Tijmen Moll¹, Eva Viho², Roan van Scheppingen³, Stefan Prekovic³, Wilbert Zwart⁴, Hazel Hunt⁵, Onno Meijer¹, Jan Kroon¹

(1) Department of Medicine, Division of Endocrinology, Leiden University Medical Center, Leiden, The Netherlands. (2) Department of Genes and Environment, Max Planck Institute of Psychiatry, Munich, Germany. (3) Center for Molecular Medicine, UMC Utrecht, Utrecht, The Netherlands . (4) Division of Oncogenomics, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, The Netherlands. (5) Corcept Therapeutics, Redwood City, USA. 

CORT118335 and CORT125385 are selective glucocorticoid receptor modulators (SGRMs) that effectively lower hepatic lipid levels in mouse models of metabolic dysfunction-associated steatotic liver disease, which is not achieved by GR agonists or antagonists. This study aims to characterize the molecular mechanisms underlying these effects. 

After induction of hepatic lipid accumulation by three weeks of high-fat high-fructose diet, male C57BL/6J mice were treated with vehicle, corticosterone (3 mg/kg/day), RU486, CORT118335 or CORT125385 (all 60 mg/kg/day) for three days. We profiled the resulting transcriptome and GR interactome in isolated livers using RNAseq and RIME and consecutively applied so-called ‘molecular filters’ by comparing contrasts and similarities between treatment groups to identify potentially relevant molecular effects.

We identified decreased interactions between the GR and several proteins involved in GR-mediated transcription for SGRMs compared to corticosterone. This included a decreased interaction with C/EBPβ, which acts as a pioneer factor for GR chromatin binding, and ACLY, which is involved in histone modification. Livers from CORT118335 and CORT125385-treated mice showed reduced association of the GR with RNA polymerase II and an overall reduced number of differentially expressed genes. Gene set enrichment analysis revealed that SGRMs maintain the anti-inflammatory effects of corticosterone but have reduced regulation of lipid-metabolism related genes. GO-term analysis on gene subsets after applying molecular filters suggested that the lipid-lowering effects of SGRMs likely involve corticosterone-like upregulation and SGRM-specific downregulation of genes. We tentatively conclude that CORT118335- and CORT125385-induced GR modulation involves alterations of GR interactions with transcriptional cofactors resulting in a unique transcriptional profile.