Hepatic deletion of X-box binding protein 1 impairs bile acid metabolism in mice

• Published in: Journal of lipid research Vol. 58; no. 3; pp. 504 - 511
• Main Authors: Liu, Xiaoying, Henkel, Anne S., LeCuyer, Brian E., Hubchak, Susan C., Schipma, Matthew J., Zhang, Eric, Green, Richard M.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.03.2017; Journal of Lipid Research; The American Society for Biochemistry and Molecular Biology; Elsevier
• Subjects: Acids; Activating transcription factor 1; Animals; Bile; Bile Acids and Salts - metabolism; Cholestenones - blood; Cholesterol; cholesterol 7-alpha hydroxylase; Cholesterol 7-alpha-Hydroxylase - genetics; Endoplasmic reticulum; Endoplasmic Reticulum Stress - genetics; Feeding; gene expression; Gene Expression Regulation; Genotypes; Humans; Hydroxylase; Inositol; Lipid metabolism; Lipid Metabolism - genetics; Liver; Liver - metabolism; Metabolism; Mice; Mice, Knockout; Protein expression; Protein folding; Protein turnover; Proteins; Rodents; serum 7α-hydroxy-4-cholesten-3-one; unfolded protein response; Unfolded Protein Response - genetics; X-Box Binding Protein 1 - genetics; unfolded protein response; cholesterol 7-alpha hydroxylase; liver; serum 7α-hydroxy-4-cholesten-3-one; cholesterol; gene expression; endoplasmic reticulum
• ISSN: 0022-2275; 1539-7262
• DOI: 10.1194/jlr.M071266

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-specific Xbp1 knockout (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 with Xbp1fl/fl mice, 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-fed Xbp1fl/fl mice, respectively. However, serum C4 levels remained unchanged and were lower than both groups of Xbp1fl/fl mice. In contrast, although feeding LS-Xbp1−/− mice cholesterol did not increase CYP7A1 expression, serum C4 levels increased significantly up to levels similar to chow-fed Xbp1fl/fl mice 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.