Studies on LXR- and FXR-mediated effects on cholesterol homeostasis in normal and cholic acid-depleted mice.
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.
Wang
J
J
Division of Clinical Chemistry, Department of Laboratory Medicine, Karolinska Institutet, Karolinska University Hospital, Huddinge, Sweden.
Einarsson
C
C
Murphy
C
C
Parini
P
P
Björkhem
I
I
Gåfvels
M
M
Eggertsen
G
G
D064286:ATP Binding Cassette Transporter 1; D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics; D000074020:ATP Binding Cassette Transporter, Subfamily B, Member 11; D000071018:ATP Binding Cassette Transporter, Subfamily G, Member 5; D000071019:ATP Binding Cassette Transporter, Subfamily G, Member 8; D018528:ATP-Binding Cassette Transporters / Q000235:genetics; D000818:Animals; D016632:Apolipoprotein A-I / Q000235:genetics; D001646:Bile / Q000737:chemistry; D001647:Bile Acids and Salts / Q000032:analysis / Q000378:metabolism; D002784:Cholesterol / Q000096:biosynthesis / Q000097:blood / Q000378:metabolism*; D002790:Cholesterol 7-alpha-Hydroxylase / Q000235:genetics; D002791:Cholesterol, Dietary / Q000008:administration & dosage / Q000494:pharmacology; D019826:Cholic Acid / Q000172:deficiency* / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000819:agonists / Q000502:physiology*; D005243:Feces / Q000737:chemistry; D005260:Female; D015870:Gene Expression / Q000187:drug effects / Q000235:genetics; D006706:Homeostasis / Q000502:physiology*; D006903:Hydroxymethylglutaryl CoA Reductases / Q000235:genetics; D007555:Isoxazoles / Q000494:pharmacology; D008055:Lipids / Q000032:analysis; D008074:Lipoproteins / Q000097:blood / Q000737:chemistry / Q000235:genetics; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D000071518:Liver X Receptors; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D057093:Orphan Nuclear Receptors; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists / Q000502:physiology*; D013253:Steroid 12-alpha-Hydroxylase / Q000235:genetics; D051780:Sterol Regulatory Element Binding Protein 1 / Q000235:genetics; D051782:Sterol Regulatory Element Binding Protein 2 / Q000235:genetics; D014157:Transcription Factors / Q000819:agonists / Q000502:physiology*; D000097202:ATP-Binding Cassette Sub-Family B Member 4; D000099150:Receptor, Farnesoid X-Activated
D064286:ATP Binding Cassette Transporter 1; D018435:ATP Binding Cassette Transporter, Subfamily B; D000074020:ATP Binding Cassette Transporter, Subfamily B, Member 11; D000071018:ATP Binding Cassette Transporter, Subfamily G, Member 5; D000071019:ATP Binding Cassette Transporter, Subfamily G, Member 8; D018528:ATP-Binding Cassette Transporters; D016632:Apolipoprotein A-I; D001647:Bile Acids and Salts; D002784:Cholesterol; D002790:Cholesterol 7-alpha-Hydroxylase; D002791:Cholesterol, Dietary; D019826:Cholic Acid; D004268:DNA-Binding Proteins; D006903:Hydroxymethylglutaryl CoA Reductases; D007555:Isoxazoles; D008055:Lipids; D008074:Lipoproteins; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D018160:Receptors, Cytoplasmic and Nuclear; D013253:Steroid 12-alpha-Hydroxylase; D051780:Sterol Regulatory Element Binding Protein 1; D051782:Sterol Regulatory Element Binding Protein 2; D014157:Transcription Factors; D000097202:ATP-Binding Cassette Sub-Family B Member 4; D000099150:Receptor, Farnesoid X-Activated; C462600:ABCG5 protein, mouse; C462601:ABCG8 protein, mouse; C490549:Abcb11 protein, mouse; C497388:Srebf1 protein, mouse; C497391:Srebf2 protein, mouse; C001521:lathosterol; C502772:Cyp7a1 protein, mouse; C412815:GW 4064