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Nuclear receptors as lipid sensors at the blood-brain barrier

Abstract

Nuclear receptors represent a large super family of ligand-dependent transcription factors that regulate the expression of target genes to affect diverse metabolic processes. Two members, peroxisome-proliferator activated receptors(PPARs) and liver X receptors(LXRs), control the transcription of key-genes involved in lipid metabolism, transport and elimination. PPARs and LXRs are lipid sensors that control central pathways in (chole)sterol and fatty acid metabolism at the blood-brain barrier (BBB). The proposed role of PPARs and LXRs at the BBB is based on the following background:(i) Several neurodegenerative disorders are tightly coupled to functional lipid and lipoprotein metabolism; (ii) Brain function and development rely on a supply with essential polyunsaturated fatty acids from the circulation; (iii) Excess brain cholesterol is eliminated after oxidative conversion to 24(S)OH-cholesterol;(iv) Brain endothelial cells express target genes for nuclear recertors that display gate-keeping functions in peripheral reverse cholesterol transport and/or in fatty acid uptake.The central hypothesis underlying the present application suggests that LXR and PPAR activation regulates reverse cholesterol transport and fatty acid supply at the BBB. Therefore, these nuclear receptors may provide promising drug target for the treatment of lipid-related neurodegenerative disorders in the near future. In order to validate this hypothesis the following aims are:
1.) Identification of the most potent endogenous ligands and therapeutic drugs for activation of the nuclear receptors PPARalpha, beta, gamma and LXRalpha, beta in porcine brain capillary endothelial cells.
2.) Evaluation of nuclear receptor-mediated regulation of the expression of specific target genes taking central roles during lipid turnover at the BBB.
3.) Effects of (synthetic) agonists for PPARs and LXRs on elimination of cholesterol and 24(S)OH-cholesterol(i.e.,on reverse cholesterol transport) across an in vitro model of the BBB.
4.) Effects of nuclear receptor ligands on the supply of essential polyunsaturated fatty acids across an in vitro model of the BBB.
5.) Identification of cerebral and brain-microvascular PPAR and LXR target genes via large-scale gene expression profiling in the mouse model.

Keywords

Blut-Hirn Schranke

Fettsäureversorgung

Neurodegenerative Störungen

Nukleäre Rezeptoren

Reverser Cholesterintransport

Project Leader:

Panzenboeck Ute

Stefulj Jasminka

Duration:

01.10.2004-30.11.2007

Programme:

Einzelprojekt

Type of Research

basic research

Staff

Panzenboeck, Ute, Project Leader

Stefulj, Jasminka, Project Leader

MUG Research Units

Division of Immunology

Division of Molecular Biology and Biochemistry

Funded by

FWF, Fonds zur Förderung der Wissenschaftlichen Forschung, Wien, Austria

FWF-Grant-DOI: 10.55776/P17474

Project results published

> Processing of endogenous AβPP in blood-brain barri... J Alzheimers Dis. 2011; 27(2):341-360

> Liver X receptor agonists and altered cellular cho... Alzheimer's Association 2011 International Conference on Alzheimer's Disease (ICAD 2011); JUL 16-21, 2011; Paris, FRANCE. 2011.

> Human endothelial cells of the placental barrier e... Circ Res. 2009; 104(5):600-608

> MECHANISMS OF STEROL TRANSPORT AT THE BLOOD-BRAIN ... [ Habilitationsschrift ] Graz Medical University; 2008.

> LXR-agonists regulate ApoM expression differential... Curr Pharm Biotechnol. 2008; 9(6): 516-521.

> CHOLESTEROL EFFLUX MECHANISMS IN ENDOTHELIAL CELLS... Journal of Clinical Lipidology2007; 1(5):356--XVI International Symposium on DRUGS AFFECTING LIPID METABOLISM; OCT 4-7, 2007; New York, USA.

> ACTIVATION OF LIVER X RECEPTORS IN THE BRAIN: REGU... Journal of Clinical Lipidology2007; 1(5):459-459.-XVI International Symposium on DRUGS AFFECTING LIPID METABOLISM; OCT 4-7, 2007; New York, USA.

> Efficient transport of a metabolite of 27-hydroxyc... XIXth International Bile Acid Meeting; OCT 6-7, 2006; Freiburg, GERMANY. 2006.

> A potential role for apoA-I binding protein (AI-BP... 13. Jahrestagung der Österreichischen Atherosklerosegesellschaft (AAS); Mai 5-6, 2006; St. Gilgen, AUSTRIA. 2006.

> LXR activation regulates target genes involved in ... 3rd Lipidomics Meeting ‘From Lipid Analysis to Genetic Disorders’; MAY 10-12, 2006; Marseille, FRANCE. 2006.

> On the mechanism of accumulation of cholestanol in... XIXth International Bile Acid Meeting; OCT 6-7, 2006; Freiburg, GERMANY. 2006.

> Cholesterol homeostasis in cerebrovascular endothe... 28th annual meeting of the European Lipoprotein Club; SEP 12-15, 2005; Tutzing, GERMANY. 2005.

> PPAR and LXR activation in brain capillary endothe... 11. Jahrestagung der Österreichischen Atherosklerosegesellschaft (AAS); MAY 14-15; Linz, AUSTRIA. 2004.

> Regulation of sterol flux at the blood-brain barri... ATHEROSCLER SUPPL 2004 5: 73-73.

> Uptake and transport of high-density lipoprotein (... J NEUROCHEM. 2004; 89(4): 939-950.

> PPAR and LXR activation modulates the expression o... XV International Symposion on Drugs affecting Lipid Metabolism; OCT 24-29, 2004; Venice, ITALY. 2004.

> Regulation of reverse sterol transport at the BBB ... 6th Symposium on Signal transduction in the blood-brain barriers; SEP 18-21; Szeged, HUNGARY. 2003.

> A role of scavenger receptor BI, endothelial lipas... 2nd international symposium on ‘PPARs: from basic science to clinical applications’; Mar 19-22, 2003; Florence, ITALY. 2003.

> A possible role of endothelial lipase (EL) and fat... 6th Symposium on Signal transduction in the blood-brain barriers; SEP 18-21, 2003; Szeged, HUNGARY. 2003.

> LXR-dependent autoregulation of `reverse sterol tr... 2nd international symposium on ‘PPARs: from basic science to clinical applications’; MAR 19-22; Florence, ITALY. 2003.

> ABCA1 and scavenger receptor class B, type I, are ... J Biol Chem. 2002; 277(45):42781-42789