Hepatic deletion of X-box binding protein 1 impairs bile acid metabolism in mice
Hepatic deletion of X-box binding protein 1 impairs bile acid metabolism in mice
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DOI：
10.1194/jlr.m071266
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发表时间：
2017-03-01
影响因子：
6.5
通讯作者：
Green, Richard M.
中科院分区：
文献类型：
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作者：
Liu, Xiaoying;Henkel, Anne S.;Green, Richard M.
未折叠蛋白反应（unfolded protein response，UPR）是一种对内质网应激的适应性反应，其中的肌醇依赖酶1 α/X-box结合蛋白1（inositol-required enzyme 1 alpha/X-box binding protein 1，IRE 1 alpha/XBP 1）通路在脂质代谢中起重要作用。然而，其在胆汁酸代谢中的作用仍然未知。我们证明，肝脏特异性Xbp 1基因敲除（LS-Xbp 1（-/-））小鼠的总胆汁酸池减少了45%。与Xbp 1（fl/fl）小鼠相比，LS-Xbp 1（-/-）小鼠的血清7 α-羟基-4-甾烯-3-酮（C4）水平较低，表明7 α-羟化酶（CYP 7A 1）合成活性降低。这种情况发生时，肝脏CYP 7A 1蛋白表达没有减少。喂食LS-Xbp 1（-/-）小鼠考来烯胺使肝脏CYP 7A 1蛋白表达水平分别比喂食考来烯胺和喂食饲料的Xbp 1（fl/fl）小鼠高2倍和8倍。然而，血清C4水平保持不变，低于两组Xbp 1（fl/fl）小鼠。相比之下，尽管喂食LS-Xbp 1（-/-）小鼠胆固醇不增加CYP 7A 1表达，但血清C4水平显著增加至与喂食Chow的Xbp 1fl/fl小鼠相似的水平，并且总胆汁酸池正常化。总之，肝脏XBP 1的损失降低了胆汁酸池和CYP 7A 1合成活性。胆固醇喂养，而不是诱导CYP 7A 1与考来烯胺，增加CYP 7A 1合成活性和纠正基因型特异性总胆汁酸池。这些数据证明了IRE 1a/XBP 1调节小鼠胆汁酸代谢的新作用。
The unfolded protein response (UPR) is an adaptive response to endoplasmic reticulum stress and the inositol-requiring enzyme 1 alpha/X-box binding protein 1 (IRE1 alpha/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 7 alpha-hydroxy-4-cholesten-3-one(C4) levels compared to Xbp1(fl/fl) mice, indicating reduced 7 alpha-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 Xbp1(fl/fl) mice, respectively. However, serum C4 levels remained unchanged and were lower than both groups of Xbp1(fl/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.jlr 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 IRE1a/XBP1 regulating bile acid metabolism in mice.