An LRH-1 agonist reverses hepatic metabolic dysfunction in obesity

Liver receptor homolog-1 (LRH-1; NR5A2) is a nuclear receptor that controls metabolic gene programs important for liver health. Here, we address two challenges with dissecting ligand-driven LRH-1 metabolism in vivo. First, we generate ME610, a potent LRH-1 agonist with favorable pharmacokinetic properties. Second, we engineer Nr5a2 ^humLBD mice, edited to recapitulate the ligand response of the human receptor. ME610 dose-dependently induces LRH-1 target genes and reduces triglycerides in livers of Nr5a2 ^humLBD mice. In a mouse model of diet-induced obesity (DIO), ME610 dramatically improves insulin sensitivity and reduces liver fat. Multi-omics integration of transcriptomics, lipidomics, and metabolomics data demonstrates a coordinated reversal of DIO-induced hepatic metabolic stress via changes in lipid, amino acid, and energy metabolism, with peroxisomal lipid metabolism emerging as a central process correlated to efficacy. These studies uncover new pathways through which LRH-1 regulates metabolism and demonstrate the therapeutic potential of synthetic LRH-1 agonists in obesity-associated metabolic diseases.