The role of fibroblast growth factor 19 in human liver

Abstract

Bile acids are synthesized in the liver and are essential for intestinal absorption of lipids. Bile acid homeostasis is crucial and if not maintained, bile acids can accumulate to toxic levels and cause severe damage to the liver. Bile acid homeostasis is therefore strictly regulated through feedback mechanisms where bile acids act as signaling molecules to control different aspects of their metabolism. The regulatory protein Fibroblast growth factor 19 (FGF19) has been of particular interest in recent years for its role in the negative feedback response of bile acid synthesis. FGF19 is induced in the terminal ileum in response to bile acids that are reabsorbed from the intestine. FGF19 is released to portal blood and will bind to its receptor in the liver to down regulate the rate-limiting enzyme in bile acid synthesis.

The studies in this thesis are focused on using human models to further understand the role of FGF19 in human bile acid metabolism in health and disease. We aimed to establish physiological levels of FGF19 and investigate how disease can change the dynamics of bile acids and FGF19. Furthermore, the response to FGF19 on a molecular level was studied in primary human hepatocytes. In Study I we found that portal levels of FGF19 do no differ from levels in systemic blood under fasted conditions, which was in contrast to bile acids that had a higher concentration in portal blood compared to systemic blood due to an efficient uptake of the bile acids by the hepatocytes. Both bile acids and FGF19 increased postprandially, but no hepatic clearance of FGF19 was observed. A strong correlation between FGF19 and bile acids was observed, indicating that high levels of bile acids result in increased levels of FGF19. In Study II, FGF19 and bile acids were investigated in cholestatic infants diagnosed with biliary atresia at time of Kasai portoenterostomy (KPE) surgery and at short-term follow-up. An adaptive response of the liver to increased hepatic bile acids and an interrupted enterohepatic circulation was observed at time of surgery, with reduced bile acid synthesis, increased levels of circulating bile acids and alterations in bile acid transporters. In addition, FGF19 levels were elevated and it was concluded that the surge in FGF19 originated from the liver in this condition. FGF19 levels had declined at follow-up and the decrease coincided with markers that indicate a restored bile flow, such as decreased levels of circulating bilirubin and conjugated chenodeoxycholic acid (CDCA). This might indicate that FGF19 could be a possible prognostic marker for outcome of KPE in biliary atresia. In Study III, the response to the primary bile acid CDCA and FGF19 was investigated in primary human hepatocytes with special regard to bile acid synthesis. Physiological levels of CDCA as well as conditioned medium containing FGF19 produced by the hepatocytes, down regulated bile acid synthesis, while recombinant FGF19 did not. In addition, physiological levels of CDCA rapidly induced FGF19 gene expression in primary human hepatocytes, indicating a possible autocrine function for FGF19 in primary human hepatocytes. Bile acid synthesis was however efficiently down regulated by CDCA following siRNA knockdown of FGF19, suggesting that an autocrine pathway of FGF19 for down regulation of bile acid synthesis is unlikely.

In summary, no difference in concentration of FGF19 was observed between portal and systemic blood. Circulating FGF19 was elevated in cholestatic infants and originated from the liver. Physiological concentrations of CDCA induced FGF19 in primary human hepatocytes, however bile acid synthesis was efficiently down regulated independently of hepatic FGF19, presumably via the regulatory nuclear receptor small heterodimer partner (SHP). Contribution of hepatic FGF19 in regulation of bile acid synthesis may therefore be negligible under normal circumstances.