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Statin-induced decrease in ATP-binding cassette transporter A1 expression via microRNA33 induction may counteract

Eric J Niesor1, Gregory G Schwartz, Anne Perez

  • 1Pharma Research & Early Development, pRED, F. Hoffmann-La Roche Ltd, Basel, Switzerland, eric_j.niesor@roche.com.

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Statins increase microRNA33 (miR33), reducing cholesterol efflux from macrophages. This may offset HDL-raising therapies in patients taking statins.

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Area of Science:

  • Biochemistry
  • Molecular Biology
  • Cardiovascular Research

Background:

  • Cholesterol efflux to HDL is crucial for preventing atherosclerosis.
  • Statins deplete cellular cholesterol, activating sterol regulatory element-binding protein (SREBP) transcription.
  • SREBP activation upregulates microRNA33 (miR33), which downregulates ABCA1 and ABCG1 expression.

Purpose of the Study:

  • To investigate if statin-induced miR33 up-regulation reduces macrophage cholesterol transporter expression.
  • To determine the impact on high-density lipoprotein (HDL)-mediated cholesterol efflux at the tissue level.

Main Methods:

  • Human THP-1 and mouse J774A.1 macrophage cell lines were used.
  • Cells were cholesterol-loaded and treated with atorvastatin or other statins.
  • MicroRNA33, ABCA1 mRNA, ABCG1 mRNA, and cholesterol efflux were measured.
  • HDL-mediated cholesterol efflux was assessed with and without dalcetrapib and rhCETP.

Main Results:

  • Atorvastatin increased miR33 and decreased ABCA1 and ABCG1 mRNA in THP-1 cells.
  • Simvastatin, pitavastatin, atorvastatin, rosuvastatin, and pravastatin decreased ABCA1 mRNA and cholesterol efflux in J774A.1 cells.
  • Dalcetrapib augmented HDL-mediated cholesterol efflux, but simvastatin negated this effect.

Conclusions:

  • In vitro, statins upregulate miR33, downregulate ABCA1, and reduce cholesterol efflux.
  • This statin-induced effect may counteract the benefits of HDL-raising therapies in patients.