Orphan Nuclear Receptor RORα Regulates Enzymatic Metabolism of Cerebral 24S-Hydroxycholesterol through CYP39A1 Intronic Response Element Activation.

Oxysterols, important regulators of cholesterol homeostasis in the brain, are affected by neurodegenerative diseases. Early-onset Alzheimer's disease is associated with higher levels of circulating brain-derived 24S-hydroxycholesterol (24S-OHC). Conversion of cholesterol to 24S-OHC is mediated by cholesterol 24S-hydroxylase in the brain, which is the major pathway for oxysterol elimination, followed by oxidation through hepatic first-pass metabolism by CYP39A1. Abnormal CYP39A1 expression results in accumulation of 24S-OHC, influencing neurodegenerative disease-related deterioration; thus, it is important to understand the normal elimination of 24S-OHC and the system regulating CYP39A1, a selective hepatic metabolic enzyme of 24S-OHC. We examined the role of transcriptional regulation by retinoic acid receptor-related orphan receptor α (RORα), a nuclear receptor that responds to oxysterol ligands. In humans, the promoter and first intronic regions of CYP39A1 contain two putative RORα response elements (ROREs). RORα binding and responses of these ROREs were assessed using electrophoretic mobility shift, chromatin immunoprecipitation, and luciferase reporter assays. CYP39A1 was upregulated by RORα overexpression in HEK293 cells, while RORα knockdown by siRNA significantly downregulated CYP39A1 expression in human hepatoma cells. Additionally, CYP39A1 was induced by RORα agonist treatment, suggesting that CYP39A1 expression is activated by RORα nuclear receptors. This may provide a way to increase CYP39A1 activity using RORα agonists, and help halt 24S-OHC accumulation in neurodegenerative illnesses.

Retinoic acid receptor-related orphan receptor α reduces lipid droplets by upregulating neutral cholesterol ester hydrolase 1 in macrophages.

BACKGROUND: Neutral cholesterol ester hydrolase 1 (NCEH1) catalyzes the hydrolysis of cholesterol ester (CE) in macrophages. Genetic ablation of NCEH1 promotes CE-laden macrophages and the development of atherosclerosis in mice. Dysregulation of NCEH1 levels is involved in the pathogenesis of multiple disorders including metabolic diseases and atherosclerosis; however, relatively little is known regarding the mechanisms regulating NCEH1. Retinoic acid receptor-related orphan receptor α (RORα)-deficient mice exhibit several phenotypes indicative of aberrant lipid metabolism, including dyslipidemia and increased susceptibility to atherosclerosis. RESULTS: In this study, inhibition of lipid droplet formation by RORα positively regulated NCEH1 expression in macrophages. In mammals, the NCEH1 promoter region was found to harbor putative RORα response elements (ROREs). Electrophoretic mobility shift, chromatin immunoprecipitation, and luciferase reporter assays showed that RORα binds and responds to ROREs in human NCEH1. Moreover, NCEH1 was upregulated through RORα via a phorbol myristate acetate-dependent mechanism during macrophage differentiation from THP1 cells. siRNA-mediated knockdown of RORα significantly downregulated NCEH1 expression and accumulated lipid droplets in human hepatoma cells. In contrast, NCEH1 expression and removal of lipid droplets were induced by RORα agonist treatments and RORα overexpression in macrophages. CONCLUSION: These data strongly suggested that NCEH1 is a direct RORα target, defining potential new roles for RORα in the inhibition of lipid droplet formation through NCEH1.

Photocatalytic hydrogenation of azobenzene to hydrazobenzene on cadmium sulfide under visible light irradiation.

Visible-light irradiation (λ < 600 nm) of commercially-available CdS in alcohol successfully promotes hydrogenation of azobenzene to hydrazobenzene with more than 95% selectivity. This is promoted by strong adsorption of azobenzene to the photoformed zerovalent Cd species adjacent to the surface S vacancies on CdS; this leads to efficient reduction to hydrazobenzene.

One-pot synthesis of imines from nitroaromatics and alcohols by tandem photocatalytic and catalytic reactions on Degussa (Evonik) P25 titanium dioxide.

Photoirradiation (λ > 300 nm) of Degussa (Evonik) P25 TiO2, a mixture of anatase and rutile particles, in alcohols containing nitroaromatics at room temperature produces the corresponding imines with very high yields (80-96%). Other commercially available anatase or rutile TiO2 particles, however, exhibit very low yields (<30%). The imine formation involves two step reactions on the TiO2 surface: (i) photocatalytic oxidation of alcohols (aldehyde formation) and reduction of nitrobenzene (aniline formation) and (ii) condensation of the formed aldehyde and aniline on the Lewis acid sites (imine formation). The respective anatase and rutile particles were isolated from P25 TiO2 by the H2O2/NH3 and HF treatments to clarify the activity of these two step reactions. Photocatalysis experiments revealed that the active sites for photocatalytic reactions on P25 TiO2 are the rutile particles, promoting efficient reduction of nitrobenzene on the surface defects. In contrast, catalysis experiments showed that the anatase particles isolated from P25 TiO2 exhibit very high activity for condensation of aldehyde and aniline, because the number of Lewis acid sites on the particles (73 µmol g(-1)) is much higher than that of other commercially available anatase or rutile particles (<15 µmol g(-1)). The P25 TiO2 particles therefore successfully promote tandem photocatalytic and catalytic reactions on the respective rutile and anatase particles, thus producing imines with very high yields.