GNPS - Bile Acid Standards for MSV000093200
Ontology highlight
ABSTRACT:
INSTRUMENT(S): Q Exactive
ORGANISM(S): Homo Sapiens (ncbitaxon:9606)
SUBMITTER: 
Pieter C Dorrestein
PROVIDER: MSV000093262 | GNPS | Thu Nov 02 10:20:00 GMT 2023
REPOSITORIES: GNPS
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Project description:Bile acid standards run alongside MSV000093200 (Gates Foundation SEPSIS project).
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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 | GSE287020 | GEO
Project description:Specific bile acids are potent signaling molecules that modulate metabolic pathways affecting lipid, glucose and bile acid homeostasis, and the microbiota. Bile acids are synthesized from cholesterol in the liver, and the key enzymes involved in bile acid synthesis (Cyp7a1, Cyp8b1) are regulated transcriptionally by the nuclear receptor FXR. We have identified an FXR-regulated pathway upstream of a transcriptional repressor that controls multiple bile acid metabolism genes. We identify MafG as an FXR target gene and show that hepatic MAFG overexpression represses genes of the bile acid synthetic pathway and modifies the biliary bile acid composition. In contrast, loss-of-function studies using MafG(+/-) mice causes de-repression of the same genes with concordant changes in biliary bile acid levels. Finally, we identify functional MafG response elements in bile acid metabolism genes using ChIP-seq analysis. Our studies identify a molecular mechanism for the complex feedback regulation of bile acid synthesis controlled by FXR.
2016-02-04 | GSE77529 | GEO
Project description:Intestinal lipid absorption, the entry-point for fats into the body, requires the coordinated actions of bile acids and lipases. Here, we uncover distinct yet cooperative roles of bile acids in driving the differential uptake of dietary fatty acids. We first decreased bile acid pool size by disrupting the rate-limiting enzyme in bile acid synthesis, Cyp7a1, using liver-directed gene editing in mice. Compared to lipase inhibition, reduced bile acids prevented diet-induced obesity, increased anorectic hormones, suppressed excessive eating, and improved systemic lipid metabolism. Remarkably, decreasing bile acids selectively decreased absorption of saturated fatty acids, but preserved polyunsaturated fatty acids. By targeting additional bile acid enzymes, we identified specific functions of individual bile acid species. Mechanistically, we show that cholic acid preferentially solubilizes polyunsaturated fatty acids into mixed micelles for intestinal uptake. Our studies demonstrate that bile acids can selectively control fatty acid uptake, revealing insights for future interventions in metabolic disease.
2025-11-17 | GSE304800 | GEO
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
Project description:Summary Ex vivo liver normothermic machine perfusion (NMP) does not fully recapitulate physiological liver function due to the absence of the enterohepatic circulation as only infusion of the bile acid taurocholate (TCA) is applied in most protocols. In this study we characterized the de novo bile acid synthesis and cholesterol homeostasis during liver NMP. We hypothesized that addition of a more diverse pool of (conjugated)bile acids during liver NMP would decrease the metabolic burden of de novo synthesis and thereby improve liver function during NMP. Method First, human and porcine livers were perfused for 360 min at 37°C and perfusate containing TCA (gene expression at t=0min and t=360min was measured by RNAseq). Next, the infusion of different conjugated bile acid mixes was assessed during porcine and human liver perfusion. Perfusate, bile and tissue samples were obtained to study liver viability, functionality, gene expression (qPCR), cholesterol and bile acid levels. Result During human and porcine perfusions with TCA infusion, composition of bile was comparable to literature however, synthesis rates were above physiological average and a decrease over time in cholesterol perfusate levels was observed. Additionally, over time a decreased expression of bile acid synthesis related genes, increased gene expression of cholesterol metabolism related genes and decreased expression in bile acid-dependent uptake and efflux transporters were detected (RNAseq). Upon infusion of a conjugated bile acid mix lower AST and ALT values and stable cholesterol homeostasis was] observed after 720 min of perfusion. Perfused human livers showed appropriate function and good functioning livers showed rapid bile acid clearance from the perfusate into the bile. Conclusion This study reveals new insights that infusion of (un)conjugated bile acids in NMP alleviated the burden of the de novo bile acid synthesis and improved liver function.
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