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Alterations in Bile Acid Physiology in Wilson Disease

ABSTRACT: Background & Aims: 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 FXR metabolic target genes in animal models of WD, including Bsep, the major determinant of bile flow. Approach & Results: We tested the hypothesis that the FXR-cistrome is decreased in Atp7b-/- mice in accord with dysregulated bile acid homeostasis. RNA-Seq and ChIP-Seq analyses of Atp7b-/- and wild-type (WT) mouse livers confirmed that significantly altered transcripts and FXR-binding events overlapped. Decreased FXR occupancy in Atp7b-/- versus WT mice was observed genes of metabolic pathways and bile acid homeostasis, while enrichment of FXR binding was observed pathways associated with cellular damage, such as the focal adhesion pathway. Consistent with decreased FXR function, serum and liver bile acid concentrations were higher in Atp7b-/- mice than in WT mice. Comparison of bile acid profiles in the serum of WD patients with “liver,” “neurological,” or “mixed” disease vs. healthy controls also revealed increases in specific bile acids in WD-liver vs. healthy controls. Conclusions: Atp7b-/- mice and WD patients exhibited changes in serum bile acid speciation, likely due to FXR dysfunction. These findings provide new insights into possible aberrant bile acid homeostasis in patients with WD.

ORGANISM(S): Mus musculus

PROVIDER: GSE287020 | GEO | 2025/06/04

REPOSITORIES: GEO

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Alterations in Bile Acid Physiology in Wilson Disease [ChIP-seq]

Project description:Background & Aims: 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 FXR metabolic target genes in animal models of WD, including Bsep, the major determinant of bile flow. Approach & Results: We tested the hypothesis that the FXR-cistrome is decreased in Atp7b-/- mice in accord with dysregulated bile acid homeostasis. RNA-Seq and ChIP-Seq analyses of Atp7b-/- and wild-type (WT) mouse livers confirmed that significantly altered transcripts and FXR-binding events overlapped. Decreased FXR occupancy in Atp7b-/- versus WT mice was observed genes of metabolic pathways and bile acid homeostasis, while enrichment of FXR binding was observed pathways associated with cellular damage, such as the focal adhesion pathway. Consistent with decreased FXR function, serum and liver bile acid concentrations were higher in Atp7b-/- mice than in WT mice. Comparison of bile acid profiles in the serum of WD patients with “liver,” “neurological,” or “mixed” disease vs. healthy controls also revealed increases in specific bile acids in WD-liver vs. healthy controls. Conclusions: Atp7b-/- mice and WD patients exhibited changes in serum bile acid speciation, likely due to FXR dysfunction. These findings provide new insights into possible aberrant bile acid homeostasis in patients with WD.

2025-06-04 | GSE286956 | GEO

The essential roles of FXR in diet and aging affected metabolic changes and liver disease development: a multi-omics study

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Inactivation of Atp7b copper transporter in the intestinal epithelial cells is associated with altered lipid processing and cell growth machinery that are independent from hepatic copper accumulation and liver histology severity

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Project description:Wilson’s disease (WD) is a relevant human genetic disease caused by mutations in the ATP7B gene, whose product is a liver enzyme responsible for copper export into bile and blood. Interestingly, the spectrum of ATP7B mutations is vast and can influence clinical presentation (a variable spectrum of hepatic and neural manifestations), though the reason for this is not well understood. Here we describe the successful generation of iPSCs from a Chinese patient with Wilson’s disease that bears the R778L Chinese hotspot mutation in the ATP7B gene. Global gene expression profiling with DNA microarrays showed that WD iPSCs cluster together with human ESCs (H9) compared to donor fibroblasts. WD patient fibroblasts were isolated and expanded from a dermal biopsy of a middle age Chinese Han male, WD iPSCs were generated by overexpression of human Oct4/Sox2/Klf4/c-Myc in WD fibroblasts and expanded on Matrigel with mTESR1 culture medium. For DNA microarray analysis, WD fibroblasts (passage 5), 3 cell lines of WD iPSCs growing on Matrigel (passage 8) and human ES H9 growing on Matrigel (passage 40) were treated with Trizol, followed by RNA extraction and hybridization.

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