胆汁盐排泄泵:生物学和病理学。
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苏奇FJ, Ananthanarayanan M
胆汁盐排泄泵:生物学和病理学。
J Pediatr杂志减轻。2006年7月,43增刊1:S10-6。
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16819395 (在PubMed]
- 文摘
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胆汁酸是主要决定因素和动力的产生胆汁流。胆汁酸在微管的膜主要是一个ATP-dependent运输过程。主要运输是胆汁盐排泄泵(BSEP、ABCB11)、腺苷的成员triphosphate-binding盒(ABC)转运蛋白家族。监管机制,可以协调基因编码胆汁酸运输蛋白质是至关重要的,以避免胆汁酸intracellar积累的肝细胞损害。胆汁盐是天然配体数核激素受体表达的肝脏和小肠。核受体是特定的配体结合的转录因子如胆汁酸和调节基因的表达细胞的代谢需求。BSEP克隆的基因,我们找到了一个结合位点的启动子farnesoid X受体(FXR),胆汁酸的核受体。FXR活动需要与9-cis heterodimerization类维生素a受体(RXRα),当受胆汁酸和视黄酸,BSEP的复杂有效激活转录。有越来越多的证据通过重构核激素受体的激活染色质的组蛋白修饰包括乙酰化、H3和H4组蛋白的甲基化。我们最近展示了一种角色coactivator-associated精氨酸甲基转移酶1 (CARM1),共激活剂的FXR / RXR FXR响应基因的受体和监管机构如BSEP。 Chromatin immunoprecipitation showed that the bile acid-dependent activation of the human BSEP is associated with a simultaneous increase of FXR and CARM1 occupation of the BSEP promoter. The increased occupation of the BSEP locus by CARM1 also corresponds with the increased deposition of Arg-17 methylation and Lys-9 acetylation of histone H3 within the FXR DNA-binding element of BSEP. Our work on the role of nuclear receptors in regulation of bile acid homeostasis has led to an increased understanding of the pathogenesis of the disorder, progressive familial intrahepatic cholestasis, type 1 (PFIC1) or Byler disease. The gene mutated in PFIC1 is called FIC1 and codes for a type IV P-type ATPase whose function is unknown. Increased ileal apical sodium-dependent bile acid transporter messenger RNA (mRNA) expression was detected in 3 patients with PFIC1. Ileal FXR and short heterodimer partner (an inhibitory nuclear receptor) messenger RNA levels were reduced in the same 3 patients. In studies of cells after antisense-mediated knock-down of endogenous FIC1, the activity of the ileal apical bile acid transporter promoter was enhanced, whereas the activities of the human FXR and BSEP promoters were reduced. Nuclear but not cytoplasmic localization of FXR is markedly decreased in FIC1-negative cells, indicating that FIC1 is necessary for posttranslational modifications necessary for the nuclear translocation of FXR. This defect leads to enhanced ileal bile salt uptake and impaired canalicular bile salt secretion by BSEP. In PFIC1, an increased load of bile acids is retained in the liver leading to cholestasis and progressive liver injury.