Wooton-Kee Clavia Ruth, Yalamanchili Hari K, Mohamed Islam, Hassan Manal, Setchell Kenneth D R, Narvaez Rivas Monica, Coskun Ayse K, Putluri Vasanta, Putluri Nagireddy, Jalal Prasun, Schilsky Michael L, Moore David D
Department of Pediatrics-Nutrition, Children's Nutrition Research Center, Baylor College of Medicine, Houston, Texas, USA.
Department of Cellular and Molecular Biology, Baylor College of Medicine, Houston, Texas, USA.
Hepatol Commun. 2025 May 23;9(6). doi: 10.1097/HC9.0000000000000707. eCollection 2025 Jun 1.
Wilson disease (WD) is an autosomal recessive disorder that results in excessive hepatic copper, causing hepatic steatosis, inflammation, fibrosis, cirrhosis, and liver failure. Previous studies have revealed dysregulation of many farnesoid X receptor (FXR) metabolic target genes in WD, including the bile salt exporter pump, the major determinant of bile flow.
We tested the hypothesis that the FXR-cistrome is decreased in Atp7b-/- mice in accord with dysregulated bile acid homeostasis.
FXR binding within Atp7b-/- mouse livers displayed surprising complexity: FXR binding was increased in distal intergenic regions but decreased in promoter regions in Atp7b-/- versus wild-type mice. Decreased FXR occupancy in Atp7b-/- versus wild-type mice was observed in hepatocyte metabolic and bile acid homeostasis pathways, while enrichment of FXR binding was observed in pathways associated with cellular damage outside of hepatocytes. Indeed, disparate FXR occupancy was identified in parenchymal and non-parenchymal marker genes in a manner that suggests decreased FXR activity in parenchymal cells, as expected, and increased FXR activity in non-parenchymal cells. Consistent with altered FXR function, serum and liver bile acid concentrations were higher in Atp7b-/- mice than in wild-type mice. Comparison of bile acid profiles in the serum of WD patients with "liver," "neurological," or "mixed" disease versus healthy controls also revealed increases in specific bile acids in WD-liver versus healthy controls.
We identified novel FXR-occupancy across the genome that varied in parenchymal and non-parenchymal cells, demonstrating complex FXR regulation of metabolic and hepatocellular stress pathways in Atp7b-/- mice. Dynamic changes in FXR activity support our novel finding of altered bile acid metabolism in Atp7b-/- mice and WD patients.
威尔逊病（WD）是一种常染色体隐性疾病，可导致肝脏铜过量，引起肝脂肪变性、炎症、纤维化、肝硬化和肝衰竭。先前的研究表明，WD患者中许多法尼醇X受体（FXR）代谢靶基因失调，包括胆汁盐输出泵，它是胆汁流动的主要决定因素。
我们检验了这样一个假设，即与胆汁酸稳态失调一致，Atp7b-/-小鼠的FXR顺式作用元件组减少。
Atp7b-/-小鼠肝脏内的FXR结合表现出惊人的复杂性：与野生型小鼠相比，Atp7b-/-小鼠的基因间远端区域FXR结合增加，而启动子区域FXR结合减少。在Atp7b-/-小鼠与野生型小鼠中，肝细胞代谢和胆汁酸稳态途径中的FXR占据减少，而在与肝细胞外细胞损伤相关的途径中观察到FXR结合富集。事实上，在实质和非实质标记基因中发现了不同的FXR占据情况，这表明实质细胞中FXR活性降低，而非实质细胞中FXR活性增加——这与预期一致。与FXR功能改变一致，Atp7b-/-小鼠的血清和肝脏胆汁酸浓度高于野生型小鼠。WD患者中患有“肝脏型”“神经型”或“混合型”疾病的患者与健康对照者血清胆汁酸谱的比较也显示，WD肝脏型患者与健康对照者相比特定胆汁酸增加。
我们在全基因组中鉴定出新型的FXR占据情况，其在实质和非实质细胞中有所不同，表明Atp7b-/-小鼠中FXR对代谢和肝细胞应激途径的调控复杂。FXR活性的动态变化支持了我们关于Atp7b-/-小鼠和WD患者胆汁酸代谢改变的新发现。
