To investigate the role of
bile acids (BAs) in the pathogenesis of diet-induced
nonalcoholic steatohepatitis (NASH), we fed a "Western-style diet" [high
fructose, high fat (HFF)] enriched with
fructose,
cholesterol, and saturated fat for 10 wk to juvenile Iberian pigs. We also supplemented probiotics with in vitro BA deconjugating activity to evaluate their potential
therapeutic effect in NASH. Liver
lipid and function,
cytokines, and
hormones were analyzed using commercially available kits. Metabolites, BAs, and
fatty acids were measured by liquid chromatography-mass spectrometry. Histology and gene and
protein expression analyses were performed using standard protocols. HFF-fed pigs developed NASH,
cholestasis, and impaired enterohepatic Farnesoid-X receptor (FXR)-
fibroblast growth factor 19 (FGF19) signaling in the absence of
obesity and
insulin resistance.
Choline depletion in HFF livers was associated with decreased
lipoprotein and
cholesterol in serum and an increase of
choline-containing
phospholipids in colon contents and
trimethylamine-N-oxide in the liver. Additionally, gut
dysbiosis and
hyperplasia increased with the severity of NASH, and were correlated with increased colonic levels of
choline metabolites and secondary BAs. Supplementation of probiotics in the HFF diet enhanced NASH, inhibited hepatic autophagy, increased excretion of
taurine and
choline, and decreased gut microbial diversity. In conclusion, dysregulation of BA homeostasis was associated with injury and
choline depletion in the liver, as well as increased biliary secretion, gut metabolism and excretion of
choline-based
phospholipids.
Choline depletion limited
lipoprotein synthesis, resulting in hepatic steatosis, whereas secondary BAs and
choline-containing
phospholipids in colon may have promoted
dysbiosis,
hyperplasia, and
trimethylamine synthesis, causing further damage to the liver.NEW & NOTEWORTHY Impaired Farnesoid-X receptor (FXR)-
fibroblast growth factor 19 (FGF19) signaling and
cholestasis has been described in
nonalcoholic fatty liver disease (
NAFLD) patients. However, therapeutic interventions with FXR agonists have produced contradictory results. In a swine model of pediatric
nonalcoholic steatohepatitis (NASH), we show that the uncoupling of intestinal FXR-FGF19 signaling and a decrease in FGF19 levels are associated with a
choline-deficient phenotype of NASH and increased
choline excretion in the gut, with the subsequent
dysbiosis, colonic
hyperplasia, and accumulation of
trimethylamine-N-oxide in the liver.