Pharmacogenetics section, Reproductive and Developmental Biology Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC, 27709, USA.
Knockout Mouse Core, National Institute of Environmental Health Sciences, National Institutes of Health Research, Triangle Park, NC, 27709, USA.
Lab Invest. 2019 Oct;99(10):1470-1483. doi: 10.1038/s41374-019-0266-1. Epub 2019 May 31.
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 (Rxrα) 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. Rxrα mice 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 in Rxrα during feeding, as observed with RXRα wild-type mice. However, Rxrα mice 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.
视黄酸 X 受体 α（RXRα）在 DNA 结合域内的苏氨酸 162（人类）和苏氨酸 167（小鼠）处具有保守的磷酸化模体。在这里，我们生成了携带 Thr 167 突变为丙氨酸的 RXRα 敲入小鼠（Rxrα），并检查了 Thr 167 突变在调节脂肪、肌肉和肝脏组织中的能量代谢中的作用。Rxrα 小鼠表现出将葡萄糖转化为脂肪酸的代谢途径下调，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。它们还减少了 WAT 中与脂肪酸分解和甘油三酯合成相关的基因以及肌肉中肾上腺素能受体 β1 等热因素的基因表达。相比之下，肝糖异生途径和与脂肪酸相关的合成途径不受这种突变的影响。在脂肪组织中受 Thr 167 突变影响的多个基因的表达对合成 RXR 激动剂 LG100268 表现出明显的反应。因此，突变小鼠脂肪中受 Thr 167 突变影响的基因表达似乎是 RXRα Thr 167 突变的直接作用，并且是突变的一些次要作用。在喂食期间，Rxrα 的血糖水平保持正常，与 RXRα 野生型小鼠相同。然而，Rxrα 小鼠表现出空腹后血糖水平下降的减弱。这种衰减与 WAT 中脂质代谢的同时下调相关，并且与 RXRα 在 Thr 167 处的磷酸化相关。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。
