Bile Acid Signaling and Metabolic Regulation

Bile acids are amphipathic molecules synthesised from cholesterol in the liver and secreted into bile to facilitate lipid digestion and absorption. Beyond their classical role as detergents, bile acids act as endocrine and paracrine signals that regulate metabolic pathways through nuclear and membrane receptors. Activation of the nuclear receptor FXR in hepatocytes and enterocytes orchestrates feedback control of bile acid synthesis, modulates lipogenesis and gluconeogenesis, and governs the enterohepatic circulation. The membrane receptor TGR5, expressed in tissues including the intestine and immune cells, mediates energy expenditure, glucose homeostasis and anti-inflammatory responses. Microbial deconjugation and transformation of bile acids further diversify the signalling repertoire, linking the gut microbiome to host metabolism. Dysregulation of these pathways underlies obesity, insulin resistance, non-alcoholic fatty liver disease and cardiovascular risk, prompting exploration of receptor modulators, bile acid analogues and sequestrants to rebalance metabolic homeostasis.

Research from Nature Portfolio

Recent studies have elucidated intestine-selective FXR inhibition as a strategy to combat obesity-related metabolic dysfunction. Oral administration of a glycine-conjugated muricholic acid analogue in murine models selectively blocks intestinal FXR, reduces ceramide synthesis and enhances energy expenditure, reversing diet-induced obesity, insulin resistance and hepatic steatosis. Parallel work has defined the role of FXR in enteroendocrine L cells, where receptor activation suppresses proglucagon expression and GLP-1 secretion by interfering with carbohydrate-responsive element binding protein–driven glycolysis. Genetic ablation or pharmacological inhibition of FXR in these cells augments postprandial GLP-1 release, improves glucose tolerance and offers new avenues for type 2 diabetes therapy.

Bile Acid Signaling and Metabolic Regulation publication trend

The graph below shows the total number of articles in bile acid signaling and metabolic regulation across all publications each year (not limited to Nature Index journals).

Technical terms

Farnesoid X receptor (FXR): A nuclear receptor activated by bile acids that regulates genes involved in bile acid synthesis, lipid and glucose metabolism.
TGR5: A cell-surface G protein-coupled receptor responsive to bile acids, mediating energy expenditure and anti-inflammatory signalling.
Enterohepatic circulation: The cyclical transport of bile acids from the liver to the intestine and back, central to bile acid homeostasis.
Ceramides: Sphingolipid metabolites whose synthesis is regulated by bile acid signalling and implicated in insulin resistance.
GLP-1: An incretin hormone produced by enteroendocrine L cells that enhances insulin secretion and is modulated by FXR activity.
Bile acid pool: The collective composition and concentration of bile acid species in enterohepatic circulation, influenced by host and microbial metabolism.

References

1. Bile acid metabolism and signaling in health and disease: molecular mechanisms and therapeutic targets. Signal Transduction and Targeted Therapy (2024).
2. The underappreciated diversity of bile acid modifications. Cell (2024).
3. Intestine-selective farnesoid X receptor inhibition improves obesity-related metabolic dysfunction. Nature Communications (2015).
4. Farnesoid X receptor inhibits glucagon-like peptide-1 production by enteroendocrine L cells. Nature Communications (2015).
5. Ursodeoxycholic acid exerts farnesoid X receptor-antagonistic effects on bile acid and lipid metabolism in morbid obesity. Journal of Hepatology (2015).
6. Bile acids as regulatory molecules. Journal of Lipid Research (2009).
7. Bile acids: regulation of synthesis Thematic Review Series: Bile Acids. Journal of Lipid Research (2009).
8. Differential regulation of bile acid homeostasis by the farnesoid X receptor in liver and intestine. Journal of Lipid Research (2007).
9. A G Protein-coupled Receptor Responsive to Bile Acids*. Journal of Biological Chemistry (2003).
10. Bile Acids Activated Receptors Regulate Innate Immunity. Frontiers in Immunology (2018).