Nuclear receptors: action, functions, and roles in disease

National Institute Of Environmental Health Sciences

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Abstract

I. RORalpha and gamma: The retinoid-related orphan receptor a and g (RORa and RORc) are members of the nuclear receptor superfamily. To identify the physiological functions of RORa and c, mice deficient in RORa and c function were analyzed. RORa and RORc have several important functions in the immune system. A series of RORc inverse agonists were shown to inhibit the activation of the IL-17 promoter and reverse the phenotypic effects associated with psoriasis suggesting that they may be useful in the treatment of this disease. In addition a relationship has been found between decreased level of ROR expression and increased malignancy of melanoma. Moreover, a RORt inverse agonist protects against pulmonary neutrophilia and allergic airway hyperresponsiveness, while ROR protects against angiotensin II-induced cardiac hypertrophy and heart failure in mouse models. Recently, we also showed that also a number of vitamin D3 hydroxy metabolites can interact with RORa and RORc and can function as inverse agonists thereby identifying an alternative mechanism by which vitamin D can mediate its physiological functions. In addition, we showed that D3 derivatives can functions as agonists for LXRs, RXRs, NURR1, and PPARa. All these receptors have a role in inflammation and may mediate the anti-inflammatory and anti-cancer effects of D3 derivatives. Some of these D3 derivatives might be useful in the treatment of inflammatory disease and cancer. II. We generated JAZF1 KO mice and shown that these mice are less susceptible to develop hepatic steatosis and reduces lipid accumulation and inflammation in the liver of mice fed a high fat diet. RNA-Seq analysis of livers from these mice identified many genes (DEGs) that were differentially expressed in livers from WT and KO mice. Pathway analysis of these DEGs identified several metabolic pathways that were down-regulated in JAZF1 KO liver and provided a mechanism for the reduced susceptibility to steatosis in JAZF1 KO mice. Mass spec analysis identified several proteins that are part of the JAZF1 transcription complex and included several proteins involved in mediating transcriptional activation of gene expression.