CORT118335 (miricorilant) is a GR ligand that acts as a selective modulator of GR activity by inducing a combination of GR agonism and antagonism, and was previously shown to reduce liver steatosis in mouse models of non-alcoholic fatty liver disease (NAFLD). Preliminary clinical data in patients with presumed non-alcoholic steatohepatitis (NASH) also show reduced hepatic lipid content upon miricorilant treatment. The aim of the current study is to further evaluate and understand the lipid-lowering effects of CORT118335 in mouse models of NAFLD. Male C57BL/6J mice received 60% high-fat diet combined with 10% fructose water for three weeks to induce liver steatosis, and mice were subsequently treated with either vehicle or 60 mg/kg/day CORT118335 via oral gavage in several treatment regimens. Hepatic triglyceride levels were dramatically reduced upon treatment with CORT118335, whereas total hepatic cholesterol remains largely unaffected. These effects occurred as early as three days after starting daily CORT118335 treatment and were accompanied by altered expression of several genes involved in hepatic lipid metabolism. In particular, Cd36 and Fabp1, which are involved in uptake and intracellular trafficking of fatty acids, appear to be downregulated upon treatment with CORT118335. We tentatively conclude that the substantial promise of NAFLD treatment via GR modulation by CORT118335 is based on a rapidly reduced lipid uptake and/or different intracellular lipid handling by hepatocytes.