FXR adapts hepatic mitochondrial function to increased substrate oxidation in patients with obesity

Metabolic pressure shifts signaling pathways of nuclear receptors, including the bile acid receptor FXR, which are sensitive to nutritional inputs. We performed an FXR ChIP-seq-centered multi-omics analysis of liver biopsy samples from individuals with or without obesity, who were treated with either placebo or the FXR agonist obeticholic acid (OCA), to define metabolic adaptions of FXR signaling pathways. FXR pre-occupies significantly more DNA binding sites in subjects with obesity and FXR activation by OCA robustly changes the transcriptional output. Integration of ChIP-seq and RNA-seq data shows that mitochondrial function and substrate oxidation are the top metabolic pathways selectively modulated by FXR activation in individuals with obesity. FXR activation restores compromised substrate oxidation by enhancing ?-oxidation and oxidative phosphorylation along with antagonizing ROS production. In line, reduced glutathione levels of patients with obesity normalized after OCA treatment. In summary, FXR signaling profoundly differs in patients with obesity, consisting of changes in DNA binding profiles and transcriptional programs, which enhance energy substrate utilization in this patient cohort.