title: Hepatic deletion of X-box binding protein 1 impairs bile acid metabolism in mice.
abstract: The unfolded protein response (UPR) is an adaptive response to endoplasmic reticulum stress and the inositol-requiring enzyme 1α/X-box binding protein 1 (IRE1α/XBP1) pathway of the UPR is important in lipid metabolism. However, its role in bile acid metabolism remains unknown. We demonstrate that liver-specificXbp1knockout (LS-Xbp1-/-) mice had a 45% reduction in total bile acid pool. LS-Xbp1-/-mice had lower serum 7α-hydroxy-4-cholesten-3-one (C4) levels compared withXbp1fl/flmice, indicating reduced cholesterol 7α-hydroxylase (CYP7A1) synthetic activity. This occurred without reductions of hepatic CYP7A1 protein expression. Feeding LS-Xbp1-/-mice cholestyramine increased hepatic CYP7A1 protein expression to levels 2-fold and 8-fold greater than cholestyramine-fed and chow-fedXbp1fl/flmice, respectively. However, serum C4 levels remained unchanged and were lower than both groups ofXbp1fl/flmice. In contrast, although feeding LS-Xbp1-/-mice cholesterol did not increase CYP7A1 expression, serum C4 levels increased significantly up to levels similar to chow-fedXbp1fl/flmice and the total bile acid pool normalized. In conclusion, loss of hepatic XBP1 decreased the bile acid pool and CYP7A1 synthetic activity. Cholesterol feeding, but not induction of CYP7A1 with cholestyramine, increased CYP7A1 synthetic activity and corrected the genotype-specific total bile acid pools. These data demonstrate a novel role of IRE1α/XBP1 regulating bile acid metabolism.
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Medicine Northwestern University Feinberg School of Medicine, Chicago, IL 60611.
authors.forename: Xiaoying
authors.initials: X
authors.lastname: Liu
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Medicine Northwestern University Feinberg School of Medicine, Chicago, IL 60611.
authors.forename: Anne S
authors.initials: AS
authors.lastname: Henkel
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Medicine Northwestern University Feinberg School of Medicine, Chicago, IL 60611.
authors.forename: Brian E
authors.initials: BE
authors.lastname: LeCuyer
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Medicine Northwestern University Feinberg School of Medicine, Chicago, IL 60611.
authors.forename: Susan C
authors.initials: SC
authors.lastname: Hubchak
authors.affiliation: Next Generation Sequencing Core: Center for Genetic Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Schipma
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Medicine Northwestern University Feinberg School of Medicine, Chicago, IL 60611.
authors.forename: Eric
authors.initials: E
authors.lastname: Zhang
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Medicine Northwestern University Feinberg School of Medicine, Chicago, IL 60611 r-green2@northwestern.edu.
authors.forename: Richard M
authors.initials: RM
authors.lastname: Green
mesh_terms: D000818:Animals; D001647:Bile Acids and Salts / Q000378:metabolism; D002783:Cholestenones / Q000097:blood; D002790:Cholesterol 7-alpha-Hydroxylase / Q000235:genetics*; D059865:Endoplasmic Reticulum Stress / Q000235:genetics; D005786:Gene Expression Regulation; D006801:Humans; D050356:Lipid Metabolism / Q000235:genetics*; D008099:Liver / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D056811:Unfolded Protein Response / Q000235:genetics; D000071717:X-Box Binding Protein 1 / Q000235:genetics*
chemical_list: D001647:Bile Acids and Salts; D002783:Cholestenones; D000071717:X-Box Binding Protein 1; C002656:7 alpha-hydroxy-4-cholesten-3-one; D002790:Cholesterol 7-alpha-Hydroxylase; C502772:Cyp7a1 protein, mouse
keywords: cholesterol; cholesterol 7-alpha hydroxylase; endoplasmic reticulum; gene expression; liver; serum 7α-hydroxy-4-cholesten-3-one; unfolded protein response