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

2020 ◽  
Author(s):  
Hiroshi MATSUOKA ◽  
Riki TOKUNAGA ◽  
Miyu KATAYAMA ◽  
Yuichiro HOSODA ◽  
Kaoruko MIYA ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Lipid Droplet ◽  
Cholesterol Ester ◽  
Lipid Droplets ◽  
Retinoic Acid Receptor ◽  
Droplet Formation ◽  
Orphan Receptor ◽  
Acid Receptor ◽  
Ester Hydrolase ◽  
Lipid Droplet Formation

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.

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

2020 ◽  
Author(s):  
Hiroshi MATSUOKA ◽  
Riki TOKUNAGA ◽  
Miyu KATAYAMA ◽  
Yuichiro HOSODA ◽  
Kaoruko MIYA ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Lipid Droplet ◽  
Cholesterol Ester ◽  
Lipid Droplets ◽  
Retinoic Acid Receptor ◽  
Droplet Formation ◽  
Orphan Receptor ◽  
Acid Receptor ◽  
Ester Hydrolase ◽  
Lipid Droplet Formation

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.

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

2020 ◽  
Author(s):  
Hiroshi MATSUOKA ◽  
Riki TOKUNAGA ◽  
Miyu KATAYAMA ◽  
Yuichiro HOSODA ◽  
Kaoruko MIYA ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Lipid Droplet ◽  
Cholesterol Ester ◽  
Lipid Droplets ◽  
Retinoic Acid Receptor ◽  
Droplet Formation ◽  
Orphan Receptor ◽  
Acid Receptor ◽  
Ester Hydrolase ◽  
Lipid Droplet Formation

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.

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

2019 ◽  
Author(s):  
Hiroshi MATSUOKA ◽  
Riki TOKUNAGA ◽  
Miyu KATAYAMA ◽  
Yuichiro HOSODA ◽  
Kaoruko MIYA ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Lipid Droplet ◽  
Cholesterol Ester ◽  
Retinoic Acid Receptor ◽  
Droplet Formation ◽  
Orphan Receptor ◽  
Acid Receptor ◽  
Cholesterol Ester Hydrolase ◽  
Ester Hydrolase ◽  
Lipid Droplet Formation

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 monocyte-derived 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 and inhibited lipid droplet formation in human hepatoma cells. In contrast, NCEH1 was induced by treatment with RORα agonists. 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. Keywords: Atherosclerosis, Cholesterol ester, Lipid droplet, Macrophage, Transcriptional regulation, Nuclear receptor, RORα, NCEH1

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

2019 ◽  
Author(s):  
Hiroshi MATSUOKA ◽  
Riki TOKUNAGA ◽  
Yuichiro HOSODA ◽  
Miyu KATAYAMA ◽  
Kaoruko MIYA ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Lipid Droplet ◽  
Cholesterol Ester ◽  
Retinoic Acid Receptor ◽  
Droplet Formation ◽  
Orphan Receptor ◽  
Acid Receptor ◽  
Cholesterol Ester Hydrolase ◽  
Ester Hydrolase ◽  
Lipid Droplet Formation

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 monocyte-derived macrophages. In mammals, the NCEH1 promoter region had putative RORα response elements (ROREs). Electrophoretic mobility shift, chromatin immunoprecipitation, and luciferase reporter assays showed that RORα bound and responded to the ROREs in human NCEH1. Moreover, NCEH1 was upregulated through RORα in a phorbol myristate acetate-dependent mechanism during macrophage differentiation from THP1 cells. siRNA-mediated knockdown of RORα significantly downregulated NCEH1 and inhibited lipid droplet formation in human hepatoma cells. In contrast, NCEH1 was induced by treatment with RORα agonists. Conclusion: These data strongly suggested that NCEH1 was a direct RORα target, defining potential new roles for RORα in inhibition of lipid droplet formation through NCEH1.

scholarly journals Hepatocyte nuclear factor-6 stimulates transcription of the alpha-fetoprotein gene and synergizes with the retinoic-acid-receptor-related orphan receptor alpha-4

2003 ◽  
Vol 369 (3) ◽  
pp. 583-591 ◽  
Author(s):  
Habib NACER-CHERIF ◽  
Brigitte BOIS-JOYEUX ◽  
Guy G. ROUSSEAU ◽  
Frédéric P. LEMAIGRE ◽  
Jean-Louis DANAN
Keyword(s):  
Retinoic Acid ◽  
Retinoic Acid Receptor ◽  
Orphan Receptor ◽  
Nuclear Factor ◽  
Hepatocyte Nuclear Factor ◽  
Acid Receptor ◽  
Splicing Isoforms ◽  
Liver Gene ◽  
A Site ◽  
Putative Binding Site

The rat α-fetoprotein (afp) gene is controlled by three enhancers whose function depends on their interaction with liver-enriched transcription factors. The afp enhancer III, located at −6kb, is composed of three regions that act in synergy. Two of these regions, called s1 and s2, contain a putative binding site for hepatocyte nuclear factor-6 (HNF-6). This factor is the prototype of the ONECUT family of cut-homoeodomain proteins and is a known regulator of liver gene expression in adults and during development. We show here that the two splicing isoforms of HNF-6 bind to a site in the s1 region and in the s2 region. The core sequence of the s1 site corresponds to none of the known HNF-6 binding sites. Nevertheless, the binding properties of the s1 site are identical with those of the s2 site and of previously characterized HNF-6 binding sequences. The HNF-6 consensus should therefore be rewritten as DRRTCVATND. Binding of HNF-6 to the s1 and s2 sites requires both the cut and the homoeo domains, is co-operative and induces DNA bending. HNF-6 strongly stimulates the activity of the afp enhancer III in transient transfection experiments. This effect requires the stereo-specific alignment of the two HNF-6 sites. Moreover, HNF-6 stimulates the enhancer in synergy with the retinoic-acid-receptor-related orphan receptor α (RORα), which binds to a neighbouring site in the s1 region. Thus expression of the afp gene requires functional interactions between HNF-6 molecules and between HNF-6 and RORα.

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