353 - Recombinant Porcine FGF19 Decreases Bile Acid Synthesis in Preterm Pigs

Poster Number: 353
Publication Number: 353.134

Caitlin E. Vonderohe, Baylor College of Medicine, Houston, TX, United States; Barbara Stoll. Stoll, Children's Nutrition Research Center, Houston, TX, United States; Gregory Guthrie, Baylor College of Medicine, Houston, TX, United States; Valeria Melendez Hebib, Baylor College of Medicine, Houston, TX, United States; Inka Didelija, Baylor College of Medicine, Houston, TX, United States; Douglas Burrin, USDA-ARS Children's Nutrition Research Center, Baylor College of Medicine, Houston, TX, United States

Background: Fibroblast growth factor-19 (FGF19) is an endocrine fibroblast growth factor that is produced in the intestine when bile acids activate the nuclear farnesoid X receptor. FGF19 circulates to the liver where it down-regulates the expression of the rate-limiting enzyme in bile acid synthesis, cytochrome p450-C family 7 subfamily A member 1 (CYP7A1).  Thus, at physiologic levels, FGF19 functions as a negative feedback on bile acid production and homeostasis. At supraphysiologic levels FGF19 has been shown to induce hypertrophic and insulin sensitizing effects on skeletal muscle and liver. We previously showed that preterm neonatal pigs have lower plasma FGF19 levels than term pigs. 

Objective: The aim of the study was to test whether inducing supraphysiological levels of FGF19 using either recombinant porcine plasma FGF19 (rpFGF19) infusion or administration of an enteral FXR agonist (Tropifexor) would lead to suppression of hepatic bile acid synthesis in preterm pigs.

Design/Methods: Thirty-three cesarean-derived preterm pigs were surgically implanted with jugular and umbilical arterial catheters, as well as an orogastric feeding tube. Pigs were assigned to either Control (CTL), 250 μg IV rpFGF19 (FGF19), 5 μg/kg Tropifexor (TRO5), or 25 μg/kg (TRO25).  Pigs received total parenteral nutrition for 5 days after birth and then partial enteral feeds from 5-8 days. Pigs received their first dose of saline (CTL), rpFGF19 or tropifexor on day 3 of the study to measure the pharmacokinetic changes in plasma FGF19. Final plasma and tissue were collected on day 8.

Results: Pigs that received rpFGF19 had significantly higher plasma FGF19, peaking at 780 ng/mL at 5 min post infusion but remaining high (40 ng/mL) in the first 12 hours of the pharmacokinetic study compared to control pigs (0.80 ng/mL). TRO5 and TRO25 treatment yielded similar levels of FGF19 12 hours after administration (7.0 ng/mL) while control pigs remained low (0.78 pg/mL). FGF19, TRO5, and TRO25 treatments resulted in lower relative expression of hepatic CYP7A1 and lower plasma levels of bile acid precursor C4.

Conclusion(s): Inducing supraphysiological levels of FGF19 by parenteral rpFGF19 infusion or enteral tropifexor feeding results in lower hepatic bile acid synthesis in preterm pig.