Liver X receptor agonists as potential therapeutic agents for dyslipidemia and atherosclerosis.
The recent identification of liver X receptors (LXR) as regulators of the cholesterol and phospholipid export pump ABCA1 has raised the possibility that LXR agonists could be developed as HDL-raising agents, possibly also acting on the artery wall to stimulate cholesterol efflux from lipid-laden macrophages. Presently several pharmaceutical companies are working to develop such compounds, which will require finding a path for separating these beneficial effects from the detrimental stimulation of triglyceride synthesis also inherent to LXR agonists. Other challenges to the drug development process include species differences, which makes prediction of in vivo effects of LXR agonists in humans difficult. This review summarizes the present state of knowledge on LXR as a drug target and discusses possible solutions for dissociating the favorable effects of LXR agonists from their unwanted effects.
Lund
Erik G
EG
Department of Atherosclerosis, Merck Research Laboratories, PO Box 2000, Rahway, NJ 0706, USA. erik_lund@merck.com
Menke
John G
JG
Sparrow
Carl P
CP
D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism*; D000818:Animals; D001158:Arteries / Q000187:drug effects / Q000378:metabolism; D001161:Arteriosclerosis / Q000188:drug therapy* / Q000378:metabolism; D022762:CCAAT-Enhancer-Binding Proteins / Q000378:metabolism; D002784:Cholesterol / Q000378:metabolism; D008076:Cholesterol, HDL / Q000097:blood / Q000187:drug effects*; D004268:DNA-Binding Proteins / Q000378:metabolism; D006706:Homeostasis; D006801:Humans; D006949:Hyperlipidemias / Q000188:drug therapy* / Q000378:metabolism; D015228:Hypertriglyceridemia / Q000517:prevention & control; D000071518:Liver X Receptors; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D057093:Orphan Nuclear Receptors; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists* / Q000037:antagonists & inhibitors; D013045:Species Specificity; D051780:Sterol Regulatory Element Binding Protein 1; D014157:Transcription Factors
C577836:ABCA1 protein, human; D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D022762:CCAAT-Enhancer-Binding Proteins; D008076:Cholesterol, HDL; D004268:DNA-Binding Proteins; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D018160:Receptors, Cytoplasmic and Nuclear; C497387:SREBF1 protein, human; C497388:Srebf1 protein, mouse; D051780:Sterol Regulatory Element Binding Protein 1; D014157:Transcription Factors; D002784:Cholesterol