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Updated: Feb 1, 2026
Real Time Monitoring of Intracellular Bile Acid Dynamics Using a Genetically Encoded FRET-based Bile Acid Sensor
Published on: January 4, 2016
Beyond bile acids synthesis: metabolomics profiling highlights extensive metabolic dysregulation and treatment
Monte A Del Monte1, Jennifer Hanson2, Penelope E Bonnen3
1Department of Ophthalmology and Visual Sciences, Kellogg Eye Center, University of Michigan, Ann Arbor, MI, USA.
Background:
Cerebrotendinous xanthomatosis (CTX) is an inherited metabolic disorder caused by variants in CYP27A1 leading to loss of sterol-27-hydroxylase activity. Sterol-27-hydroxylase generates two classes of bioactive signaling molecules: bile acids and oxysterols. The broader metabolic consequences resulting from perturbations in bile acid and oxysterol signaling and their reversibility with FDA-approved treatment chenodeoxycholic acid (CDCA), are not fully described.
Methods:
To establish a comprehensive map of metabolic consequences of CTX, we performed large-scale, untargeted plasma metabolomics in a single subject with CTX, both before and after 6 months of CDCA therapy, and compared results with a reference cohort of over 1100 individuals. Data were analyzed for significant metabolite changes and pathway alterations.
Results:
Untreated CTX exhibited marked depletion of bile acid intermediates and elevations in sterol precursors, consistent with the known enzymatic block in this pathway. Metabolomics highlighted additional pathways affected by bile acid and oxysterol signaling such as fatty acid metabolism, NAD+ de novo synthesis, phosphatidylethanolamines, sphingolipids and ferroptosis. Following six months of CDCA therapy, sterol precursors normalized, bile acid intermediates partially recovered, and phosphatidylethanolamines were restored toward reference ranges, while steroid and phosphatidylcholine metabolites remained largely unchanged.
Conclusions:
This study exposes the comprehensive nature of metabolic disturbance in CTX beyond the bile acids pathway, revealing perturbations in bile acids, steroids, fatty acids, phospholipids and NAD+ synthesis and highlights the dynamic early response to CDCA therapy. The metabolomic profile of untreated CTX can be leveraged for diagnostic screening. These findings report new candidate biomarkers for diagnosis and monitoring and underscore the potential of metabolomics to uncover broader metabolic consequences in rare disease.
Insights
Cerebrotendinous xanthomatosis (CTX) causes widespread metabolic issues beyond bile acids. Chenodeoxycholic acid (CDCA) therapy shows early promise in restoring metabolic balance, suggesting potential for diagnosis and monitoring.
Area of Science:
- Biochemistry
- Genetics
- Metabolomics
Background:
- Cerebrotendinous xanthomatosis (CTX) is an inherited disorder stemming from CYP27A1 variants, impairing sterol-27-hydroxylase activity.
- This enzyme deficiency disrupts bile acid and oxysterol signaling, with full metabolic impacts and treatment reversibility needing further elucidation.
Purpose of the Study:
- To comprehensively map the metabolic consequences of Cerebrotendinous xanthomatosis (CTX).
- To assess the metabolic changes and reversibility with chenodeoxycholic acid (CDCA) therapy in CTX.
Main Methods:
- Large-scale, untargeted plasma metabolomics was performed on a single CTX subject before and after 6 months of CDCA treatment.
- Results were compared against a reference cohort of over 1100 individuals to identify significant metabolite and pathway alterations.
Main Results:
- Untreated CTX showed depleted bile acid intermediates and elevated sterol precursors.
- Metabolomics revealed additional affected pathways including fatty acid metabolism, NAD+ synthesis, phosphatidylethanolamines, sphingolipids, and ferroptosis.
- CDCA therapy normalized sterol precursors, partially recovered bile acid intermediates, and restored phosphatidylethanolamines.
Conclusions:
- CTX presents a broad metabolic disturbance affecting bile acids, steroids, fatty acids, phospholipids, and NAD+ synthesis.
- Early CDCA therapy demonstrates a dynamic metabolic response, offering potential for diagnostic biomarkers and monitoring rare diseases.
- Metabolomic profiling of untreated CTX can aid in diagnostic screening.
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