Anna P. Plazzo, Verena Filz, Michaela Prothiwa, Rebekka Lambrecht, M. Eugenia Delgado, Jennifer R. Fleming, Jerome Duschek, Elia Pilgram, Juliane Friedrich, Raphael Eisenring, Lea Kurtz, Kerstin Stemmer, Lotta K. Stenman, Fabian Amaya Garcia, Miriam Unterlass, Olga Mayans, Thomas Böttcher, Thomas Brunner
- Interactions between microbiota and the host can profoundly affect human health. In particular, microbiota-derived metabolites influence liver physiology and contribute to the development of metabolic diseases, yet the molecular mechanisms underlying microbiome-host communication remain incompletely understood. Here, we identify bacterial lipids as modulators of the nuclear receptor Liver Receptor Homolog-1 (LRH-1/NR5A2), a regulator of hepatic metabolism. Lipid extracts from multiple bacterial species, including the probiotic Bifidobacterium animalis subsp. lactis B420TM, activated LRH-1, leading to the identification of the long-chain fatty acid vaccenic acid (VA) as a previously unrecognized endogenous LRH-1 ligand. VA directly bound the LRH-1 ligand-binding domain and stimulated receptor-dependent transcriptional activity. In high-fat diet-induced obese and hyperglycemic mice, VA-mediated LRH-1 activation improved glucose homeostasis and attenuated metabolic liver disease.Interactions between microbiota and the host can profoundly affect human health. In particular, microbiota-derived metabolites influence liver physiology and contribute to the development of metabolic diseases, yet the molecular mechanisms underlying microbiome-host communication remain incompletely understood. Here, we identify bacterial lipids as modulators of the nuclear receptor Liver Receptor Homolog-1 (LRH-1/NR5A2), a regulator of hepatic metabolism. Lipid extracts from multiple bacterial species, including the probiotic Bifidobacterium animalis subsp. lactis B420TM, activated LRH-1, leading to the identification of the long-chain fatty acid vaccenic acid (VA) as a previously unrecognized endogenous LRH-1 ligand. VA directly bound the LRH-1 ligand-binding domain and stimulated receptor-dependent transcriptional activity. In high-fat diet-induced obese and hyperglycemic mice, VA-mediated LRH-1 activation improved glucose homeostasis and attenuated metabolic liver disease. Transcriptomic analyses revealed suppression of hepatic de novo lipogenesis as a principle downstream response to LRH-1 activation. Together, these findings establish a microbiota-LRH-1 signaling axis that links bacterial lipid metabolism to host metabolic regulation, identify VA as a functional LRH-1 agonist, and provide a mechanistic rationale for targeting LRH-1 in metabolic liver disease.…
