Decreased FXR agonism in the bile acid pool is associated with impaired FXR signaling in a pig model of pediatric NAFLD

Authors: MAJ, MAGDALENA - California Polytechnic State University; Burrin, Douglas - Doug; MANJARIN, RODRIGO - California Polytechnic State University

Submitted to: Biomedicines
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 12/8/2023
Publication Date: 12/13/2023
Citation: Maj, M.A., Burrin, D.G., Manjarin, R. 2023. Decreased FXR agonism in the bile acid pool is associated with impaired FXR signaling in a pig model of pediatric NAFLD. Biomedicines. 11(12). Article 3303. https://doi.org/10.3390/biomedicines11123303.
DOI: https://doi.org/10.3390/biomedicines11123303

Interpretive Summary: Non-alcoholic fatty liver disease (NAFLD) represents the major cause of pediatric chronic liver pathology in the U.S. The cause of NAFLD in children has been linked to excessive consumption of a nutrient rich diet, but it is not clear how specific nutrients lead to liver disease. One factor that contributes to NAFLD is disruption of bile acid function. Bile acids are made by the liver mainly to help digest dietary fat, but these molecules also regulate metabolism in liver cells. Importantly, different bile acids have greater of lesser capacity to impact the amount of bile acids made in liver cells. When bile acids accumulate in the liver cells it leads to liver injury and poor function. A key cell target of bile acids is the farnesoid X receptor and this receptor impacts the types of bile acids that are made in the liver. In this study, we used our new model of pediatric NAFLD using a strain of Iberian pigs to test how a high fat-high fructose (HFF) diet influence the bile acid profile and hepatic genes that make different bile acids, especially the hepatic 12-alpha-hydrolase (CYP8B1) gene. We found that pigs fed the HFF diet had higher CYP8B1 expression than control fed pigs. This change in CYP8B1 was associated with increase production of bile acids that have a weak capacity to feedback and suppress bile acid production in the liver. Thus, HFF diet fed pigs have significantly higher bile acid levels in their livers and this leads to liver disease. This study provides an important new mechanism to explain why consuming HFF diets may lead to pediatric NAFLD.

Technical Abstract: The objective of this study was to investigate whether the impairment of farneosid X receptor (FXR)-fibroblast growth factor 19 (FGF19) signaling in juvenile pigs with non-alcoholic fatty liver disease (NAFLD) is associated with changes in the composition of enterohepatic bile acid pool. Eighteen 15-day-old Iberian pigs, pair-housed in pens, were randomly assigned to receive for 10 weeks either a control (CON) or high-fructose high-fat (HFF) diet. Animals were euthanized on week 10 and liver, blood and distal ileum (DI) samples were collected. HFF-fed pigs developed NAFLD and had decreased FGF19 expression in DI and lower FGF19 levels in blood. Compared with CON, HFF diet increased total cholic acid (CA) and CA to chenodeoxicholic acid (CDCA) ratio in liver, DI and blood. CA and CDCA levels in DI were negatively and positively correlated with ileal FGF19 expression, respectively, and blood levels of FGF19 decreased with increasing ileal CA to CDCA ratio. Compared with CON, HFF diet increased the expression of hepatic 12-alpha-hydrolase, which catalyzes the synthesis of CA in the liver. Since CA species are weaker FXR ligands than CDCA, our results suggest that impairment of FXR-FGF19 signaling in NAFLD pigs is associated with a decrease in FXR agonism of the bile acid pool.