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

Abstract

c NCoR1 (nuclear receptor corepressor) and SMRT (silencing mediator of retinoid and thyroid hormone receptors; NCoR2) are well-recognized coregulators of nuclear receptor (NR) action. However, their unique roles in the regulation of thyroid hormone (TH) signaling in specific cell types have not been determined. To accomplish this we generated mice that lacked function of either NCoR1, SMRT, or both in the liver only and additionally a global SMRT knockout model. Despite both corepressors being present in the liver, deletion of SMRT in either euthyroid or hypothyroid animals had little effect on TH signaling. In contrast, disruption of NCoR1 action confirmed that NCoR1 is the principal mediator of TH sensitivity in vivo. Similarly, global disruption of SMRT, unlike the global disruption of NCoR1, did not affect TH levels. While SMRT played little role in TH-regulated pathways, when disrupted in combination with NCoR1, it greatly accentuated the synthesis and storage of hepatic lipid. Taken together, these data demonstrate that corepressor specificity exists in vivo and that NCoR1 is the principal regulator of TH action. However, both corepressors collaborate to control hepatic lipid content, which likely reflects their cooperative activity in regulating the action of multiple NRs including the TH receptor (TR).T hyroid hormone (TH) is one of the most important metabolic regulators in humans, and its actions in the liver include the regulation of cholesterol and lipid metabolism. Thyroxine (T4) is the major circulating form of thyroid hormone, and it is converted to its active form, triiodothyronine (T3), by a family of deiodinases (1). T3 regulates metabolic processes via thyroid hormone receptor (TR) isoforms that are expressed in all peripheral tissues, including liver. The TRs mediate target gene regulation by recruiting a constellation of coregulators that include corepressors (CoRs) and coactivators depending upon the presence of T3 (2). While classical models suggest that the corepressors are mainly recruited by the unliganded TR, the mechanisms by which T3 coordinates specific signaling in the liver both positively and negatively are still unknown (3). Indeed, recent work by our laboratory and others has demonstrated that the corepressors appear to play a critical role in mediating ligand sensitivity regardless of the concentration of ligand (4-7).The two principal corepressors that are suggested to be involved in mediating TH action are nuclear receptor corepressor 1 (NCoR1) and silencing mediator of retinoid and thyroid hormone receptors (SMRT) (4). They are highly homologous modular proteins and have three similar nuclear receptor (NR) interaction domains (NRIDs) at their C termini (8). Importantly, whole-body gene knockouts (KOs) of NCoR1 or SMRT result in embryonic lethality, but mutation or deletion of only the NRIDs allows for full development (6, 9, 10). In NCoR⌬ID mice, which express an altered NCoR1 allele that lacks the N3 and N2 NRIDs, there is evidence for increased thyroid hormone sensitivity...

Role of co-regulators in metabolic and transcriptional actions of thyroid hormone

“…Surprisingly, hepatocyte-specific deletion of Smrt revealed that SMRT alone, in contrast to NCoR, plays no role in the regulation of positive or negative TH targets or the lipogenic pathway in general (Shimizu et al 2015. At the same time, SMRT appears to be important for RAR signaling and regulation of RAR target genes (Shimizu et al 2015), confirming the in vitro data on preferential interactions between specific RIDs and NRs , Cohen et al 2000, Makowski et al 2003, Webb et al 2000.…”

“…At the same time, SMRT appears to be important for RAR signaling and regulation of RAR target genes (Shimizu et al 2015), confirming the in vitro data on preferential interactions between specific RIDs and NRs , Cohen et al 2000, Makowski et al 2003, Webb et al 2000. Interestingly, the combination of a hepatic SMRT knockout and L-NCoR∆ID expression demonstrated that SMRT works coordinately with NCoR to regulate lipid synthesis and sequestration, and the regulation of some of TH targets.…”

“…Hypothyroid Smrt mRID mice demonstrate significant derepression of some TH target genes in the liver and improvement of hypothyroidisminduced hypercholesterolemia, indicating that SMRT plays a role in repression of positive TR targets in the absence of hormone. This is contrary to what was seen in the liver-specific Smrt knockout (Shimizu et al 2015), and whether the differences are due to the whole-body vs liver-specific deletion or the ability of mutant SMRT mRID to still bind HDAC3 and other components of the repression machinery remains to be clarified.…”

“…Remarkably, the rise of TSH during hypothyroidism was also blunted in these animals, in contrast with Src1 knockout mice. While serum T 4 concentrations were slightly reduced in Smrt mRID mice on C57/BL6 background (Pei et al 2011), postnatal global ablation of SMRT had no effect on circulating T 4 levels or TSH subunit expression in the pituitary, confirming that similarly to the liver, specificity of co-repressor recruitment exists in HPT axis, and NCoR is the preferred TR co-repressor (Shimizu et al 2015). A somewhat different phenotype related to dysregulation of HPT axis was found in N-DADm mice (You et al 2010).…”

“…A conditional Smrt knockout allele has also been generated, and liver-specific and adult whole-body Smrt knockout models have been published (Shimizu et al 2015.…”