PXR ablation alleviates diet-induced and genetic obesity and insulin resistance in mice.
PXR ablation alleviates diet-induced and genetic obesity and insulin resistance in mice.
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作者：
He J;Gao J;Xu M;Ren S;Stefanovic-Racic M;O'Doherty RM;Xie W
孕烷X受体（PXR）及其姊妹受体构成雄烷受体（CAR）最初被定性为调节药物代谢的异种受体。在这项研究中，我们发现了PXR在肥胖和2型糖尿病中意想不到的内源性作用。PXR消融术抑制高脂肪饮食（HFD）诱导的肥胖、肝脂肪变性和胰岛素抵抗，这与氧气消耗增加、线粒体β氧化增加、肝脏脂肪生成和炎症抑制以及胰岛素信号敏化有关。在一个独立的模型中，在ob/ob背景中引入PXR−/−等位基因也改善了身体组成并缓解了糖尿病表型。PXR缺乏的ob/ob小鼠在正糖钳夹期间表现出氧气消耗和能量消耗增加，糖异生抑制和葡萄糖处置率增加。从机制上讲，PXR消融的代谢益处与抑制c-Jun nh2末端激酶激活和下调PXR新靶基因脂素-1有关。PXR消融的代谢益处与报道的CAR消融对糖尿病的影响相反。我们的研究结果可能有助于建立PXR作为一个新的治疗靶点，PXR拮抗剂可能用于预防和治疗肥胖和2型糖尿病。
The pregnane X receptor (PXR), along with its sister receptor constitutive androstane receptor (CAR), was initially characterized as a xenobiotic receptor that regulates drug metabolism. In this study, we have uncovered an unexpected endobiotic role of PXR in obesity and type 2 diabetes. PXR ablation inhibited high-fat diet (HFD)–induced obesity, hepatic steatosis, and insulin resistance, which were accounted for by increased oxygen consumption, increased mitochondrial β-oxidation, inhibition of hepatic lipogenesis and inflammation, and sensitization of insulin signaling. In an independent model, introducing the PXR−/− allele into the ob/ob background also improved body composition and relieved the diabetic phenotype. The ob/ob mice deficient of PXR showed increased oxygen consumption and energy expenditure, as well as inhibition of gluconeogenesis and increased rate of glucose disposal during euglycemic clamp. Mechanistically, the metabolic benefits of PXR ablation were associated with the inhibition of c-Jun NH2-terminal kinase activation and downregulation of lipin-1, a novel PXR target gene. The metabolic benefit of PXR ablation was opposite to the reported prodiabetic effect of CAR ablation. Our results may help to establish PXR as a novel therapeutic target, and PXR antagonists may be used for the prevention and treatment of obesity and type 2 diabetes.
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影响因子：
3.5
作者：
ALRUBEAAN, K;RYAN, EA
通讯作者：
RYAN, EA
DOI：
10.1093/ajhp/38.10.1508
发表时间：
1981-01-01
期刊：
AMERICAN JOURNAL OF HOSPITAL PHARMACY
影响因子：
--
作者：
CARTER, BL;SMALL, RE;STARKMAN, MT
通讯作者：
STARKMAN, MT
影响因子：
4.8
作者：
Gao, Jie;He, Jinhan;Xie, Wen
通讯作者：
Xie, Wen
影响因子：
3.9
作者：
Lindley, C;Hamilton, G;LeCluyse, EL
通讯作者：
LeCluyse, EL
影响因子：
7.7
作者：
Gao J;He J;Shi X;Stefanovic-Racic M;Xu M;O'Doherty RM;Garcia-Ocana A;Xie W
通讯作者：
Xie W