Regulatory effects of synthetic liver X receptor- and peroxisome-proliferator activated receptor agonists on sterol transport pathways in polarized cerebrovascular endothelial cells.
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.
Panzenboeck
Ute
U
Medical University Graz, Center of Molecular Medicine, Institute of Molecular Biology and Biochemistry, Harrachgasse 21, A-8010 Graz, Austria. ute.panzenboeck@meduni-graz.at
Kratzer
Ingrid
I
Sovic
Andrea
A
Wintersperger
Andrea
A
Bernhart
Eva
E
Hammer
Astrid
A
Malle
Ernst
E
Sattler
Wolfgang
W
D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism; D000818:Animals; D016632:Apolipoprotein A-I / Q000235:genetics / Q000378:metabolism; D001692:Biological Transport / Q000187:drug effects / Q000502:physiology; D016764:Cell Polarity / Q000502:physiology*; D002478:Cells, Cultured; D002995:Clofibric Acid / Q000138:chemical synthesis / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000819:agonists* / Q000378:metabolism; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D015151:Immunoblotting; D008075:Lipoproteins, HDL / Q000378:metabolism; D053440:Lipoproteins, HDL3; D000071518:Liver X Receptors; D008856:Microscopy, Fluorescence; D008954:Models, Biological; D057093:Orphan Nuclear Receptors; D047492:Peroxisome Proliferator-Activated Receptors / Q000819:agonists* / Q000378:metabolism; D000077205:Pioglitazone; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists* / Q000378:metabolism; D051122:Scavenger Receptors, Class B / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013261:Sterols / Q000737:chemistry / Q000378:metabolism*; D013552:Swine; D045162:Thiazolidinediones / Q000138:chemical synthesis / Q000494:pharmacology; D014158:Transcription, Genetic / Q000187:drug effects / Q000235:genetics
D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D016632:Apolipoprotein A-I; D004268:DNA-Binding Proteins; D008075:Lipoproteins, HDL; D053440:Lipoproteins, HDL3; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D047492:Peroxisome Proliferator-Activated Receptors; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D051122:Scavenger Receptors, Class B; D013261:Sterols; D045162:Thiazolidinediones; D002995:Clofibric Acid; D000077205:Pioglitazone