Both STAT3 activation and cholesterol efflux contribute to the anti-inflammatory effect of apoA-I/ABCA1 interaction in macrophages.

Autor:	Tang C; Division of Metabolism, Endocrinology and Nutrition, Diabetes Obesity Center for Excellence, University of Washington, Seattle, WA 98109 crtang@u.washington.edu., Houston BA; Division of Metabolism, Endocrinology and Nutrition, Diabetes Obesity Center for Excellence, University of Washington, Seattle, WA 98109., Storey C; Division of Metabolism, Endocrinology and Nutrition, Diabetes Obesity Center for Excellence, University of Washington, Seattle, WA 98109., LeBoeuf RC; Division of Metabolism, Endocrinology and Nutrition, Diabetes Obesity Center for Excellence, University of Washington, Seattle, WA 98109.
Jazyk:	angličtina
Zdroj:	Journal of lipid research [J Lipid Res] 2016 May; Vol. 57 (5), pp. 848-57. Date of Electronic Publication: 2016 Mar 17.
DOI:	10.1194/jlr.M065797
Abstrakt:	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. (Copyright © 2016 by the American Society for Biochemistry and Molecular Biology, Inc.)
Databáze:	MEDLINE
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