Overall, the data reported here show 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, does not inhibit gallbladder emptying in mice, and improves liver steatosis and insulin sensitivity in a mouse model of NAFLD and mild insulin resistance. Here, PYY is linked to metabolic dysfunction-associated steatotic liver disease.