CORT118335 is a selective Glucocorticoid Receptor (GR) modulator that was previously shown to prevent diet-induced liver steatosis in male mice. CORT118335 displayed specific GR antagonism on fatty acid uptake while maintaining lipid efflux, whereas corticosterone stimulated both the influx and the efflux of lipids. Currently, the molecular mechanisms underlying the beneficial properties of CORT118335 in liver lipid metabolism are yet unknown.

In order to unravel how CORT118335 prevents liver steatosis, we previously performed RNA-sequencing on livers of mice under high-fat diet supplemented with vehicle, corticosterone or CORT118335. We identified 54 genes that were significantly upregulated by corticosterone but not by CORT118335 treatment. These genes are likely involved in CORT118335 prevention of lipid uptake in the liver.

Here, we evaluated the expression of genes in this shortlist and GR classic target genes in the human HepG2 cell line after CORT118335 and cortisol treatment over time. The results suggest that CORT118335 generally acts as a partial agonist on Fkbp5, Gilz and Per1 expression in HepG2 cells, but that the extent of partial agonism is gene- and time- specific. For instance, Mt2 and Cd36 that are in the top differential expression shortlist displayed a significant difference in expression after 12 hours of CORT118335 compared to cortisol treatment.

We next evaluated how CORT118335 may induce a different expression pattern as compared to corticosterone. We hypothesized that CORT118335-specific effects relied on an altered GR-interactome. Indeed, the MARCoNI assay revealed that 5 coregulators interacted with GR in the presence of cortisol but not CORT118335: UBE3A, NCOA6, BRD8, PELP1 and LCOR. Our present hypothesis is that differential interaction with this subset of coregulators is responsible for the selective GR modulator characteristics of CORT118335.