Nuclear Receptor CoRepressors, NCOR1 and SMRT, are required for maintaining systemic metabolic homeostasis.
Nuclear Receptor CoRepressors, NCOR1 and SMRT, are required for maintaining systemic metabolic homeostasis.
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DOI：
10.1016/j.molmet.2021.101315
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发表时间：
2021-11
影响因子：
8.1
通讯作者：
Hollenberg AN
中科院分区：
文献类型：
--
作者：
Ritter MJ;Amano I;Imai N;Soares De Oliveira L;Vella KR;Hollenberg AN
核受体辅阻遏物1（NCOR 1）和视黄酸和甲状腺激素的沉默介导物（SMRT，也称为NCOR 2）在核受体作用中起关键和特异性作用。NCOR 1在体外和体内特异性调节甲状腺激素（TH）在单个器官（如肝脏）中的作用，以及在下丘脑-垂体-甲状腺（HPT）轴中的全身作用。相比之下，在肝脏或全局中选择性缺失SMRT表明其在TH信号传导中起非常小的作用。然而，NCOR 1和SMRT在肝脏代谢和脂肪生成中具有一些重叠的作用。在这里，我们确定了NCOR 1和SMRT在全球生理功能中的作用，并发现SMRT是否可以在TH作用的调节中发挥补偿作用。我们使用出生后删除策略在8-9周龄的雄性和雌性小鼠的所有组织中同时破坏NCOR 1和SMRT。这是使用他莫昔芬诱导型Cre重组酶（UBC-Cre-ERT 2）来KO（敲除）NCOR 1、SMRT或NCOR 1和SMRT一起进行的。我们使用相同的策略在相同年龄的雄性和雌性小鼠中KO HDAC 3。分析代谢参数、基因表达和甲状腺功能试验。令人惊讶的是，获得NCOR 1和SMRT缺失的成年小鼠迅速变得低血糖和低体温，并在两种辅阻遏物缺失后10天内死亡。出生后缺失NCOR 1或SMRT对死亡率没有影响。NCOR 1/SMRT KO小鼠迅速发生脂肪肝，肝功能检查轻度升高。此外，脂肪生成、β氧化以及肝脏甘油三酯和糖原水平的变化沿着，提示肝脏代谢缺陷。在NCOR 1/SMRT敲除（KO）小鼠中肠功能是完整的。HDAC 3的KO导致与NCOR 1/SMRT KO小鼠不同的表型，而HDAC 3 KO小鼠在他莫昔芬注射后均未死亡。NCOR 1和SMRT的KO迅速导致无法生存的严重代谢异常-包括低血糖、体温过低和体重减轻。肝脂肪变性迅速发展沿着肝代谢的改变，表明肝损伤对引人注目的表型有贡献。NCOR 1/SMRT KO小鼠的葡萄糖产生和吸收是完整的，表明导致其死亡的多因素过程。HDAC 3 KO小鼠具有与NCOR 1/SMRT KO小鼠不同的表型，这意味着NCOR 1/SMRT共同调节成年期生存所需的关键途径，并且与HDAC 3分开。辅阻遏物NCoR 1和SMRT的敲除是快速致死的。观察到的代谢异常包括低血糖和体温过低。尽管低血糖，肝脏葡萄糖产生和肠吸收是完整的。NCoR 1/SMRT缺失的致死作用不依赖于HDAC 3。
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. 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. 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. 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. The knockout of corepressors NCoR1 and SMRT is rapidly lethal. Metabolic abnormalities observed include hypoglycemia and hypothermia. Hepatic glucose production and intestinal absorption is intact despite hypoglycemia. The lethal action of NCoR1/SMRT deletion is independent of HDAC3.
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DOI：
10.1006/bbrc.1997.7124
发表时间：
1997-08-28
影响因子：
3.1
作者：
Feil, R;Wagner, J;Chambon, P
通讯作者：
Chambon, P
DOI：
10.1126/science.1198125
发表时间：
2011-03-11
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Feng D;Liu T;Sun Z;Bugge A;Mullican SE;Alenghat T;Liu XS;Lazar MA
通讯作者：
Lazar MA
影响因子：
64.5
作者：
Jepsen, K;Hermanson, O;Rosenfeld, MG
通讯作者：
Rosenfeld, MG
影响因子：
--
作者：
Astapova, Inna;Vella, Kristen R.;Hollenberg, Anthony N.
通讯作者：
Hollenberg, Anthony N.
影响因子：
29
作者：
Badman, Michael K.;Pissios, Pavlos;Maratos-Flier, Eleftheria
通讯作者：
Maratos-Flier, Eleftheria