Nuclear Receptor CoRepressors, NCOR1 and SMRT, are required for maintaining systemic metabolic homeostasis

Abstract

Objective The nuclear receptor corepressor 1 (NCOR1) and the silencing mediator of retinoic acid and thyroid hormone (SMRT, also known as NCOR2) play critical and specific roles in nuclear receptor action. NCOR1, both in vitro and in vivo specifically regulates thyroid hormone (TH) action in the context of individual organs such as the liver, and systemically in the context of the hypothalamic-pituitary-thyroid (HPT) axis. In contrast, selective deletion of SMRT in the liver or globally has shown that it plays very little role in TH signaling. However, both NCOR1 and SMRT have some overlapping roles in hepatic metabolism and lipogenesis. Here, we determine the roles of NCOR1 and SMRT in global physiologic function and find if SMRT could play a compensatory role in the regulation of TH action, globally. Methods We used a postnatal deletion strategy to disrupt both NCOR1 and SMRT together in all tissues at 8–9 weeks of age in male and female mice. This was performed using a tamoxifen-inducible Cre recombinase (UBC-Cre-ERT2) to KO (knockout) NCOR1, SMRT, or NCOR1 and SMRT together. We used the same strategy to KO HDAC3 in male and female mice of the same age. Metabolic parameters, gene expression, and thyroid function tests were analyzed. Results Surprisingly, adult mice that acquired NCOR1 and SMRT deletion rapidly became hypoglycemic and hypothermic and perished within ten days of deletion of both corepressors. Postnatal deletion of either NCOR1 or SMRT had no impact on mortality. NCOR1/SMRT KO mice rapidly developed hepatosteatosis and mild elevations in liver function tests. Additionally, alterations in lipogenesis, beta oxidation, along with hepatic triglyceride and glycogen levels suggested defects in hepatic metabolism. The intestinal function was intact in the NCOR1/SMRT knockout (KO) mice. The KO of HDAC3 resulted in a distinct phenotype from the NCOR1/SMRT KO mice, whereas none of the HDAC3 KO mice succumbed after tamoxifen injection. Conclusions The KO of NCOR1 and SMRT rapidly leads to significant metabolic abnormalities that do not survive – including hypoglycemia, hypothermia, and weight loss. Hepatosteatosis rapidly developed along with alterations in hepatic metabolism suggesting a contribution to the dramatic phenotype from liver injury. Glucose production and absorption were intact in NCOR1/SMRT KO mice, demonstrating a multifactorial process leading to their demise. HDAC3 KO mice have a distinct phenotype from the NCOR1/SMRT KO mice—which implies that NCOR1/SMRT together regulate a critical pathway that is required for survival in adulthood and is separate from HDAC3.

Novel hydroxamic acid derivative induces apoptosis and constrains autophagy in leukemic cells

“…These include the control of cell proliferation, apoptosis, DNA replication fork stability, and genomic integrity [31,49–55]. Intriguingly, a full-body knockout of HDAC3 was not lethal in mice [56]. These data together with CRISPR-Cas9 screening data from a panel of myeloid and lymphoid cancer cell lines suggest that HDAC3 is a particular vulnerability of blood cancer cells and that future research on HDACi should focus on agents with strong activity against HDAC3.…”

Molecular Signature Expands the Landscape of Driver Negative Thyroid Cancers

“…In addition to its role in cell cycle regulation, NCOR1 was identified as a central transcriptional repressor check point of genes involved in inflammation [58]. NCOR1 was also involved in regulation of mitochondrial function and ROS generation [52] and required to maintain systemic metabolic homeostasis in vivo [59]. Its alteration has also been associated with enhanced tumor immunogenicity and higher TMB in patients with bladder cancer.…”

Transcriptome Sequencing Analysis of Sex-Related Genes in the Gonads of Mytilus unguiculatus

“…The duplication and divergence of the nuclear receptor co-repressor (NCoR) gene during vertebrate evolution has resulted in NCoR1 (also known as NCoR) and NCoR2 (also known as SMRT), which have distinct molecular properties and mediate different biological functions [86][87][88][89][90][91][92]. NCoR1 and NCoR2 were initially recognized as transcriptional corepressors that interact with unliganded thyroid and retinoid receptors [93,94].…”