TY - JOUR
T1 - Dysregulated FXR-FGF19 signaling and choline metabolism are associated with gut dysbiosis and hyperplasia in a novel pig model of pediatric NASH
AU - Hernandez, Gabriella V.
AU - Smith, Victoria A.
AU - Melnyk, Megan
AU - Burd, Matthew A.
AU - Sprayberry, Kimberly A.
AU - Edwards, Mark S.
AU - Peterson, Daniel G.
AU - Bennet, Darin C.
AU - Fanter, Rob K.
AU - Columbus, Daniel A.
AU - Steibel, Juan P.
AU - Glanz, Hunter
AU - Immoos, Chad
AU - Rice, Margaret S.
AU - Santiago-Rodriguez, Tasha M.
AU - Blank, Jason
AU - VanderKelen, Jennifer J.
AU - Kitts, Christopher L.
AU - Piccolo, Brian D.
AU - La Frano, Michael R.
AU - Burrin, Douglas G.
AU - Maj, Magdalena
AU - Manjarin, Rodrigo
N1 - Funding Information:
This work was supported by California State University Agriculture Research Institute (Grants 58873 and 58913), CalPoly internal funding programs Baker/Koob, RSCA, and STRIDE, the US Department of Agriculture, Agricultural Research Service Grants 3092-51000-060-01 and 6026-51000-012-06S, the National Institutes of Health Grant DK-094616, and the Texas Medical Center Digestive Diseases Center (NIH Grant P30 DK-56338), BiOWiSH Technologies, Hilmar Ingredients and Acorn Seekers.
Publisher Copyright:
© 2020 American Physiological Society. All rights reserved.
PY - 2020
Y1 - 2020
N2 - 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.
AB - 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.
KW - Metabolomics
KW - One-carbon metabolism
KW - Probiotics
KW - Secondary bile acids
KW - Trimethylamine-N-oxide
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UR - http://www.scopus.com/inward/citedby.url?scp=85081944750&partnerID=8YFLogxK
U2 - 10.1152/ajpgi.00344.2019
DO - 10.1152/ajpgi.00344.2019
M3 - Article
C2 - 32003601
AN - SCOPUS:85081944750
SN - 0193-1857
VL - 318
SP - G582-G609
JO - American Journal of Physiology - Gastrointestinal and Liver Physiology
JF - American Journal of Physiology - Gastrointestinal and Liver Physiology
IS - 3
ER -