CORT118335 (miricorilant) and CORT125385 are structurally similar selective GR modulators (SGRMs) that combine GR agonism and antagonism and were previously shown to reduce diet-induced liver steatosis in preclinical mouse models. Preliminary clinical data in patients with presumed non-alcoholic steatohepatitis also show reduced hepatic lipid content upon CORT118335 treatment. Our current studies aim to further understand the lipid-lowering effects of CORT118335 and CORT125385.

Male and female C57BL/6J mice received 60% high-fat diet (HFD) combined with 10% fructose water for three weeks to induce liver steatosis and were subsequently treated with 60 mg/kg/day CORT118335 via oral gavage in several treatment regimens. As early as three days after treatment initiation, CORT118335 dramatically reduced hepatic triglyceride levels in male mice, whereas hepatic cholesterol remained largely unaffected. CORT118335-induced reduction of liver triglycerides was accompanied by decreased expression of fatty acid transporters Cd36 and Fabp1. Surprisingly, CORT118335 treatment did not lower diet-induced lipid accumulation in female mice. On the other hand, treatment with CORT125385 (supplemented to 60% HFD combined with 10% fructose water for three weeks) lowered hepatic triglyceride levels in both male and female mice.

We tentatively conclude that the substantial promise of liver steatosis treatment by SGRMs is based on a rapidly reduced lipid uptake and/or different intracellular lipid handling by hepatocytes. To further investigate the molecular mechanisms underlying the effects of GR modulation, our research now focuses on the evaluation of differences in GR coregulator recruitment and transcriptional effects in response to different GR ligands using RIME and RNAseq in mouse liver tissue.