title: Both STAT3 activation and cholesterol efflux contribute to the anti-inflammatory effect of apoA-I/ABCA1 interaction in macrophages.
abstract: ABCA1 exports excess cholesterol from cells to apoA-I and is essential for HDL synthesis. Genetic studies have shown that ABCA1 protects against cardiovascular disease. We have previously shown that the interaction of apoA-I with ABCA1 activates signaling molecule Janus kinase 2 (JAK2), which optimizes the cholesterol efflux activity of ABCA1. ABCA1-mediated activation of JAK2 also activates signal transducer and activator of transcription 3 (STAT3), which significantly attenuates proinflammatory cytokine expression in macrophages. To determine the mechanisms of the anti-inflammatory effects of apoA-I/ABCA1 interaction, we identified two special ABCA1 mutants, one with normal STAT3-activating capacity but lacking cholesterol efflux ability and the other with normal cholesterol efflux ability but lacking STAT3-activating capacity. We showed that activation of STAT3 by the interaction of apoA-I/ABCA1 without cholesterol efflux could significantly decrease proinflammatory cytokine expression in macrophages. Mechanistic studies showed that the anti-inflammatory effect of the apoA-I/ABCA1/STAT3 pathway is suppressor of cytokine signaling 3 dependent. Moreover, we showed that apoA-I/ABCA1-mediated cholesterol efflux without STAT3 activation can also reduce proinflammatory cytokine expression in macrophages. These findings suggest that the interaction of apoA-I/ABCA1 activates cholesterol efflux and STAT3 branch pathways to synergistically suppress inflammation in macrophages.
authors.affiliation: Division of Metabolism, Endocrinology and Nutrition, Diabetes Obesity Center for Excellence, University of Washington, Seattle, WA 98109 crtang@u.washington.edu.
authors.forename: Chongren
authors.initials: C
authors.lastname: Tang
authors.affiliation: Division of Metabolism, Endocrinology and Nutrition, Diabetes Obesity Center for Excellence, University of Washington, Seattle, WA 98109.
authors.forename: Barbara A
authors.initials: BA
authors.lastname: Houston
authors.affiliation: Division of Metabolism, Endocrinology and Nutrition, Diabetes Obesity Center for Excellence, University of Washington, Seattle, WA 98109.
authors.forename: Carl
authors.initials: C
authors.lastname: Storey
authors.affiliation: Division of Metabolism, Endocrinology and Nutrition, Diabetes Obesity Center for Excellence, University of Washington, Seattle, WA 98109.
authors.forename: Renee C
authors.initials: RC
authors.lastname: LeBoeuf
mesh_terms: D064286:ATP Binding Cassette Transporter 1 / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D016632:Apolipoprotein A-I / Q000378:metabolism*; D002460:Cell Line; D002784:Cholesterol / Q000378:metabolism*; D006224:Cricetinae; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression; D017737:Macrophages, Peritoneal / Q000276:immunology / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D018345:Mice, Knockout; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D000071223:Suppressor of Cytokine Signaling 3 Protein / Q000378:metabolism
chemical_list: D064286:ATP Binding Cassette Transporter 1; D016632:Apolipoprotein A-I; D002784:Cholesterol; D016207:Cytokines; D050796:STAT3 Transcription Factor; D000071223:Suppressor of Cytokine Signaling 3 Protein; C577833:Abca1 protein, mouse; C491411:Socs3 protein, mouse; C494087:Stat3 protein, mouse
keywords: ATP binding cassette transporter A1; apolipoprotein A-I; high density lipoprotein; inflammation; signal transducer and activator of transcription 3; suppressor of cytokine signaling 3