Hepatic nuclear corepressor 1 regulates cholesterol absorption through a TRβ1-governed pathway
Inna Astapova, … , David E. Cohen, Anthony N. Hollenberg
Inna Astapova, … , David E. Cohen, Anthony N. Hollenberg
Published April 8, 2014
Citation Information: J Clin Invest. 2014;124(5):1976-1986. https://doi.org/10.1172/JCI73419.
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Hepatic nuclear corepressor 1 regulates cholesterol absorption through a TRβ1-governed pathway

Abstract

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.

Authors

Inna Astapova, Preeti Ramadoss, Ricardo H. Costa-e-Sousa, Felix Ye, Kaila A. Holtz, Yingxia Li, Michele W. Niepel, David E. Cohen, Anthony N. Hollenberg

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Figure 6

Cyp27a1, Cyp3a11, and Abcb11 are TR targets.

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Cyp27a1, Cyp3a11, and Abcb11 are TR targets. (A) Expression of indica...
(A) Expression of indicated genes was quantified by QPCR on RNA isolated from the livers of euthyroid (chow), hypothyroid (PTU), and hyperthyroid (PTU+T3) WT mice. (n = 6–7 animals per group). (B) ChIP followed by QPCR for indicated regions of Cyp27a1, Cyp3a11, and Abcb11 genes was performed using streptavidin-agarose and chromatin isolated from livers of mice with hepatic adenovirus–mediated overexpression of GFP (control) or biotinylated TRβ1 (n = 5 affinity precipitation reactions per group). Statistical analysis was performed using 1-way ANOVA followed by Tukey’s multiple comparisons test. *P ≤ 0.05; **P ≤ 0.01; ***P ≤ 0.001. (C) Snapshots of UCSC genome browser showing alignment of histograms for TR ChIP peaks obtained in our laboratory (TRβ T3, TRβ PTU) and NCoR1 ChIP peaks (NCoR) obtained by Feng et al. (42).