Document Detail

The nuclear receptors FXR and LXRalpha: potential targets for the development of drugs affecting lipid metabolism and neoplastic diseases.
MedLine Citation:
PMID:  11254888     Owner:  NLM     Status:  MEDLINE    
The orphan nuclear receptors FXR and LXRalpha have become challenging targets for the discovery of new therapeutic agents. Bile acids and hydroxysterol intermediates are the respective natural ligands of these two structurally and functionally closely related receptors. Both FXR and LXRalpha; are thought to play a major role in the control of cholesterol catabolism by regulating the expression of cholesterol 7alpha-hydroxylase, the rate limiting enzyme of bile acid synthesis. Reverse cholesterol transport might also be affected by FXR and LXR since they control the expression of PLTP and CETP, two proteins involved in the transfer of phospholipid, cholesterol and cholesteryl esters among plasma lipoproteins. A new class of potent synthetic activators of FXR, the 1,1-bisphosphonate esters, has been discovered which up regulate the Intestinal Bile Acid Binding Protein gene (I-BABP) as demonstrated for chenodeoxycholic acid, however there are no known synthetic activators yet identified for LXRalpha. The evaluation of FXR as a potential target for the development of drugs affecting plasma cholesterol can take advantage of the fact that the activators of FXR (farnesol, bile acids and the 1,1-bisphosphonate esters) have been studied in various in vitro and in vivo models. Administration of chenodeoxycholic acid to animals and man did not result in the increase in plasma cholesterol expected from a decrease in cholesterol 7alpha-hydroxylase expression. Like farnesol, the 1,1-bisphosphonate esters increase the rate of degradation of HMGCoA reductase and have the unexpected property of inducing hypocholesterolemia in normal animals. The natural and synthetic FXR agonists trigger differentiation, inhibit cell proliferation and are potent inducers of apoptosis. The 1,1-bisphosphonate ester SR-45023A (Apomine) is presently being developed as an antineoplastic drug.
E J Niesor; J Flach; I Lopes-Antoni; A Perez; C L Bentzen
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Publication Detail:
Type:  Journal Article; Review    
Journal Detail:
Title:  Current pharmaceutical design     Volume:  7     ISSN:  1381-6128     ISO Abbreviation:  Curr. Pharm. Des.     Publication Date:  2001 Mar 
Date Detail:
Created Date:  2001-03-20     Completed Date:  2001-05-03     Revised Date:  2009-11-19    
Medline Journal Info:
Nlm Unique ID:  9602487     Medline TA:  Curr Pharm Des     Country:  Netherlands    
Other Details:
Languages:  eng     Pagination:  231-59     Citation Subset:  IM    
Symphar, Innovative Pharmaceutical Research, 1290 Versoix, Geneva, Switzerland.
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MeSH Terms
Amino Acid Sequence
Anticholesteremic Agents / pharmacology
Antineoplastic Agents / pharmacology*
Bile Acids and Salts / metabolism
Cholesterol / metabolism
Cholesterol 7-alpha-Hydroxylase / physiology
DNA-Binding Proteins / drug effects*,  physiology
Drug Design
Lipid Metabolism*
Molecular Sequence Data
Orphan Nuclear Receptors
Receptors, Cytoplasmic and Nuclear / drug effects*,  physiology
Receptors, Steroid / chemistry
Transcription Factors / drug effects*,  physiology
Reg. No./Substance:
0/Anticholesteremic Agents; 0/Antineoplastic Agents; 0/Bile Acids and Salts; 0/DNA-Binding Proteins; 0/Orphan Nuclear Receptors; 0/Receptors, Cytoplasmic and Nuclear; 0/Receptors, Steroid; 0/Transcription Factors; 0/farnesoid X-activated receptor; 0/liver X receptor; 57-88-5/Cholesterol; EC 7-alpha-Hydroxylase

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