Prematurity and postnatal development regulate the expression of the FXR‐FGF19 axis in neonatal pigs

Abstract

The farnesoid X receptor (FXR) is a nuclear bile acid receptor that regulates bile acid homeostasis. A key FXR target is fibroblast growth factor 19 (FGF19), which functions as an endocrine hormone. FGF19 is produced in both the intestine and liver in humans and pigs, whereas mice and rats express the human ortholog FGF15 only in the intestine, thus making pigs a more relevant model of human FGF19 biology. Gut bile acids activate small intestinal FXR triggering FGF19 secretion which circulates via the portal blood to inhibit hepatic bile acid synthesis by suppressing the rate limiting enzyme in bile acid synthesis, CYP7A1, via activation of extracellular‐signal‐regulated kinases (ERK) and c‐Jun N‐terminal kinase (JNK‐1) MAP kinase pathways and the orphan nuclear receptor, small heterodimer partner (SHP). Thus, enterohepatic FXR‐FGF19 signaling functions as a negative feedback signal to regulate bile acid homeostasis. Bile acid secretion has been shown to increase with gestational age. We hypothesized that expression and activation of the intestinal FXR‐FGF19 axis would be diminished in premature vs. term pigs and increased with postnatal age. We studied piglets delivered by cesarean‐section at 10 days preterm and full term. All pigs were fitted with orogastric and umbilical arterial catheters and fed minimal enteral nutrition with bovine colostrum for 5 d and then bovine mature milk until 26 d‐of‐age. Plasma and tissue samples were collected at days 0, 5, 11, and 26 d. We developed a porcine FGF19 specific sandwich ELISA assay by cloning the porcine FGF19 gene, overexpressing the protein using a baculovirus expression system, and developing monoclonal antibodies. We quantified the plasma FGF19 concentration using the ELISA and assayed distal intestinal gene expression of FGF19 and FXR by RT qPCR. We found that plasma FGF19 levels are strikingly lower (P<0.05) in premature vs. term newborn pigs. In addition, postnatal age markedly altered activity of the FXR‐FGF19 axis, where plasma FGF19 levels increased significantly 5 d after birth in preterm, but not term pigs. Plasma FGF19 levels then decreased (P<0.05) significantly between 5 and 26 d‐of‐age in both preterm and term pigs. Intestinal FXR and FGF19 expression were lower (P<0.05) in premature vs term newborn pigs and decreased (P<0.05) between day 5 and 26 d‐of‐age. We conclude that both prematurity and postnatal age regulate the FXR‐FGF19 axis in neonatal pigs. These findings have implications for the bile acid homeostasis, FGF19 function and growth of preterm and term infants during early postnatal life.Support or Funding InformationAgricultural Research Institute, USDA‐ARS, NIH, CalPoly Summer Undergraduate Research Program (SURP), NEOMUNEThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.