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Cholesterol Efflux Assay
07:54

Cholesterol Efflux Assay

Published on: March 6, 2012

Atorvastatin inhibits ABCA1 expression and cholesterol efflux in THP-1 macrophages by an LXR-dependent pathway

Guosong Qiu1, John S Hill

  • 1Atherosclerosis Specialty Laboratory, Healthy Heart Program, St. Paul's Hospital, University of British Columbia, Vancouver, Canada.

Journal of Cardiovascular Pharmacology
|April 23, 2008
PubMed

Insights

Atorvastatin reduces cholesterol transporter ABCA1 expression and efflux in macrophages, an effect mediated by LXRalpha, not Rho. This impact is lessened in cholesterol-loaded cells.

Area of Science:

  • Biochemistry
  • Cell Biology
  • Pharmacology

Background:

  • The role of atorvastatin in regulating cholesterol homeostasis is complex and debated.
  • Adenosine triphosphate (ATP)-binding cassette transporter A1 (ABCA1) and apolipoprotein AI (apoAI)-mediated cholesterol efflux are critical in lipid metabolism.
  • Liver X receptor alpha (LXRalpha) and Rho signaling pathways influence ABCA1 expression and function.

Purpose of the Study:

  • To investigate the precise effects of atorvastatin on ABCA1 expression and cholesterol efflux in THP-1 macrophages.
  • To elucidate the roles of LXRalpha and Rho signaling in atorvastatin-mediated changes in ABCA1 and cholesterol transport.

Main Methods:

  • Dose-dependent treatment of THP-1 macrophages and human monocyte-derived macrophages with atorvastatin.
  • Measurement of ABCA1 expression and apoAI-mediated cholesterol efflux.
  • Manipulation of Rho signaling using activators (FPP, LPA, mevalonate, GTPgammaS) and inhibitors (C3 exoenzyme).
  • Assessment of LXRalpha activity using agonists and Western blot analysis for Rho/LXRalpha interaction.

Main Results:

  • Atorvastatin dose-dependently inhibited ABCA1 expression and reduced apoAI-mediated cholesterol efflux in non-cholesterol-loaded THP-1 cells.
  • The inhibitory effect of atorvastatin on cholesterol efflux was abolished by acetylated low-density lipoprotein (LDL) pretreatment.
  • Atorvastatin reduced LXRalpha expression and Rho activation; LXRalpha agonists prevented atorvastatin's inhibitory effects.
  • Rho activation modulated ABCA1 expression and cholesterol efflux, but not in a manner that salvaged atorvastatin's effects; Rho inhibition increased ABCA1 mRNA.
  • Western blot analysis revealed reciprocal inhibition between Rho and LXRalpha.

Conclusions:

  • Atorvastatin decreases ABCA1 expression and cholesterol efflux in non-cholesterol-loaded macrophages via an LXRalpha-dependent pathway.
  • Rho signaling is not the primary mediator of atorvastatin's effects on ABCA1 in this context.
  • Cholesterol loading, such as via acetylated LDL, can compromise the inhibitory effects of atorvastatin on ABCA1 and cholesterol efflux.

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