title: Vitamin D Protects Against Atherosclerosis via Regulation of Cholesterol Efflux and Macrophage Polarization in Hypercholesterolemic Swine.
abstract: OBJECTIVE
  Prevalence of vitamin D (VD) deficiency and its association with the risk of cardiovascular disease prompted us to evaluate the effect of VD status on lipid metabolism and atherosclerosis in hypercholesterolemic microswine.
  
  
  RESULTS
  Yucatan microswine were fed with VD-deficient (0 IU/d), VD-sufficient (1000 IU/d), or VD-supplemented (3000 IU/d) high-cholesterol diet for 48 weeks. Serum lipids and 25(OH)-cholecalciferol levels were measured biweekly. Histology and biochemical parameters of liver and arteries were analyzed. Effect of 1,25(OH)2D3 on cholesterol metabolism was examined in human hepatocyte carcinoma cell line (HepG2) and human monocytic cell line (THP-1) macrophage-derived foam cells. VD deficiency decreased plasma high-density lipoprotein levels, expression of liver X receptors, ATP-binding membrane cassette transporter A1, and ATP-binding membrane cassette transporter G1 and promoted cholesterol accumulation and atherosclerosis in hypercholesterolemic microswine. VD promoted nascent high-density lipoprotein formation in HepG2 cells via ATP-binding membrane cassette transporter A1-mediated cholesterol efflux. Cytochrome P450 (CYP)27B1 and VD receptor were predominantly present in the CD206(+) M2 macrophage foam cell-accumulated cores in coronary artery plaques. 1,25(OH)2D3 increased the expression of liver X receptors, ATP-binding membrane cassette transporter A1, and ATP-binding membrane cassette transporter G1 and promoted cholesterol efflux in THP-1 macrophage-derived foam cells. 1,25(OH)2D3 decreased intracellular free cholesterol and polarized macrophages to M2 phenotype with decreased expression of tumor necrosis factor-α, interleukin-1β, interleukin-6 under lipopolysaccharide stimulation. 1,25(OH)2D3 markedly induced CYP27A1 expression via a VD receptor-dependent c-Jun N-terminal kinase (JNK) 1/2 signaling pathway and increased 27-hydroxycholesterol levels, which induced liver X receptors, ATP-binding membrane cassette transporter A1, and ATP-binding membrane cassette transporter G1 expression and stimulated cholesterol efflux that was inhibited by VD receptor antagonist and JNK1/2 signaling inhibitor in THP-1 macrophage-derived foam cell.
  
  
  CONCLUSIONS
  VD protects against atherosclerosis in hypercholesterolemic swine via controlling cholesterol efflux and macrophage polarization via increased CYP27A1 activation.
authors.affiliation: From the Center for Clinical & Translational Science, Creighton University School of Medicine, Omaha, NE.
authors.forename: Kai
authors.initials: K
authors.lastname: Yin
authors.affiliation: From the Center for Clinical & Translational Science, Creighton University School of Medicine, Omaha, NE.
authors.forename: Yong
authors.initials: Y
authors.lastname: You
authors.affiliation: From the Center for Clinical & Translational Science, Creighton University School of Medicine, Omaha, NE.
authors.forename: Vicki
authors.initials: V
authors.lastname: Swier
authors.affiliation: From the Center for Clinical & Translational Science, Creighton University School of Medicine, Omaha, NE.
authors.forename: Lin
authors.initials: L
authors.lastname: Tang
authors.affiliation: From the Center for Clinical & Translational Science, Creighton University School of Medicine, Omaha, NE.
authors.forename: Mohamed M
authors.initials: MM
authors.lastname: Radwan
authors.affiliation: From the Center for Clinical & Translational Science, Creighton University School of Medicine, Omaha, NE.
authors.forename: Amit N
authors.initials: AN
authors.lastname: Pandya
authors.affiliation: From the Center for Clinical & Translational Science, Creighton University School of Medicine, Omaha, NE. dkagr@creighton.edu.
authors.forename: Devendra K
authors.initials: DK
authors.lastname: Agrawal
mesh_terms: D015090:25-Hydroxyvitamin D3 1-alpha-Hydroxylase / Q000378:metabolism; D064286:ATP Binding Cassette Transporter 1 / Q000378:metabolism; D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism; D000818:Animals; D050197:Atherosclerosis / Q000097:blood / Q000175:diagnosis / Q000209:etiology / Q000517:prevention & control*; D015415:Biomarkers / Q000097:blood; D002112:Calcifediol / Q000097:blood; D002117:Calcitriol / Q000494:pharmacology*; D002784:Cholesterol / Q000378:metabolism*; D008076:Cholesterol, HDL / Q000097:blood; D004195:Disease Models, Animal; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D006888:Hydroxycholesterols / Q000378:metabolism; D006937:Hypercholesterolemia / Q000097:blood / Q000150:complications / Q000175:diagnosis / Q000188:drug therapy*; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D000071518:Liver X Receptors; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism; D057093:Orphan Nuclear Receptors / Q000378:metabolism; D010641:Phenotype; D018167:Receptors, Calcitriol / Q000819:agonists / Q000378:metabolism; D013552:Swine; D013556:Swine, Miniature; D013997:Time Factors; D014808:Vitamin D Deficiency / Q000097:blood / Q000150:complications / Q000175:diagnosis / Q000188:drug therapy*
chemical_list: C577836:ABCA1 protein, human; C419353:ABCG1 protein, human; D064286:ATP Binding Cassette Transporter 1; D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D018528:ATP-Binding Cassette Transporters; D015415:Biomarkers; D008076:Cholesterol, HDL; D006888:Hydroxycholesterols; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D018167:Receptors, Calcitriol; C579457:VDR protein, human; C076996:27-hydroxycholesterol; D002784:Cholesterol; D015090:25-Hydroxyvitamin D3 1-alpha-Hydroxylase; D048031:JNK Mitogen-Activated Protein Kinases; D002117:Calcitriol; D002112:Calcifediol
keywords: atherosclerosis; cardivascular disease; cholesterol efflux; hydroxycholesterols; macrophage polarization; vitamin D