LXR agonists for the treatment of atherosclerosis.
Liver X receptor (LXR) alpha/beta nuclear receptors are intracellular sterol sensors that regulate expression of genes controlling cholesterol absorption, excretion, catabolism and cellular efflux in target organs, including small intestine, liver and macrophages. Through co-ordination of the expression of target genes in multiple tissues, LXR agonists increase the flux of cholesterol from the periphery to the liver, where it is metabolized and excreted into the bile. Synthetic dual LXR alpha/beta agonists decrease atherosclerosis in mice, however, upregulation of lipogenic target genes and triglyceride elevation in rodents reveals a narrow therapeutic window. LXR subtype-selective agonists or LXR modulators may dissociate the anti-atherosclerotic and lipogenic effects of current dual LXR agonists.
Jaye
Michael
M
Vascular Biology and Thrombosis Department, Cardiovascular Center for Excellence in Drug Discovery, GlaxoSmithKline, 709 Swedeland Road, King of Prussia, PA 19406-0939, USA. michael.c.jaye@gsk.com
D000818:Animals; D000924:Anticholesteremic Agents / Q000737:chemistry / Q000627:therapeutic use*; D002784:Cholesterol / Q000378:metabolism; D003324:Coronary Artery Disease / Q000188:drug therapy* / Q000378:metabolism; D004268:DNA-Binding Proteins; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D000071518:Liver X Receptors; D008264:Macrophages / Q000378:metabolism; D015394:Molecular Structure; D057093:Orphan Nuclear Receptors; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists* / Q000235:genetics
D000924:Anticholesteremic Agents; D004268:DNA-Binding Proteins; D000071518:Liver X Receptors; C000605213:NR1H3 protein, human; C000605214:Nr1h3 protein, mouse; D057093:Orphan Nuclear Receptors; D018160:Receptors, Cytoplasmic and Nuclear; D002784:Cholesterol