Farnesoid X receptor signaling activates the hepatic X-box binding protein 1 pathway in vitro and in mice.
Farnesoid X receptor signaling activates the hepatic X-box binding protein 1 pathway in vitro and in mice.
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DOI：
10.1002/hep.29815
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发表时间：
2018-07
期刊：
影响因子：
--
通讯作者：
Green RM
中科院分区：
文献类型：
--
作者：
Liu X;Guo GL;Kong B;Hilburn DB;Hubchak SC;Park S;LeCuyer B;Hsieh A;Wang L;Fang D;Green RM
胆汁酸是核受体法尼醇X受体（FXR）的内源性配体，并且正在开发用于治疗几种肝脏疾病的药理学FXR调节剂。未折叠蛋白反应（unfolded protein response，UPR）的肌醇需要酶1α/X-box binding protein 1（IRE 1 α/XBP 1）通路是内质网应激时激活的一条保护性细胞信号通路。我们研究了FXR信号在肝脏XBP 1通路激活中的作用。用脱氧胆酸（DCA）、消胆胺、GW 4064处理小鼠或进行胆管结扎（BDL），并测量肝脏UPR活化。用FXR激动剂、抑制剂、siRNA或SHP siRNA处理Huh 7-Ntcp和HepG 2细胞，以确定IRE 1 α/XBP 1通路激活的机制。DCA喂养和BDL增加肝脏XBP 1的表达，考来烯胺降低肝脏XBP 1的表达。在用胆汁酸、6-ECDCA或GW 4064处理的Huh 7-Ntcp和HepG 2细胞中，XBP 1途径活化增加。这种作用随着FXR敲低和用FXR抑制剂guggulsterone治疗而降低。FXR激动剂增加了XBP 1剪接和磷酸化IRE 1 α表达。小异源二聚体伴侣（SHP）的过表达同样增加了XBP 1剪接，XBP 1 s和磷酸化IRE 1 α蛋白的表达。SHP敲低减弱了FXR激动剂诱导的XBP 1 s和磷酸化IRE 1 α蛋白表达。免疫共沉淀试验证明HEK 293 T细胞中过表达的GFP-SHP和FLAG-IRE 1 α之间存在物理相互作用。用GW 4064处理的小鼠增加了基础Xbp 1 s基因表达，而FXR和SHP敲除小鼠减少了基础Xbp 1 s基因表达。FXR信号在体内和体外激活IRE 1 α/XBP 1通路。FXR通路激活增加了XBP 1剪接并增强了磷酸化IRE 1 α表达。这些效应至少部分是由SHP介导的。胆汁酸和药理学FXR激动剂激活IRE 1 α/XBP 1通路可能在肝损伤期间具有保护作用，并可能对肝脏疾病具有治疗意义。
Bile acids are endogenous ligands of the nuclear receptor farnesoid X receptor (FXR), and pharmacologic FXR modulators are under development for the treatment of several liver disorders. The inositol-requiring enzyme 1α/X-box binding protein 1 (IRE1α/XBP1) pathway of the unfolded protein response (UPR) is a protective cellular signaling pathway activated in response to endoplasmic reticulum stress. We investigated the role of FXR signaling in the activation of the hepatic XBP1 pathway. Mice were treated with deoxycholic acid (DCA), cholestyramine, GW4064 or underwent bile duct ligation (BDL) and the hepatic UPR activation was measured. Huh7-Ntcp and HepG2 cells were treated with FXR agonists, inhibitor, siRNA or SHP siRNA to determine the mechanisms of IRE1α/XBP1 pathway activation. DCA feeding and BDL increased and cholestyramine decreased expression of hepatic XBP1s. XBP1 pathway activation increased in Huh7-Ntcp and HepG2 cells treated with bile acids, 6-ECDCA or GW4064. This effect decreased with FXR knockdown and treatment with FXR inhibitor guggulsterone. FXR agonists increased XBP1 splicing and phosphorylated-IRE1α expression. Overexpression of small heterodimer partner (SHP) similarly increased XBP1 splicing, XBP1s and phosphorylated-IRE1α protein expression. SHP knockdown attenuated FXR agonist-induced XBP1s and phosphorylated-IRE1α protein expression. Co-immunoprecipitation assays demonstrate a physical interaction between overexpressed GFP-SHP and FLAG-IRE1α in HEK293T cells. Mice treated with GW4064 had increased, and FXR and SHP null mice had decreased, basal Xbp1s gene expression. FXR signaling activates the IRE1α/XBP1 pathway in vivo and in vitro. FXR pathway activation increases XBP1 splicing and enhances phosphorylated-IRE1α expression. These effects are mediated, at least in part, by SHP. IRE1α/XBP1 pathway activation by bile acids and pharmacologic FXR agonists may be protective during liver injury and may have therapeutic implications for liver diseases.
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影响因子：
25.7
作者：
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13.5
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