Abstract
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.
MeSH terms
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Animals
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Anticholesteremic Agents / pharmacology
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Apolipoproteins E / genetics
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Cholesterol / metabolism*
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Cholesterol, Dietary / pharmacology
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Cholic Acids / administration & dosage
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Cholic Acids / pharmacokinetics
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Cholic Acids / pharmacology
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Cricetinae
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DNA-Binding Proteins
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Disease Models, Animal
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Gene Deletion
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Humans
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Hydrocarbons, Fluorinated
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Hypercholesterolemia / chemically induced
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Hypercholesterolemia / metabolism
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Hypolipidemic Agents / administration & dosage
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Hypolipidemic Agents / pharmacokinetics
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Hypolipidemic Agents / pharmacology*
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Liver / drug effects
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Liver / metabolism
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Liver / pathology
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Liver X Receptors
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Male
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Orphan Nuclear Receptors
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Rats
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Receptors, Cytoplasmic and Nuclear / agonists*
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Receptors, Cytoplasmic and Nuclear / metabolism
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Substrate Specificity
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Sulfonamides
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Transcriptional Activation / drug effects
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Triglycerides / metabolism
Substances
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3,6-dihydroxy-5-cholanoic acid-N-methyl-N-methoxy-24-amide
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Anticholesteremic Agents
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Apolipoproteins E
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Cholesterol, Dietary
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Cholic Acids
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DNA-Binding Proteins
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Hydrocarbons, Fluorinated
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Hypolipidemic Agents
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Liver X Receptors
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NR1H2 protein, human
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NR1H3 protein, human
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Nr1h2 protein, mouse
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Nr1h2 protein, rat
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Nr1h3 protein, mouse
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Nr1h3 protein, rat
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Orphan Nuclear Receptors
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Receptors, Cytoplasmic and Nuclear
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Sulfonamides
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T0901317
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Triglycerides
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Cholesterol