title: 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.
authors.affiliation: Department of Cell Biology and Genetics, Key Laboratory of Molecular Biology in High Cancer Incidence Coastal Chaoshan Area of Guangdong Higher Education Institutes, Shantou University Medical College, Shantou, 515041, China.
authors.forename: Xina
authors.initials: X
authors.lastname: Xie
authors.affiliation: Department of Cell Biology and Genetics, Key Laboratory of Molecular Biology in High Cancer Incidence Coastal Chaoshan Area of Guangdong Higher Education Institutes, Shantou University Medical College, Shantou, 515041, China.
authors.forename: Xuhong
authors.initials: X
authors.lastname: Song
authors.affiliation: Department of Cell Biology and Genetics, Key Laboratory of Molecular Biology in High Cancer Incidence Coastal Chaoshan Area of Guangdong Higher Education Institutes, Shantou University Medical College, Shantou, 515041, China.
authors.forename: Song
authors.initials: S
authors.lastname: Yuan
authors.affiliation: Department of Cell Biology and Genetics, Key Laboratory of Molecular Biology in High Cancer Incidence Coastal Chaoshan Area of Guangdong Higher Education Institutes, Shantou University Medical College, Shantou, 515041, China.
authors.forename: Haitao
authors.initials: H
authors.lastname: Cai
authors.affiliation: Department of Community Surveillance, The First Affiliated Hospital of Shantou, University Medical College, Shantou, 515041, China.
authors.forename: Yequn
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Department of Cell Biology and Genetics, Key Laboratory of Molecular Biology in High Cancer Incidence Coastal Chaoshan Area of Guangdong Higher Education Institutes, Shantou University Medical College, Shantou, 515041, China.
authors.forename: Xiaolan
authors.initials: X
authors.lastname: Chang
authors.affiliation: Department of Cell Biology and Genetics, Key Laboratory of Molecular Biology in High Cancer Incidence Coastal Chaoshan Area of Guangdong Higher Education Institutes, Shantou University Medical College, Shantou, 515041, China huangdy@stu.edu.cn bliang@stu.edu.cn.
authors.forename: Bin
authors.initials: B
authors.lastname: Liang
authors.affiliation: Department of Cell Biology and Genetics, Key Laboratory of Molecular Biology in High Cancer Incidence Coastal Chaoshan Area of Guangdong Higher Education Institutes, Shantou University Medical College, Shantou, 515041, China huangdy@stu.edu.cn bliang@stu.edu.cn.
authors.forename: Dongyang
authors.initials: D
authors.lastname: Huang
mesh_terms: D000107:Acetylation; D000328:Adult; D000368:Aged; D001665:Binding Sites; D016022:Case-Control Studies; D018932:Chemokine CCL2 / Q000378:metabolism; D002784:Cholesterol / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation; D006655:Histone Deacetylases / Q000378:metabolism; D006657:Histones / Q000378:metabolism*; D006801:Humans; D006937:Hypercholesterolemia / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D007249:Inflammation / Q000097:blood / Q000235:genetics / Q000378:metabolism* / Q000517:prevention & control; D018836:Inflammation Mediators / Q000097:blood / Q000378:metabolism*; D015850:Interleukin-6 / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism*; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1 / Q000819:agonists / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D010648:Phenylacetates / Q000494:pharmacology; D011401:Promoter Regions, Genetic; D011499:Protein Processing, Post-Translational; D034622:RNA Interference; D012333:RNA, Messenger / Q000378:metabolism; D014162:Transfection; D020298:U937 Cells; D050880:p300-CBP Transcription Factors / Q000378:metabolism; D000099224:p300-CBP-Associated Factor
chemical_list: D018932:Chemokine CCL2; D002784:Cholesterol; D006655:Histone Deacetylases; D006657:Histones; D018836:Inflammation Mediators; D015850:Interleukin-6; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D010648:Phenylacetates; D012333:RNA, Messenger; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor; C111835:CCL2 protein, human; C508600:IL6 protein, human; C539821:NR4A1 protein, human; C531461:cytosporone B; C543273:HDAC7 protein, human
keywords: NR4A1; atherosclerosis; histone acetylation; hypercholesterolaemia; inflammation; monocytes