Inhibition of RORα/γ suppresses atherosclerosis via inhibition of both cholesterol absorption and inflammation

Billon, Cyrielle; Sitaula, Sadichha; Burris, Thomas P.

doi:10.1016/j.molmet.2016.07.001

Cited by 30 publications

(30 citation statements)

References 22 publications

(29 reference statements)

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“…al. (49) showing that SR1001 has no effect on Treg development in vitro, but consistent with in vivo studies (7,48), here we show that SR1001 increases lung Tregs, suggesting an additional mechanism by which SR1001 could have prevented and reversed CH-induced PH (12). However, several lines of evidence support T H 17 cells as the major effector inflammatory cells following CH, including the following: 1) the majority of perivascular T cells were IL-17A ϩ cells; 2) SR1001 did not affect the number of perivascular CD3 ϩ T cells in normoxic mice while preventing CH-induced perivascular inflammation; and 3) CH did not increase lung Tregs.…”

Section: Discussionsupporting

confidence: 72%

Central role of T helper 17 cells in chronic hypoxia-induced pulmonary hypertension

Maston

Jones

Giermakowska

et al. 2017

American Journal of Physiology-Lung Cellular and Molecular Phys

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Inflammation is a prominent pathological feature in pulmonary arterial hypertension, as demonstrated by pulmonary vascular infiltration of inflammatory cells, including T and B lymphocytes. However, the contribution of the adaptive immune system is not well characterized in pulmonary hypertension caused by chronic hypoxia. CD4 T cells are required for initiating and maintaining inflammation, suggesting that these cells could play an important role in the pathogenesis of hypoxic pulmonary hypertension. Our objective was to test the hypothesis that CD4 T cells, specifically the T helper 17 subset, contribute to chronic hypoxia-induced pulmonary hypertension. We compared indices of pulmonary hypertension resulting from chronic hypoxia (3 wk) in wild-type mice and recombination-activating gene 1 knockout mice (RAG1, lacking mature T and B cells). Separate sets of mice were adoptively transferred with CD4, CD8, or T helper 17 cells before normoxic or chronic hypoxic exposure to evaluate the involvement of specific T cell subsets. RAG1 mice had diminished right ventricular systolic pressure and arterial remodeling compared with wild-type mice exposed to chronic hypoxia. Adoptive transfer of CD4 but not CD8 T cells restored the hypertensive phenotype in RAG1 mice. Interestingly, RAG1 mice receiving T helper 17 cells displayed evidence of pulmonary hypertension independent of chronic hypoxia. Supporting our hypothesis, depletion of CD4 cells or treatment with SR1001, an inhibitor of T helper 17 cell development, prevented increased pressure and remodeling responses to chronic hypoxia. We conclude that T helper 17 cells play a key role in the development of chronic hypoxia-induced pulmonary hypertension.

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Section: Discussionsupporting

confidence: 72%

Central role of T helper 17 cells in chronic hypoxia-induced pulmonary hypertension

Maston

Jones

Giermakowska

et al. 2017

American Journal of Physiology-Lung Cellular and Molecular Phys

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“…Moreover, the treatment of liver macrophages with synthetic RORα ligands was found to modulate nonalcoholic steatohepatitis (NASH); activation of RORα by SR1078 [52] as an RORα agonist results in protection against NASH and loss of RORα function, whereas inhibition of RORα function by SR3335 [25], an RORα-selective inverse agonist, results in the progression of NASH [53]. Further pharmacological and pathophysiological studies are currently investigating the development of candidate RORα ligands for various applications [54,55]. In pharmacological therapies involving nuclear receptor ligands, increased activity of lipoprotein lipase (LPL) in response to various peroxisome proliferator-activated receptors (PPARs) might explain the hypotriglyceridemic effects of fibrates, thiazolindinediones, and fatty acids, which are known activators (and/or ligands) of the various PPARs.…”

Section: Discussionmentioning

confidence: 99%

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

Matsuoka

TOKUNAGA

KATAYAMA

et al. 2020

BMC Mol and Cell Biol

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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. siRNAmediated 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.

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“…In peritoneal cells lacking BMAL1 (transcriptional factor of REV-ERBα), phosphorylation of p65 after LPS treatment was increased to levels greater than those noted in control cells [33]. Knockout of the retinoid-related orphan receptoralpha (RORα), which is a potent competitive repressor of REV-ERBα, decreases cytokine production, and RORα inhibition decreases the inflammatory profile and suppresses atherosclerosis [34]. In contrast, REV-ERBα activation by SR9009 decreases cytokine production via inhibition of the NF-κB pathway and promotes survival in myocardial inaction animals [35], suggesting inhibitory effects of REV-ERBα on the NF-κB pathway.…”

Section: Discussionmentioning

confidence: 99%

Pharmacological activation of REV-ERBα represses LPS-induced microglial activation through the NF-κB pathway

et al. 2018

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REV-ERBα, the NR1D1 (nuclear receptor subfamily 1, group D, member 1) gene product, is a dominant transcriptional silencer that represses the expression of genes involved in numerous physiological functions, including circadian rhythm, inflammation, and metabolism, and plays a crucial role in maintaining immune functions. Microglia-mediated neuroinflammation is tightly associated with various neurodegenerative diseases and psychiatric disorders. However, the role of REV-ERBα in neuroinflammation is largely unclear. In this study, we investigated whether and how pharmacological activation of REV-ERBα affected lipopolysaccharide (LPS)-induced neuroinflammation in mouse microglia in vitro and in vivo. In BV2 cells or primary mouse cultured microglia, application of REV-ERBα agonist GSK4112 or SR9011 dose-dependently suppressed LPS-induced microglial activation through the nuclear factor kappa B (NF-κB) pathway. In BV2 cells, pretreatment with GSK4112 inhibited LPS-induced phosphorylation of the inhibitor of NF-κB alpha (IκBα) kinase (IκK), thus restraining the phosphorylation and degradation of IκBα, and blocked the nuclear translocation of p65, a NF-κB subunit, thereby suppressing the expression and secretion of the proinflammatory cytokines, such as interleukin 6 (IL-6) and tumor necrosis factor α (TNFα). Moreover, REV-ERBα agonist-induced inhibition on neuroinflammation protected neurons from microglial activation-induced damage, which were also demonstrated in mice with their ventral midbrain microinjected with GSK4112, and then stimulated with LPS. Our results reveal that enhanced REV-ERBα activity suppresses microglial activation through the NF-κB pathway in the central nervous system.

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Inhibition of RORα/γ suppresses atherosclerosis via inhibition of both cholesterol absorption and inflammation

Cited by 30 publications

References 22 publications

Central role of T helper 17 cells in chronic hypoxia-induced pulmonary hypertension

Central role of T helper 17 cells in chronic hypoxia-induced pulmonary hypertension

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

Pharmacological activation of REV-ERBα represses LPS-induced microglial activation through the NF-κB pathway

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