kidneys.

The hypothesis is that FGF19 inter-organ flux shifts during obstructive cholestasis towards production or release of FGF19 by other abdominal organs rather than the small intestine. Serum FGF19 elevation and FGF19 mRNA expression in the liver of patients with obstructive cholestasis support this concept.

The aim of this study is to investigate FGF19 signalling in patients with cholestasis compared to non-cholestatic patients by calculating fluxes across the portal drained organs. Secondly, the investigators will investigate the metabolic and functional consequences (glucose, lipid homeostasis, cholestatic itch, gut barrier function, bile salt composition) of a disturbed FXR-FGF19 pathway in humans. Findings from this study will provide novel insights into enterohepatic bile salt-FGF19 signaling in humans and may lead to potential therapeutic strategies in cholestatic liver diseases.