Abstract
As previously reported by us, mice with targeted disruption of the CYP8B1 gene (CYP8B1-/-) fail to produce cholic acid (CA), upregulate their bile acid synthesis, reduce the absorption of dietary cholesterol and, after cholesterol feeding, accumulate less liver cholesterol than wild-type (CYP8B1+/+) mice. In the present study, cholesterol-enriched diet (0.5%) or administration of a synthetic liver X receptor (LXR) agonist strongly upregulated CYP7A1 expression in CYP8B1-/- mice, compared to CYP8B1+/+ mice. Cholesterol-fed CYP8B1-/- mice also showed a significant rise in HDL cholesterol and increased levels of liver ABCA1 mRNA. A combined CA (0.25%)/cholesterol (0.5%) diet enhanced absorption of intestinal cholesterol in both groups of mice, increased their liver cholesterol content, and reduced their expression of CYP7A1 mRNA. The ABCG5/G8 liver mRNA was increased in both groups of mice, but cholesterol crystals were only observed in bile from the CYP8B1+/+ mice. The results demonstrate the cholesterol-sparing effects of CA: enhanced absorption and reduced conversion into bile acids. Farnesoid X receptor (FXR)-mediated suppression of CYP7A1 in mice seems to be a predominant mechanism for regulation of bile acid synthesis under normal conditions and, as confirmed, able to override LXR-mediated mechanisms. Interaction between FXR- and LXR-mediated stimuli might also regulate expression of liver ABCG5/G8.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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ATP Binding Cassette Transporter 1
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ATP Binding Cassette Transporter, Subfamily B / genetics
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ATP Binding Cassette Transporter, Subfamily B, Member 11
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ATP Binding Cassette Transporter, Subfamily G, Member 5
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ATP Binding Cassette Transporter, Subfamily G, Member 8
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ATP-Binding Cassette Sub-Family B Member 4
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ATP-Binding Cassette Transporters / genetics
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Animals
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Apolipoprotein A-I / genetics
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Bile / chemistry
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Bile Acids and Salts / analysis
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Bile Acids and Salts / metabolism
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Cholesterol / biosynthesis
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Cholesterol / blood
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Cholesterol / metabolism*
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Cholesterol 7-alpha-Hydroxylase / genetics
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Cholesterol, Dietary / administration & dosage
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Cholesterol, Dietary / pharmacology
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Cholic Acid / deficiency*
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Cholic Acid / pharmacology
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DNA-Binding Proteins / agonists
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DNA-Binding Proteins / physiology*
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Feces / chemistry
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Female
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Gene Expression / drug effects
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Gene Expression / genetics
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Homeostasis / physiology*
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Hydroxymethylglutaryl CoA Reductases / genetics
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Isoxazoles / pharmacology
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Lipids / analysis
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Lipoproteins / blood
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Lipoproteins / chemistry
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Lipoproteins / genetics
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Liver / drug effects
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Liver / metabolism
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Liver X Receptors
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Male
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Mice
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Mice, Knockout
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Orphan Nuclear Receptors
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Receptors, Cytoplasmic and Nuclear / agonists
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Receptors, Cytoplasmic and Nuclear / physiology*
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Steroid 12-alpha-Hydroxylase / genetics
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Sterol Regulatory Element Binding Protein 1 / genetics
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Sterol Regulatory Element Binding Protein 2 / genetics
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Transcription Factors / agonists
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Transcription Factors / physiology*
Substances
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ABCG5 protein, mouse
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ABCG8 protein, mouse
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ATP Binding Cassette Transporter 1
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ATP Binding Cassette Transporter, Subfamily B
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ATP Binding Cassette Transporter, Subfamily B, Member 11
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ATP Binding Cassette Transporter, Subfamily G, Member 5
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ATP Binding Cassette Transporter, Subfamily G, Member 8
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ATP-Binding Cassette Transporters
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Abcb11 protein, mouse
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Apolipoprotein A-I
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Bile Acids and Salts
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Cholesterol, Dietary
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DNA-Binding Proteins
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Isoxazoles
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Lipids
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Lipoproteins
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Liver X Receptors
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Orphan Nuclear Receptors
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Receptors, Cytoplasmic and Nuclear
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Srebf1 protein, mouse
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Srebf2 protein, mouse
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Sterol Regulatory Element Binding Protein 1
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Sterol Regulatory Element Binding Protein 2
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Transcription Factors
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farnesoid X-activated receptor
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lathosterol
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Cholesterol
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Hydroxymethylglutaryl CoA Reductases
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Cholesterol 7-alpha-Hydroxylase
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Cyp7a1 protein, mouse
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Steroid 12-alpha-Hydroxylase
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Cholic Acid
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GW 4064