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Programming Effects of Infant Diet on Cholesterol/Bile Acid Synthesis and Absorption in Piglets
Author(s) -
Mercer Kelly E,
DiazRubio Maria Elena,
Bhattacharyya Sudeepa,
Sharma Neha,
Yeruva Laxmi
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.267.6
Subject(s) - taurine , breast milk , bile acid , cholesterol , medicine , endocrinology , taurocholic acid , metabolism , breast feeding , infant formula , biology , chemistry , biochemistry , amino acid , pediatrics
Unlike breast milk, infant milk formula contains little cholesterol, and requirements necessary for normal growth and development are met through increased endogenous cholesterol synthesis in the liver. Human studies looking at the long‐term metabolic implications of manipulating cholesterol homeostasis during infancy have reported lower circulating cholesterol and triglycerides in adults that were breast fed when compared those that received formula. To determine the molecular etiology of diet‐associated changes in early‐life cholesterol metabolism, we employed a neonatal piglet feeding model to investigate differences in cholesterol homeostasis between two infant diets (sow's milk and a cow's milk‐based formula). Male and female piglets (n=12) were breast fed and compared to piglets (n=12) receiving a commercially available milk‐based formula from postnatal day 2 to day 21. As expected, we observed a significant up‐regulation of liver transcripts associated with hepatic cholesterol synthesis, including 3‐hydroxy‐3‐methylglutaryl‐Co‐A synthase (HMGCS1) and reductase (HMGR) in formula fed piglets. Using a non‐targeted metabolomic approach in the liver, we identified 47 significant features that differed between breast fed and formula fed piglets. Pathway analysis identified taurine metabolism and bile acid metabolism among the top pathways elevated in formula fed piglets compared to those breast fed. Presently, we have confirmed increases in hepatic taurine (p=0.02), taurochenodeoxycholic acid (p=0.002) and glycoursodexoycholic acid, (p=0.002) and a decrease in taurocholic acid (p=0.01) in the formula fed group compared to breast fed piglets. Consistent with these data, in formula fed males and females we also observed a significant increase in cholesterol 7α‐hydroxylase (CYP7A1) mRNA and protein expression (p<0.05), indicating excessive bile acid production. In the liver farnesoid X receptor (FXR) regulation of bile acid synthesis and export were intact. We observed a significant decrease in CYP8B1 mRNA expression, with 2‐fold increases in mRNA expression of the bile acid export pump (BSEP) and multidrug resistance protein 2 (MDR2), p<0.05. In females, intestinal mRNA expression of the cholesterol pathway regulator fibroblast factor 19 (FGF 19) was reduced by 4‐fold in response to the formula diet (p<0.05), suggesting that loss of intestinal FGF19 signaling is responsible for the increase in CYP7A1 expression. In conclusion, formula feeding elicits profound metabolic programming effects on hepatic and intestinal regulation of cholesterol/bile acid metabolism in a neonatal piglet model of human infant nutrition. Support or Funding Information This work was funded by USDA‐ARS Project 6026‐5100‐010‐05S.