REV-ERB is a member of the nuclear receptor superfamily consisting of two similar proteins: REV-ERBα and REV-ERBβ. Like other NRs, REV-ERBs can be regulated by ligands, including naturally occurring heme. Two REV-ERB molecules, usually present as a dimer, compete with the retinoic acid receptor-related orphan receptors (ROR) for the binding to the ROR response element DNA sequence (RORE) region. REV-ERB plays an important role in many physiological processes, including the regulation of metabolism, development, and immunity as well as the circadian rhythm.
REV-ERBβ plays an important role in the regulation of fatty acid and lipid absorption, energy expenditure, and lipogenesis in muscle. REV-ERBα can regulate hepatic glucose metabolism that directly regulates the expression of the genes encoding the gluconeogenic enzymes PCK and G6PC. Besides, REV-ERB is a key regulator of the oxidative capacity of skeletal muscle and mitochondrial biogenesis. What’s more, overexpression of REV-ERBα in 3T3-L1 cells results in increased expression of markers of adipogenesis. Meanwhile, REV-ERBα can regulate the production and release of the pro-inflammatory cytokine interleukin-6 (IL-6) in macrophages. Accordingly, REV-ERB is a promising, but difficult drug target for the treatment of numerous diseases.
SR12418, a REV-ERB-specific synthetic ligand, can enhance REV-ERBα and REV-ERBβ activity.
From: Wang S, et al. Theranostics. 2020 Mar 4;10(9):4168-4182.
In vitro, SR12418 suppresses TH17 cell development and function. Meanwhile, SR1241 can suppress TH17-mediated autoimmunity in vivo. Importantly, SR12418 is effective in two separate models of TH17-mediated inflammatory diseases, colitis, and experimental autoimmune encephalomyelitis. Furthermore, SR12418 does not demonstrate overt signs of toxicity, as the weight of the animals remains relatively constant throughout the experiment. Evaluation of the liver demonstrates that SR12418 does not appear to significantly perturb the circadian rhythm in other tissues evaluated. Collectively, SR12418 can suppress the progression of TH17-driven autoimmunity and chronic inflammatory disorders.
All in all, SR12418, a REV-ERB-specific synthetic ligand, can suppress the progression of TH17-driven autoimmunity and chronic inflammatory disorders.