出版社：American Society for Biochemistry and Molecular Biology
摘要：Bile acid malabsorption, which in patients leads to excessivefecal bile acid excretion and diarrhea, is characterized bya vicious cycle in which the feedback regulation of bile acidsynthesis is interrupted, resulting in additional bile acidproduction. Feedback regulation of bile acid synthesis is underthe control of an endocrine pathway wherein activation of thenuclear bile acid receptor, farnesoid X receptor (FXR), inducesenteric expression of the hormone, fibroblast growth factor15 (FGF15). In liver, FGF15 acts together with FXR-mediatedexpression of small heterodimer partner to repress bile acidsynthesis. Here, we show that the FXR-FGF15 pathway is disruptedin mice lacking apical ileal bile acid transporter, a modelof bile acid malabsorption. Treatment of Asbt–/–mice with either a synthetic FXR agonist or FGF15 downregulateshepatic cholesterol 7-hydroxylase mRNA levels, decreases bileacid pool size, and reduces fecal bile acid excretion. Thesefindings suggest that FXR agonists or FGF15 could be used therapeuticallyto interrupt the cycle of excessive bile acid production inpatients with bile acid malabsorption.Supplementary key words bile acid metabolism • nuclear receptors • transporters • farnesoid X receptor • fibroblast growth factor 15
Abbreviations: ASBT, apical sodium-dependent bile acid transporter; CYP7A1, cholesterol 7-hydroxylase; CYP8B1, sterol 12-hydroxylase; FGF15, fibroblast growth factor 15; FXR, farnesoid X receptor; IBABP, ileal bile acid binding protein; SHP, small heterodimer partner; TCA, taurocholate; TßMCA, tauro-ß-muricholate
-hydroxylase mRNA levels, decreases bile acid pool size, and reduces fecal bile acid excretion. These findings suggest that FXR agonists or FGF15 could be used therapeutically to interrupt the cycle of excessive bile acid production in patients with bile acid malabsorption.
Supplementary key words bile acid metabolism • nuclear receptors • transporters • farnesoid X receptor • fibroblast growth factor 15
Abbreviations: ASBT, apical sodium-dependent bile acid transporter; CYP7A1, cholesterol 7
