Tissue-specific mechanisms of bile acid homeostasis and activation of FXR-FGF19 signaling in preterm and term neonatal pigs

Abstract

Background & Aims: The tissue specific molecular mechanisms involved in perinatal liver and intestinal FXR-FGF19 signaling are poorly defined. Our aim was to establish how gestational age and feeding status affect bile acid synthesis pathway, bile acid pool size, ileal response to bile acid stimulation, genes involved in bile acid-FXR-FGF19 signaling and plasma FGF19 in neonatal pigs. Methods Term (n=23) and preterm (n=33) pigs were born via cesarean section at 100% and 90% gestation, respectively. Plasma FGF19, hepatic bile acid and oxysterol profiles, and FXR target gene expression was assessed in pigs at birth and after a bolus feed on day 3 of life. Pig ileal tissue explants were used to measure signaling response to bile acids. Results Preterm pigs had smaller, more hydrophobic bile acid pools, lower plasma FGF19, and blunted FXR-mediated ileal response to bile acid stimulation than term pigs. GATA-4 expression was higher in jejunum than ileum, and was higher in preterm than term pig ileum. Hepatic oxysterol analysis suggested dominance of the alternative pathway of bile acid synthesis in neonates, regardless of gestational age and persists in preterm pigs after feeding on day 3. Conclusion These results highlight the tissue-specific molecular basis for the immature enterohepatic bile acid signaling via FXR-FGF19 in preterm pigs and may have implications for disturbances of bile acid homeostasis and metabolism in preterm infants.

Acquisition of Immune Privilege in GBM Tumors: Role of Prostaglandins and Bile Salts

“…Circulating FGF19 binds to the receptor FGFR4 of liver cells, signaling a downregulation of CYP7A1 expression and, thus, dropping the rate of bile acid synthesis. Adults cannot support high levels of bile synthesis in FGF19 [ 71 , 108 ]. In contrast, the livers of neonates generate primary bile acids using the acidic bile synthesis pathway, where the CYP27A1 gene product is the most rate-controlling enzyme [ 71 , 107 , 109 ].…”

“…In neonates, CYP7A1 activity is undetectable prior to 30 weeks of gestation. This co-incidence of bile synthesis by the acidic pathway and elevation of FGF19 in a subset of GBM tumors is observed in neonates and preterm infants [ 71 , 108 ].…”