Hepatic nuclear corepressor 1 regulates cholesterol absorption through a TRβ1-governed pathway

Transcriptional core tors 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 (NCoR Delta ID) 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 NCoR Delta ID in mouse liver improves dietary cholesterol tolerance in an LXR alpha-independent manner. NCoR Delta ID-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 TR beta 1 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.