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

Abstract

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.

KIAA1363 affects retinyl ester turnover in cultured murine and human hepatic stellate cells

“…KIAA1363 has been shown to be expressed in heart, adrenal glands, kidney, brain, and macrophages, whereas no expression was detectable in liver ( 22 ). Furthermore, KIAA1363 expression is induced by retinoic acid receptor-related orphan receptor α-agonist ( 31 ) but is not a target of protein kinase A ( 24 ). In our study, we found that hepatic KIAA1363 mRNA expression is lower in mice fed a vitamin A-deficient diet, suggesting that KIAA1363 expression might be regulated by the availability of vitamin A to meet requirements of the body.…”

Lovastatin Suppresses the Transcriptional Regulation of <i>CLDND1</i> in Human Hepatoma Cells

“…Cholesterol and its derivative oxysterol serve as ligands for RORα. 6,7) Synthetic RORα ligands may be used as drug targets for the treatment of several diseases such as ather-osclerosis 8,9) and non-alcoholic steatohepatitis. 10) We previously reported that RORα is involved in the transcriptional activation of CLDND1 by binding to a RORE present in the CLDND1 promoter region, 11) and the micro-RNA miR-124 plays a role in the post-transcriptional regulation of CLDND1.…”