caa a22 4500 60615826X CHVBK 20210128100618.0 cr unu---uuuuu 210128e20150201xx s 000 0 eng 10.1007/s10557-015-6570-0 doi (NATIONALLICENCE)springer-10.1007/s10557-015-6570-0 Statin-Induced Decrease in ATP-Binding Cassette Transporter A1 Expression via microRNA33 Induction may Counteract Cholesterol Efflux to High-Density Lipoprotein [Elektronische Daten] [Eric Niesor, Gregory Schwartz, Anne Perez, Andrea Stauffer, Alexandre Durrwell, Gabriela Bucklar-Suchankova, Renée Benghozi, Markus Abt, David Kallend] Purpose: Cholesterol efflux from macrophages to HDL, measured in vitro, is augmented by treatment with agents which raise HDL cholesterol. In vitro, cholesterol depletion by statins is known to trigger a positive feedback on the cholesterol synthetic pathway via sterol regulatory element-binding protein (SREBP) transcription and changes in expression of SREBP regulated genes including microRNA33 (miR33) which is co-transcribed with SREBPand down-regulates ABCA1 and ABCG1 expression. Methods: We investigated whether miR33 up-regulation, associated with SREBP increased transcription by statins, reduces macrophage ATP-binding cassette (ABC) transporter expression, thereby decreasing HDL-mediated cholesterol efflux at the tissue level. Results: In human macrophage THP-1 cells cholesterol-loaded with acetylated LDL, incubation with 1μM atorvastatin increased miR33 by 33% (P < 0.05), and decreased ABCA1 messenger RNA (mRNA) and ABCG1 mRNA by 47% (P < 0.05) and 27% (NS), respectively. InJ774A.1mouse macrophage, labelled with 3H-cholesterol, ABCA1 mRNA and ABCA1-mediated cholesterol efflux were decreased by 1μM statin: simvastatin > pitavastatin > atorvastatin > rosuvastatin > pravastatin. HDL incubated with rhCETP and dalcetrapib increased ABCA1-mediated cholesterol efflux. However, incremental simvastatin concentrations decreased cholesterol efflux to HDL treated with rhCETP and dalcetrapib. When HDL was incubated with rhCETP, addition of dalcetrapib augmented ABCA1-mediated cholesterol efflux from J774A.1 macrophages. However, simvastatin ≥1μM virtually eliminated any HDL-ABCA1-mediated cholesterol efflux and any augmentation of that process by dalcetrapib. Conclusions: In vitro, statins increase miR33 expression, and decrease ABCA1 expression and cholesterol efflux from peripheral tissues; this may counteract the potential benefit of agents that raise HDL and apolipoprotein A-I in statin-treated patients. Springer Science+Business Media New York, 2015 ABCA1 nationallicence Cholesterol efflux nationallicence HDL nationallicence microRNA33 nationallicence Statin nationallicence Niesor Eric Pharma Research & Early Development, pRED, F. Hoffmann-La Roche Ltd, Basel, Switzerland aut Schwartz Gregory Veterans Affairs Medical Center and University of Colorado School of Medicine, Denver, CO, USA aut Perez Anne Pharma Research & Early Development, pRED, F. Hoffmann-La Roche Ltd, Basel, Switzerland aut Stauffer Andrea Pharma Research & Early Development, pRED, F. Hoffmann-La Roche Ltd, Basel, Switzerland aut Durrwell Alexandre Pharma Research & Early Development, pRED, F. Hoffmann-La Roche Ltd, Basel, Switzerland aut Bucklar-Suchankova Gabriela Roche Professional Diagnostics, Basel, Switzerland aut Benghozi Renée Pharma Development, F. Hoffmann-La Roche Ltd, Basel, Switzerland aut Abt Markus Biostatistics, F. Hoffmann-La Roche Ltd, Basel, Switzerland aut Kallend David Pharma Development, F. Hoffmann-La Roche Ltd, Basel, Switzerland aut Cardiovascular Drugs and Therapy Springer US; http://www.springer-ny.com 29/1(2015-02-01), 7-14 0920-3206 29:1<7 2015 29 10557 https://doi.org/10.1007/s10557-015-6570-0 text/html Onlinezugriff via DOI BK010053 XK010053 XK010000 Metadata rights reserved Springer special CC-BY-NC licence nationallicence 1 research-article jats NATIONALLICENCE NATIONALLICENCE NL-springer NATIONALLICENCE 856 40 https://doi.org/10.1007/s10557-015-6570-0 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Niesor Eric Pharma Research & Early Development, pRED, F. Hoffmann-La Roche Ltd, Basel, Switzerland aut NATIONALLICENCE 700 1- Schwartz Gregory Veterans Affairs Medical Center and University of Colorado School of Medicine, Denver, CO, USA aut NATIONALLICENCE 700 1- Perez Anne Pharma Research & Early Development, pRED, F. Hoffmann-La Roche Ltd, Basel, Switzerland aut NATIONALLICENCE 700 1- Stauffer Andrea Pharma Research & Early Development, pRED, F. Hoffmann-La Roche Ltd, Basel, Switzerland aut NATIONALLICENCE 700 1- Durrwell Alexandre Pharma Research & Early Development, pRED, F. Hoffmann-La Roche Ltd, Basel, Switzerland aut NATIONALLICENCE 700 1- Bucklar-Suchankova Gabriela Roche Professional Diagnostics, Basel, Switzerland aut NATIONALLICENCE 700 1- Benghozi Renée Pharma Development, F. Hoffmann-La Roche Ltd, Basel, Switzerland aut NATIONALLICENCE 700 1- Abt Markus Biostatistics, F. Hoffmann-La Roche Ltd, Basel, Switzerland aut NATIONALLICENCE 700 1- Kallend David Pharma Development, F. Hoffmann-La Roche Ltd, Basel, Switzerland aut NATIONALLICENCE 773 0- Cardiovascular Drugs and Therapy Springer US; http://www.springer-ny.com 29/1(2015-02-01), 7-14 0920-3206 29:1<7 2015 29 10557