Edited by Luke O'NeillRAR-related orphan receptor ␥ (ROR␥) is a nuclear receptor that plays an essential role in the development of T helper 17 (T h 17) cells of the adaptive immune system. The NLRP3 inflammasome is a component of the innate immune system that processes interleukin (IL)-1 into a mature cytokine. Elevated activity of the NLRP3 inflammasome contributes to the progression of an array of inflammatory diseases. Bone marrowderived macrophages (BMDMs) isolated from ROR␥-null mice displayed reduced capacity to secrete IL-1, and they also displayed a reduction in Nlrp3 and Il1b gene expression. Examination of the promoters of the Il1b and Nlrp3 genes revealed multiple putative ROR response elements (ROREs) that were occupied by ROR␥. ROR␥ inverse agonists were effective inhibitors of the inflammasome. ROR␥ inverse agonists suppressed lipopolysaccharide (LPS)/ATP-stimulated IL-1 secretion and expression of Il1b and Nlrp3 in BMDMs. Additionally, the ability of the ROR␥ inverse agonists to suppress IL-1 secretion was lost in Nlrp3-null macrophages. The potential for targeting the NLRP3 inflammasome in vivo using ROR␥ inverse agonists was examined in two models: LPS-induced sepsis and fulminant hepatitis. Pharmacological inhibition of ROR␥ activity reduced plasma IL-1 as well as IL-1 production by peritoneal macrophages in a model of LPS-induced sepsis. Additionally, ROR␥ inverse agonists reduced mortality in an LPS/D-galactosamineinduced fulminant hepatitis mouse model. These results illustrate a major role for ROR␥ in regulation of innate immunity via modulation of NLRP3 inflammasome activity. Furthermore, these data suggest that inhibiting the NLRP3 inflammasome with ROR␥ inverse agonists may be an effective method to treat NLRP3-associated diseases.
The estrogen related receptors (ERRs) are a subgroup of nuclear receptors that play a role in regulation of cellular metabolism. Prostate cancer (PCa) cells display altered metabolic signatures, such as the Warburg effect, and the ERRs have been implicated in driving this phenotype. Despite the lack of a known endogenous ligand, synthetic ligands that target the ERRs have been discovered. For example, the ERRα inverse agonist XCT790 modulates metabolic pathways in PCa cells, but it also functions as a mitochondrial uncoupler independent of targeting ERRα. Here, we describe a novel dual ERRα/γ inverse agonist, SLU-PP-1072, derived from the GSK4716 ERRγ agonist scaffold that is distinct from the XCT790 scaffold. SLU-PP-1072 alters PCa cell metabolism and gene expression, resulting in cell cycle dysregulation and increased apoptosis without acute mitochondrial uncoupling activity. Our data suggest that inhibition of ERRα/γ may be beneficial in treatment of PCa, and SLU-PP-1072 provides a unique chemical tool to evaluate the pharmacology of ERRα and ERRγ.
Non-alcoholic fatty liver (NAFLD) over the past years has become a metabolic pandemic linked to a collection of metabolic diseases. The nuclear receptors ERRs, REV-ERBs, RORs, FXR, PPARs, and LXR are master regulators of metabolism and liver physiology. The characterization of these nuclear receptors and their biology has promoted the development of synthetic ligands. The possibility of targeting these receptors to treat NAFLD is promising, as several compounds including Cilofexor, thiazolidinediones, and Saroglitazar are currently undergoing clinical trials. This review focuses on the latest development of the pharmacology of these metabolic nuclear receptors and how they may be utilized to treat NAFLD and subsequent comorbidities.
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