Glycodeoxycholic acid inhibits primary bile acid synthesis with minor effects on glucose- and lipid homeostasis in humans

Emma C. E. Meessen, Soumia Majait, Ümran Ay, Steven W. Olde Damink, Johannes A. Romijn, Jens J. Holst, Bolette Hartmann, Folkert Kuipers, Max Nieuwdorp, Frank G. Schaap, Albert K Groen, E Marleen Kemper, Maarten R. Soeters*

*Corresponding author for this work

Research output: Contribution to journalJournal articleResearchpeer-review

Abstract

BACKGROUND: Bile acids play vital roles in control of lipid-, glucose-, and energy metabolism by activating Takeda G protein-coupled receptor 5 (TGR5) and Farnesoid X receptor (FXR), the latter promoting production of the endocrine-acting fibroblast growth factor 19 (FGF19). Short-term administration of single bile acids has been reported to enhance plasma levels of GLP-1 and to enhance energy expenditure. However, prolonged bile acid supplementation, e.g. of chenodeoxycholic acid (CDCA) for gallstone dissolution, has been reported to have adverse effects.

STUDY DESIGN: In this proof-of-concept study, we assessed the safety and metabolic effects of oral glycine-conjugated deoxycholic acid (GDCA) administration at 10 mg/kg/day using regular and slow-release capsules (mimicking physiological bile acid release) over 30 days in two groups of each 10 healthy lean men respectively.

MAIN FINDINGS: GDCA increased postprandial total bile acid and FGF19 concentrations while suppressing those of the primary bile acids CDCA and cholic acid. Plasma levels of 7α-hydroxy-4-cholesten-3-one were reduced, indicating repressed hepatic bile acid synthesis. There were minimal effects on indices of lipid-, glucose-, and energy metabolism. No serious adverse events were reported during GDCA administration in either capsule types, although 50% of participants showed mild increases in plasma levels of liver transaminases and 80% (regular capsules) and 50% (slow-release capsules) of participants experienced gastrointestinal adverse events.

CONCLUSION: GDCA administration leads to elevated FGF19 levels and effectively inhibits primary bile acid synthesis, supporting therapy compliance and its effectiveness. However, effects on lipid, glucose- and energy metabolism were minimal, indicating that expanding the pool of this relatively hydrophobic bile acid does not impact energy metabolism in healthy subjects.

Original languageEnglish
JournalThe Journal of clinical endocrinology and metabolism
ISSN0021-972X
DOIs
Publication statusE-pub ahead of print - 2024

Bibliographical note

© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society.

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