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Histone acetylation regulates orphan nuclear receptor NR4A1 expression in hypercholesterolaemia.

Abstract
Hypercholesterolaemia and inflammation are correlated with atherogenesis. Orphan nuclear receptor NR4A1, as a key regulator of inflammation, is closely associated with lipid levels in vivo. However, the mechanism by which lipids regulate NR4A1 expression remains unknown. We aimed to elucidate the underlying mechanism of NR4A1 expression in monocytes during hypercholesterolaemia, and reveal the potential role of NR4A1 in hypercholesterolaemia-induced circulating inflammation. Circulating leucocytes were collected from blood samples of 139 patients with hypercholesterolaemia and 139 sex- and age-matched healthy subjects. We found that there was a low-grade inflammatory state and higher expression of NR4A1 in patients. Both total cholesterol and low-density lipoprotein cholesterol levels in plasma were positively correlated with NR4A1 mRNA level. ChIP revealed that acetylation of histone H3 was enriched in the NR4A1 promoter region in patients. Human mononuclear cell lines THP-1 and U937 were treated with cholesterol. Supporting our clinical observations, cholesterol enhanced p300 acetyltransferase and decreased HDAC7 (histone deacetylase 7) recruitment to the NR4A1 promoter region, resulting in histone H3 hyperacetylation and further contributing to NR4A1 up-regulation in monocytes. Moreover, cytosporone B, an NR4A1 agonist, completely reversed cholesterol-induced IL-6 (interleukin 6) and MCP-1 (monocyte chemoattractant protein 1) expression to below basal levels, and knockdown of NR4A1 expression by siRNA not only mimicked, but also exaggerated the effects of cholesterol on inflammatory biomarker up-regulation. Thus we conclude that histone acetylation contributes to the regulation of NR4A1 expression in hypercholesterolaemia, and that NR4A1 expression reduces hypercholesterolaemia-induced inflammation.
AuthorsXina Xie, Xuhong Song, Song Yuan, Haitao Cai, Yequn Chen, Xiaolan Chang, Bin Liang, Dongyang Huang
JournalClinical science (London, England : 1979) (Clin Sci (Lond)) Vol. 129 Issue 12 Pg. 1151-61 (Dec 2015) ISSN: 1470-8736 [Electronic] England
PMID26396259 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Copyright© 2015 Authors; published by Portland Press Limited.
Chemical References
  • CCL2 protein, human
  • Chemokine CCL2
  • Histones
  • IL6 protein, human
  • Inflammation Mediators
  • Interleukin-6
  • NR4A1 protein, human
  • Nuclear Receptor Subfamily 4, Group A, Member 1
  • Phenylacetates
  • RNA, Messenger
  • cytosporone B
  • Cholesterol
  • p300-CBP Transcription Factors
  • p300-CBP-associated factor
  • HDAC7 protein, human
  • Histone Deacetylases
Topics
  • Acetylation
  • Adult
  • Aged
  • Binding Sites
  • Case-Control Studies
  • Chemokine CCL2 (metabolism)
  • Cholesterol (metabolism)
  • Female
  • Gene Expression Regulation
  • Histone Deacetylases (metabolism)
  • Histones (metabolism)
  • Humans
  • Hypercholesterolemia (blood, genetics, metabolism)
  • Inflammation (blood, genetics, metabolism, prevention & control)
  • Inflammation Mediators (blood, metabolism)
  • Interleukin-6 (metabolism)
  • Male
  • Middle Aged
  • Monocytes (drug effects, metabolism)
  • Nuclear Receptor Subfamily 4, Group A, Member 1 (agonists, blood, genetics, metabolism)
  • Phenylacetates (pharmacology)
  • Promoter Regions, Genetic
  • Protein Processing, Post-Translational
  • RNA Interference
  • RNA, Messenger (metabolism)
  • Transfection
  • U937 Cells
  • p300-CBP Transcription Factors (metabolism)

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