title: Bile acid flux through portal but not peripheral veins inhibits CYP7A1 expression without involvement of ileal FGF19 in rabbits.
abstract: It was proposed that CYP7A1 expression is suppressed through the gut-hepatic signaling pathway fibroblast growth factor (FGF) 15/19-fibroblast growth factor receptor 4, which is initiated by activation of farnesoid X receptor in the intestine rather than in the liver. The present study tested whether portal bile acid flux alone without ileal FGF19 could downregulate CYP7A1 expression in rabbits. A rabbit model was developed by infusing glycodeoxycholic acid (GDCA) through the splenic vein to bypass ileal FGF19. Study was conducted in four groups of rabbits: control; bile fistula + bovine serum albumin solution perfusion (BF); BF + GDCA (by portal perfusion); and BF + GDCA-f (by femoral perfusion). Compared with only BF, BF + GDCA (6 h portal perfusion) suppressed CYP7A1 mRNA, whereas BF + GDCA-f (via femoral vein) with the same perfusion rate of GDCA did not show inhibitory effects. Meanwhile, there was a decrease in ileal FGF19 expression and portal FGF19 protein levels, but an equivalent increase in biliary bile acid outputs in both GDCA perfusion groups. This study demonstrated that portal bile acid flux alone downregulated CYP7A1 expression with diminished FGF19 expression and protein levels, whereas the same bile acid flux reaching the liver through the hepatic artery via femoral vein had no inhibitory effect on CYP7A1. We propose that bile acid flux through the portal venous system may be a kind of "intestinal factor" that suppresses CYP7A1 expression.
authors.affiliation: Department of Medicine, Rutgers, New Jersey Medical School, Newark, New Jersey; Medical Research Service, Veterans Affairs Medical Center, East Orange, New Jersey;
authors.forename: Quan
authors.initials: Q
authors.lastname: Shang
authors.affiliation: Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, New Jersey; and.
authors.forename: Grace L
authors.initials: GL
authors.lastname: Guo
authors.affiliation: Department of Gastroenterology, Ibaraki Medical Center, Tokyo Medical University, Ibaraki, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Honda
authors.affiliation: Medical Research Service, Veterans Affairs Medical Center, East Orange, New Jersey;
authors.forename: Daniel
authors.initials: D
authors.lastname: Shi
authors.affiliation: Medical Research Service, Veterans Affairs Medical Center, East Orange, New Jersey;
authors.forename: Monica
authors.initials: M
authors.lastname: Saumoy
authors.affiliation: Department of Medicine, Rutgers, New Jersey Medical School, Newark, New Jersey;
authors.forename: Gerald
authors.initials: G
authors.lastname: Salen
authors.affiliation: Department of Medicine, Rutgers, New Jersey Medical School, Newark, New Jersey; Medical Research Service, Veterans Affairs Medical Center, East Orange, New Jersey; guorong.xu@va.gov.
authors.forename: Guorong
authors.initials: G
authors.lastname: Xu
mesh_terms: D000818:Animals; D001658:Biliary Fistula; D002790:Cholesterol 7-alpha-Hydroxylase / Q000096:biosynthesis*; D015536:Down-Regulation; D005346:Fibroblast Growth Factors / Q000378:metabolism; D006002:Glycodeoxycholic Acid / Q000494:pharmacology*; D007082:Ileum / Q000378:metabolism*; D011169:Portal Vein; D011817:Rabbits
chemical_list: D006002:Glycodeoxycholic Acid; D005346:Fibroblast Growth Factors; D002790:Cholesterol 7-alpha-Hydroxylase
keywords: bile acid synthesis; cholesterol 7α-hydroxylase; fibroblast growth factor 19