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. IntroductionCholesterol metabolism in the liver is critical for normal systemic regulation of serum cholesterol levels and eventual cardiac risk. Both the thyroid hormone receptor (TR) and liver X receptor (LXR) regulate multiple cholesterol clearance pathways and have been targeted as potential therapeutic avenues to improve cholesterol metabolism in humans (1-4). Thyroid hormone (TH) and its liver-specific analogs have been shown to lower serum cholesterol levels through increased expression of the LDL-R and/or HDL receptor SR-B1 in the liver (2, 5, 6), stimulate cholesterol elimination via conversion to bile acids (3, 5, 7-9), enhance biliary cholesterol excretion through ATP-binding cassette transporter G5 and G8 (ABCG5/G8), and decrease cholesterol absorption (10-12). The effects of TH on the cholesterol metabolism in the liver are mediated by the TRβ1 isoform (7, 13).LXRα and LXRβ are activated by oxysterols and act as intracellular cholesterol sensors (14). LXRα is the major isoform in the liver that plays a predominant role in maintaining hepatic cholesterol homeostasis. Global or liver-specific KO of Lxra leads to a dramatic hepatic cholesterol accumulation in mice fed diets with high cholesterol content (15-17). LXRα controls cholesterol clearance through regulation of intestinal cholesterol absorption and biliary cholesterol secretion as well as cholesterol conversion into bile acids (15,(17)(18)(19). Thus, TRβ1 and LXRα regulate both distinct and overlapping pathways to control cholesterol metabolism in the liver. Based on this, we hypothesized that targeting common nuclear receptor (NR) coregulators could amplify beneficial effects of both pathways on cholesterol metabolism.Previous work from our laboratory and others has demonstrated that the NR corepressor, nuclear corepressor 1 (N...

NCoR1 and SMRT Play Unique Roles in Thyroid Hormone Action In Vivo

“…Further work will be required to determine how hepatic cholesterol is increased in this model, given that we have recently shown that expression of NCoR⌬ID reduces hepatic cholesterol accumulation via a decrease in cholesterol absorption ( Fig. 3D and E) (21).…”

“…6A). To genetically confirm a TR-specific pathway for the activation of ChREBP and because liver X receptor (LXR) has also been shown to regulate expression of ChREBP and interact with NCoR1, we used a model where the principal hepatic LXR isoform (LXR␣) has been deleted in either the presence or absence of (5,21,33,34). In these animals the hepatic expression of NCoR⌬ID clearly activates the expression of both ChREBP isoforms.…”

“…Mice were maintained on a mixed B6/129S background (21). To obtain a mouse strain with global deletion of SMRT (SMRT loxP/loxP UBC-Cre or UBC-SKO mice), we crossed SMRT loxP/loxP animals with mice that expressed a tamoxifen-inducible Cre recombinase under the control of the human ubiquitin C promoter using an identical strategy to that described previously for NCoR1 (11).…”

NCOR1 Orchestrates Transcriptional Landscapes and Effector Functions of CD4+ T Cells

“…The transcriptional changes in naïve CD4 + T cells caused by the absence of NCOR1 led to the dysregulation of pathways and hallmark gene sets associated with various cellular processes. NCOR1, via binding to LXR, has been described as a key regulator for repressing cholesterol homeostasis-related genes in hepatocytes (46). The observation that cholesterol homeostasis gene sets are enriched in NCOR1-deficient CD4 + T cells suggests that NCOR1 has also a similar repressive function in naïve CD4 + T cells.…”

Thyroid Hormone and Alcoholic Fatty Liver: The Developmental Input

“…An important TH target organ is the liver. TH prominently regulate pathways involved in lipid metabolism and cholesterol physiology (Astapova et al., , ), and many clinical parameters of liver function are dependent on systemic TH status (Johansson et al., ). TH receptors also cross talk with liver X receptors to regulate genes involved in lipid metabolism pathways (Hashimoto and Mori, ).…”