Here, we have shown that RDX8940 is a potent, selective, and minimally systemic oral TGR5 agonist that induces GLP-1, GLP-2, and PYY secretion from mouse intestinal L cells and improves liver steatosis and insulin sensitivity in a model of NAFLD and mild insulin resistance. This evidence concerns the gene GPBAR1 and metabolic dysfunction-associated steatotic liver disease.