Hepatic nuclear corepressor 1 regulates cholesterol absorption through a TRβ1-governed pathway.
Transcriptional coregulators are important components of nuclear receptor (NR) signaling machinery and provide additional mechanisms for modulation of NR activity. Expression of a mutated nuclear corepressor 1 (NCoR1) that lacks 2 NR interacting domains (NCoRΔID) in the liver leads to elevated expression of genes regulated by thyroid hormone receptor (TR) and liver X receptor (LXR), both of which control hepatic cholesterol metabolism. Here, we demonstrate that expression of NCoRΔID in mouse liver improves dietary cholesterol tolerance in an LXRα-independent manner. NCoRΔID-associated cholesterol tolerance was primarily due to diminished intestinal cholesterol absorption as the result of changes in the composition and hydrophobicity of the bile salt pool. Alterations of the bile salt pool were mediated by increased expression of genes encoding the bile acid metabolism enzymes CYP27A1 and CYP3A11 as well as canalicular bile salt pump ABCB11. We have determined that these genes are regulated by thyroid hormone and that TRβ1 is recruited to their regulatory regions. Together, these data indicate that interactions between NCoR1 and TR control a specific pathway involved in regulation of cholesterol metabolism and clearance.
Inna
I
Astapova
Preeti
P
Ramadoss
Ricardo H
RH
Costa-e-Sousa
Felix
F
Ye
Kaila A
KA
Holtz
Yingxia
Y
Li
Michele W
MW
Niepel
David E
DE
Cohen
Anthony N
AN
Hollenberg
D000074020:ATP Binding Cassette Transporter, Subfamily B, Member 11; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism; D000818:Animals; D053493:Cholestanetriol 26-Monooxygenase / Q000235:genetics / Q000378:metabolism; D002784:Cholesterol / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D051544:Cytochrome P-450 CYP3A / Q000235:genetics / Q000378:metabolism; D004041:Dietary Fats / Q000494:pharmacology; D008099:Liver / Q000378:metabolism*; D000071518:Liver X Receptors; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D018345:Mice, Knockout; D056971:Nuclear Receptor Co-Repressor 1 / Q000235:genetics / Q000378:metabolism*; D057093:Orphan Nuclear Receptors / Q000235:genetics / Q000378:metabolism; D037042:Thyroid Hormone Receptors beta / Q000235:genetics / Q000276:immunology*; D013963:Thyroid Hormones / Q000235:genetics / Q000378:metabolism
D000074020:ATP Binding Cassette Transporter, Subfamily B, Member 11; D018528:ATP-Binding Cassette Transporters; C490549:Abcb11 protein, mouse; D004041:Dietary Fats; D000071518:Liver X Receptors; D008565:Membrane Proteins; C539128:Ncor1 protein, mouse; C000605214:Nr1h3 protein, mouse; D056971:Nuclear Receptor Co-Repressor 1; D057093:Orphan Nuclear Receptors; D037042:Thyroid Hormone Receptors beta; D013963:Thyroid Hormones; D002784:Cholesterol; C496508:Cyp3a11 protein, mouse; D051544:Cytochrome P-450 CYP3A; D053493:Cholestanetriol 26-Monooxygenase; C506832:Cyp27a1 protein, mouse