A phosphorylation-deficient mutant of retinoid X receptor α at Thr 167 alters fasting response and energy metabolism in mice.
A phosphorylation-deficient mutant of retinoid X receptor α at Thr 167 alters fasting response and energy metabolism in mice.
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类维生素A X 受体α 在Thr 167 处的磷酸化缺陷突变体改变了小鼠的禁食反应和能量代谢。
DOI：
10.1038/s41374-019-0266-1
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发表时间：
2019
期刊：
影响因子：
--
通讯作者：
Negishi,Masahiko
中科院分区：
文献类型：
--
作者：
Sueyoshi,Tatsuya;Sakuma,Tsutomu;Shindo,Sawako;Fashe,Muluneh;Kanayama,Tomohiko;Ray,Manas;Moore,Rick;Negishi,Masahiko
视黄醇X受体α (RXRα)在dna结合域的苏氨酸162位点（人类）和苏氨酸167位点（小鼠）有一个保守的磷酸化基序。在这里，我们产生了RXRα敲入小鼠（RXRα t167a），携带Thr 167到丙氨酸的单一突变，并检查了Thr 167在脂肪、肌肉和肝脏组织中调节能量代谢的作用。RxrαT167Amice下调葡萄糖转化为脂肪酸的代谢途径，如白色脂肪组织（WAT）中的乙酰辅酶a羧化酶和肌肉中的ATP柠檬酸裂解酶。他们还减少了WAT中脂肪酸分解代谢和甘油三酯合成相关基因的表达，并控制了肌肉中肾上腺素能受体β1等热因子。相反，与脂肪酸相关的肝糖异生途径和合成途径不受这种突变的影响。脂肪组织中受Thr 167突变影响的多个基因的表达对合成RXR激动剂LG100268有明显的反应。因此，突变小鼠脂肪中基因表达的改变可能是RXRα Thr 167突变的直接影响，也可能是该突变的一些继发性影响。与RXRα野生型小鼠相比，RXRα t167在饲养期间血糖水平保持正常。然而，RxrαT167Amice表现出空腹后血糖水平下降的减弱。这种衰减与WAT中脂质代谢的下调相关，并与RXRα在Thr 167位点的磷酸化有关。因此，Thr 167使RXRα能够协调这三个器官来调节能量代谢和维持葡萄糖稳态。
Retinoid X receptor α (RXRα) has a conserved phosphorylation motif at threonine 162 (humans) and threonine 167 (mice) within the DNA-binding domain. Here we have generated RXRα knock-in mice (RxrαT167A) bearing a single mutation of Thr 167 to alanine and examined the roles of Thr 167 in the regulation of energy metabolism within adipose, muscle, and liver tissues.RxrαT167Amice exhibited down-regulation of metabolic pathways converting glucose to fatty acids, such as acetyl-CoA carboxylase in the white adipose tissue (WAT) and ATP citrate lyase in the muscle. They also reduced gene expression for genes related to fatty acid catabolism and triglyceride synthesis in WAT and controlled heat factors such as adrenergic receptor β1 in muscles. In contrast, hepatic gluconeogenic pathways and synthetic pathways related to fatty acids remained unaffected by this mutation. Expression of multiple genes that were affected by the Thr 167 mutation in adipose tissue exhibited clear response to LG100268, a synthetic RXR agonist. Thus, the altered gene expression in mutant mice adipose appeared to be a direct effect of RXRα Thr 167 mutation and by some secondary effect of the mutation. Blood glucose levels remained normal inRxrαT167Aduring feeding, as observed with RXRα wild-type mice. However,RxrαT167Amice exhibited an attenuated decrease of blood glucose levels that occurred after fasting. This attenuation correlated with a concomitant down-regulation of lipid metabolism in WAT and was associated with RXRα phosphorylation at Thr 167. Thus, Thr 167 enabled RXRα to coordinate these three organs for regulation of energy metabolism and maintenance of glucose homeostasis.
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DOI：
--
发表时间：
1980
期刊：
影响因子：
--
作者：
H. Winick
通讯作者：
H. Winick
通过实时 X 射线衍射监测水合卵磷脂主要相变的动力学。
影响因子：
3.4
作者：
Caffrey,M;Bilderback,DH
通讯作者：
Bilderback,DH
DOI：
--
发表时间：
1978
期刊：
Biochimica et Biophysica Acta
影响因子：
--
作者：
E. Luna;H. Mcconnell
通讯作者：
H. Mcconnell
DOI：
10.1016/0167-5087(83)91173-0
发表时间：
1983-01-01
期刊：
NUCLEAR INSTRUMENTS & METHODS IN PHYSICS RESEARCH
影响因子：
--
作者：
CAFFREY, M;BILDERBACK, DH
通讯作者：
BILDERBACK, DH
自发进行囊泡-囊泡和囊泡-细胞转移的放射性碘化磷脂类似物的合成和性质。
影响因子：
2.9
作者：
Schroit,AJ;Madsen,JW
通讯作者：
Madsen,JW