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.
Highlights
ABCA1 exports excess cholesterol from cells to apoA-I and is essential for HDL synthesis
The cholesterol export function of ABCA1 occurs by a cascade of events involving direct binding of apoA-I to ABCA1, activation of signaling pathways, and solubilization of cholesterol and phospholipid domains formed by Abbreviations: Baby hamster kidney (BHK), baby hamster kidney; CTB, cholera toxin subunit; FACS, fluorescence-activated cell sorting; IL, interleukin; JAK2, Janus kinase 2; LPS, lipopolysaccharide; SOCS3, suppressor of cytokine signaling 3; STAT3, signal transducer and activator of transcription 3
We showed that the interaction of apoA-I or its mimetic peptides with ABCA1 activates the transcription factor signal transducer and activator of transcription 3 (STAT3) [24]
Summary
STAT3, phospho-STAT3, and phosopho-JAK2 antibodies were purchased from Cell Signaling Technology (MA); STAT1, phopshoSTAT1, JAK2, and SOCS3 antibodies were purchased from Santa Cruz Biotechnology (TX). ABCA1 antibody was purchased from Novus Biological (CO). ApoA-I was purified from HDL as described previously [29]. STAT3flox/flox/C57BL/6 mice were a gift from Shizuo Akiro, Osaka University. Lys-M-Cre/C57BL/6 mice were a gift from Karin Bornfeldt, University of Washington. To generate mice lacking STAT3 in macrophages and neutrophils, STAT3flox/. Flox were crossed with Lys-M-Cre mice to generate mice that carried the homozygous STAT3flox/flox/Lys-M-Cre mice. Control WT mice were generated by interbreeding STAT3 wt/wt with LysM-Cre mice [24].
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