Glucocorticoid resistance remodels liver lipids and prompts lipogenesis, eicosanoid, and inflammatory pathways.

We have previously demonstrated that the glucocorticoid receptor β (GRβ) isoform induces hepatic steatosis in mice fed a normal chow diet. The GRβ isoform inhibits the glucocorticoid-binding isoform GRα, reducing responsiveness and inducing glucocorticoid resistance. We hypothesized that GRβ regulates lipids that cause metabolic dysfunction. To determine the effect of GRβ on hepatic lipid classes and molecular species, we overexpressed GRβ (GRβ-Ad) and vector (Vec-Ad) using adenovirus delivery, as we previously described. We fed the mice a normal chow diet for 5 days and harvested the livers. We utilized liquid chromatography-mass spectrometry (LC-MS) analyses of the livers to determine the lipid species driven by GRβ. The most significant changes in the lipidome were monoacylglycerides and cholesterol esters. There was also increased gene expression in the GRβ-Ad mice for lipogenesis, eicosanoid synthesis, and inflammatory pathways. These indicate that GRβ-induced glucocorticoid resistance may drive hepatic fat accumulation, providing new therapeutic advantages.