Regulatory effects of synthetic liver X receptor- and peroxisome-proliferator activated receptor agonists on sterol transport pathways in polarized cerebrovascular endothelial cells

Int J Biochem Cell Biol. 2006;38(8):1314-29. doi: 10.1016/j.biocel.2006.01.013. Epub 2006 Feb 24.

Abstract

The blood-brain barrier contributes to maintain brain cholesterol metabolism and protects this uniquely balanced system from exchange with plasma lipoprotein cholesterol. Brain capillary endothelial cells, representing a physiological barrier to the central nervous system, express apolipoprotein A-I (apoA-I, the major high-density lipoprotein (HDL)-associated apolipoprotein), ATP-binding cassette transporter A1 (ABCA1), and scavenger receptor, class B, type I (SR-BI), proteins that promote cellular cholesterol mobilization. Liver X receptors (LXRs) and peroxisome-proliferator activated receptors (PPARs) are regulators of cholesterol transport, and activation of LXRs and PPARs has potential therapeutic implications for lipid-related neurodegenerative diseases. To clarify the functional impact of LXR/PPAR activation, sterol transport along the: (i) ABCA1/apoA-I and (ii) SR-BI/HDL pathway was investigated in primary, polarized brain capillary endothelial cells, an in vitro model of the blood-brain barrier. Activation of LXR (24(S)OH-cholesterol, TO901317), PPARalpha (bezafibrate, fenofibrate), and PPARgamma (troglitazone, pioglitazone) modulated expression of apoA-I, ABCA1, and SR-BI on mRNA and/or protein levels without compromising transendothelial electrical resistance or tight junction protein expression. LXR-agonists and troglitazone enhanced basolateral-to-apical cholesterol mobilization in the absence of exogenous sterol acceptors. Along with the induction of cell surface-located ABCA1, several agonists enhanced cholesterol mobilization in the presence of exogenous apoA-I, while efflux of 24(S)OH-cholesterol (the major brain cholesterol metabolite) in the presence of exogenous HDL remained unaffected. Summarizing, in cerebrovascular endothelial cells apoA-I, ABCA1, and SR-BI represent drug targets for LXR and PPAR-agonists to interfere with cholesterol homeostasis at the periphery of the central nervous system.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter 1
  • ATP-Binding Cassette Transporters / genetics
  • ATP-Binding Cassette Transporters / metabolism
  • Animals
  • Apolipoprotein A-I / genetics
  • Apolipoprotein A-I / metabolism
  • Biological Transport / drug effects
  • Biological Transport / physiology
  • Cell Polarity / physiology*
  • Cells, Cultured
  • Clofibric Acid / chemical synthesis
  • Clofibric Acid / pharmacology
  • DNA-Binding Proteins / agonists*
  • DNA-Binding Proteins / metabolism
  • Endothelium, Vascular / cytology
  • Endothelium, Vascular / drug effects
  • Endothelium, Vascular / metabolism*
  • Immunoblotting
  • Lipoproteins, HDL / metabolism
  • Lipoproteins, HDL3
  • Liver X Receptors
  • Microscopy, Fluorescence
  • Models, Biological
  • Orphan Nuclear Receptors
  • Peroxisome Proliferator-Activated Receptors / agonists*
  • Peroxisome Proliferator-Activated Receptors / metabolism
  • Pioglitazone
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Receptors, Cytoplasmic and Nuclear / agonists*
  • Receptors, Cytoplasmic and Nuclear / metabolism
  • Scavenger Receptors, Class B / genetics
  • Scavenger Receptors, Class B / metabolism
  • Signal Transduction / drug effects
  • Sterols / chemistry
  • Sterols / metabolism*
  • Swine
  • Thiazolidinediones / chemical synthesis
  • Thiazolidinediones / pharmacology
  • Transcription, Genetic / drug effects
  • Transcription, Genetic / genetics

Substances

  • ATP Binding Cassette Transporter 1
  • ATP-Binding Cassette Transporters
  • Apolipoprotein A-I
  • DNA-Binding Proteins
  • Lipoproteins, HDL
  • Lipoproteins, HDL3
  • Liver X Receptors
  • Orphan Nuclear Receptors
  • Peroxisome Proliferator-Activated Receptors
  • RNA, Messenger
  • Receptors, Cytoplasmic and Nuclear
  • Scavenger Receptors, Class B
  • Sterols
  • Thiazolidinediones
  • Clofibric Acid
  • Pioglitazone