Targeting the Enterohepatic Bile Acid Signaling Induces Hepatic Autophagy via a CYP7A1-AKT-mTOR Axis in Mice.
Targeting the Enterohepatic Bile Acid Signaling Induces Hepatic Autophagy via a CYP7A1-AKT-mTOR Axis in Mice.
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DOI：
10.1016/j.jcmgh.2016.10.002
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发表时间：
2017-03
影响因子：
7.2
通讯作者：
Li T
中科院分区：
文献类型：
--
作者：
Wang Y;Ding Y;Li J;Chavan H;Matye D;Ni HM;Chiang JY;Krishnamurthy P;Ding WX;Li T
肝脏胆固醇积聚和自噬缺陷导致脂肪肝中的肝细胞损伤。胆汁酸合成是肝脏胆固醇代谢的主要途径。本研究旨在了解胆固醇和胆汁酸代谢与肝脏自噬活性之间的分子联系。在细胞模型中研究了胆固醇和胆固醇7α-羟化酶（CYP 7A 1）表达对自噬和溶酶体功能的影响。研究了阻断肝肠胆汁酸循环对小鼠肝脏自噬的影响及其机制。结果首先显示游离胆固醇和胆固醇酯对肝自噬的差异调节，由此细胞游离胆固醇而不是胆固醇酯的适度增加损害溶酶体功能并引起显著的自溶酶体积累。我们发现，无论是在小鼠中通过喂食消胆胺或在肝细胞中通过腺病毒介导的CYP 7A 1表达，CYP 7A 1诱导都会引起强烈的自噬诱导。从机制上讲，我们发现CYP 7A 1表达显著减弱了生长因子/AKT信号对雷帕霉素机制靶点（mTOR）的激活，但在体外和体内对mTOR的氨基酸信号没有影响。代谢组学分析进一步发现，CYP 7A 1诱导不仅降低了肝脏胆固醇，而且改变了磷脂和鞘脂组成。总的来说，这些结果表明，CYP 7A 1诱导干扰生长因子激活AKT/mTOR信号可能通过改变膜脂质组成。最后，我们发现，考来烯胺喂养恢复受损的肝脏自噬和改善西方饮食喂养小鼠的代谢稳态。这项研究确定了一种新的CYP 7A 1-AKT-mTOR信号传导轴，它选择性地诱导肝脏自噬，这有助于改善肝细胞的完整性和代谢稳态。
Hepatic cholesterol accumulation and autophagy defects contribute to hepatocyte injury in fatty liver disease. Bile acid synthesis is a major pathway for cholesterol catabolism in the liver. This study aims to understand the molecular link between cholesterol and bile acid metabolism and hepatic autophagy activity. The effects of cholesterol and cholesterol 7α-hydroxylase (CYP7A1) expression on autophagy and lysosome function were studied in cell models. The effects and mechanism of disrupting enterohepatic bile acid circulation on hepatic autophagy were studied in mice. The results first showed differential regulation of hepatic autophagy by free cholesterol and cholesterol ester, whereby a modest increase of cellular free cholesterol, but not cholesterol ester, impaired lysosome function and caused marked autolysosome accumulation. We found that CYP7A1 induction, either by cholestyramine feeding in mice or adenovirus-mediated CYP7A1 expression in hepatocytes, caused strong autophagy induction. Mechanistically, we showed that CYP7A1 expression markedly attenuated growth factor/AKT signaling activation of mechanistic target of rapamycin (mTOR), but not amino acid signaling to mTOR in vitro and in vivo. Metabolomics analysis further found that CYP7A1 induction not only decreased hepatic cholesterol but also altered phospholipid and sphingolipid compositions. Collectively, these results suggest that CYP7A1 induction interferes with growth factor activation of AKT/mTOR signaling possibly by altering membrane lipid composition. Finally, we showed that cholestyramine feeding restored impaired hepatic autophagy and improved metabolic homeostasis in Western diet–fed mice. This study identified a novel CYP7A1–AKT–mTOR signaling axis that selectively induces hepatic autophagy, which helps improve hepatocellular integrity and metabolic homeostasis.