Hypolipidemic effects of selective liver X receptor alpha agonists.
Recently, a number of nuclear receptors have been identified as key regulators of cholesterol homeostasis. Two of these, liver X receptor alpha (LXRalpha) (NR1H3) [1] and ubiquitous receptor (UR) (NR1H2) [1], appear to be involved in cholesterol reverse transport and disposal. LXRalpha null gene mice fail to adapt metabolically to high-cholesterol diets. We have recently shown that some 6alpha-hydroxylated bile acid analogs are selective activators of LXRalpha. In this report, we show that these orally administered LXRalpha agonists have an overall hypolipidemic effect in hypercholesterolemic rats, mice and hamsters, which indicates that in these animal models, endogenous LXRalpha agonist is a limiting factor for induction of cholesterol disposal. Furthermore, in animals, these 6alpha-hydroxylated bile acid analogs exhibit a unique pharmacokinetic profile and do not increase the serum triglyceride level; therefore, they may represent a novel class of therapeutic agents for cholesterol management.
Song
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The Ben May Institute for Cancer Research, Department of Biochemistry and Molecular Biology, the Tang Center for Herbal Medicine Research, 5841 South Maryland Avenue, , Chicago, Illinois 60637, USA.
Liao
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D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology; D001057:Apolipoproteins E / Q000235:genetics; D002784:Cholesterol / Q000378:metabolism*; D002791:Cholesterol, Dietary / Q000494:pharmacology; D002793:Cholic Acids / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology; D006224:Cricetinae; D004268:DNA-Binding Proteins; D004195:Disease Models, Animal; D017353:Gene Deletion; D006801:Humans; D006845:Hydrocarbons, Fluorinated; D006937:Hypercholesterolemia / Q000139:chemically induced / Q000378:metabolism; D000960:Hypolipidemic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D000071518:Liver X Receptors; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D057093:Orphan Nuclear Receptors; D051381:Rats; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists* / Q000378:metabolism; D013379:Substrate Specificity; D013449:Sulfonamides; D015533:Transcriptional Activation / Q000187:drug effects; D014280:Triglycerides / Q000378:metabolism; D005466:Fluorocarbons; D000096926:Benzenesulfonamides
D000924:Anticholesteremic Agents; D001057:Apolipoproteins E; D002784:Cholesterol; D002791:Cholesterol, Dietary; D002793:Cholic Acids; D004268:DNA-Binding Proteins; D006845:Hydrocarbons, Fluorinated; D000960:Hypolipidemic Agents; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D018160:Receptors, Cytoplasmic and Nuclear; D013449:Sulfonamides; D014280:Triglycerides; C438184:3,6-dihydroxy-5-cholanoic acid-N-methyl-N-methoxy-24-amide; C000605210:NR1H2 protein, human; C000605213:NR1H3 protein, human; C000605211:Nr1h2 protein, mouse; C000605212:Nr1h2 protein, rat; C000605214:Nr1h3 protein, mouse; C000605215:Nr1h3 protein, rat; C423915:T0901317; D005466:Fluorocarbons; D000096926:Benzenesulfonamides