Non-alcoholic fatty liver disease (NAFLD) is a very common chronic liver condition mostly characterized by excessive lipid accumulation. Glucocorticoid (GC) stress hormones can cause liver lipid accumulation, and therefore provide a potential therapeutic target. Miricorilant is a selective glucocorticoid receptor modulator (SGRM) which was previously shown to prevent and reverse NAFLD in mice via downregulation of genes involved in liver lipid uptake (Cd36, Fabp1) and upregulation of genes involved in lipid efflux (Mttp, ApoB). We hypothesized that this ability to combine both agonism and antagonism at the glucocorticoid receptor (GR) involved both cell type- and gene-specific signaling mechanisms.

We investigated cell type specificity by using publicly available single cell RNA sequencing (scRNA-seq) data from human liver. The scRNA-seq data revealed predominant expression of Cd36 in human liver endothelial cells, while Fabp1, Mttp and ApoB were mainly expressed in hepatocytes. These data suggest that predominant GR antagonism in endothelial cells could contribute to the effects of miricorilant. To understand ligand-specific signaling, rapid immunoprecipitation mass spectrometry for endogenous proteins (RIME) was performed in human HepG2 cells to analyze GR protein partners after miricorilant treatment. RIME analysis showed that in comparison to cortisol, miricorilant-bound GR interactome missed essential protein partners such as the coactivator NCOA3, and SMARCD1 which allows GR interaction with the SWI/SNF chromatin remodeling complex.

Altogether, our results suggest that cell type- and gene-specific GR activity underlies miricorilant effects on liver lipid metabolism pathways. Our current hypothesis is that the “selective efficacy” of SRGM treatment in NAFLD may lie on an heterogeneous cellular response related to gene-specific GR protein recruitment.