RORα controls hepatic lipid homeostasis via negative regulation of PPARγ transcriptional network.
RORα controls hepatic lipid homeostasis via negative regulation of PPARγ transcriptional network.
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DOI：
10.1038/s41467-017-00215-1
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发表时间：
2017-07-31
影响因子：
16.6
通讯作者：
Baek SH
中科院分区：
文献类型：
--
作者：
Kim K;Boo K;Yu YS;Oh SK;Kim H;Jeon Y;Bhin J;Hwang D;Kim KI;Lee JS;Im SS;Yoon SG;Kim IY;Seong JK;Lee H;Fang S;Baek SH
视黄酸受体相关孤儿受体-α (RORα) 是多种生物过程的重要调节因子，包括小脑发育、昼夜节律和癌症。在此，我们发现肝脏 RORα 通过负向调节介导肝脏脂质代谢的过氧化物酶体增殖物激活受体-γ (PPARγ) 的转录活性来控制脂质稳态。肝脏特异性 Rorα 缺陷小鼠在受到高脂肪饮食 (HFD) 挑战时会出现肝脂肪变性、肥胖和胰岛素抵抗。全球转录组分析表明，肝脏特异性删除 Rorα 会导致 PPARγ 信号传导失调，并增加肝脏葡萄糖和脂质代谢。 RORα 特异性结合组蛋白脱乙酰酶 3 (HDAC3) 并将其募集至 PPARγ 靶启动子，以抑制 PPARγ 的转录。 PPARγ 拮抗作用可恢复 HFD 喂养的肝脏特异性 Rorα 缺陷小鼠的代谢稳态。我们的数据表明 RORα 在肝脏脂质稳态的调节中具有关键作用。旨在调节 RORα 活性的治疗策略可能有益于代谢性疾病的治疗。肝脏脂肪变性的发生可能是由脂质代谢失调引起的，脂质代谢由包括 PPAR 家族在内的多种转录因子进行微调。这里 Kim 等人。研究表明核受体 RORα 通过与 HDAC3 相互作用并竞争脂肪生成基因的启动子来抑制 PPARγ 介导的转录活性。
The retinoic acid receptor-related orphan receptor-α (RORα) is an important regulator of various biological processes, including cerebellum development, circadian rhythm and cancer. Here, we show that hepatic RORα controls lipid homeostasis by negatively regulating transcriptional activity of peroxisome proliferators-activated receptor-γ (PPARγ) that mediates hepatic lipid metabolism. Liver-specific Rorα-deficient mice develop hepatic steatosis, obesity and insulin resistance when challenged with a high-fat diet (HFD). Global transcriptome analysis reveals that liver-specific deletion of Rorα leads to the dysregulation of PPARγ signaling and increases hepatic glucose and lipid metabolism. RORα specifically binds and recruits histone deacetylase 3 (HDAC3) to PPARγ target promoters for the transcriptional repression of PPARγ. PPARγ antagonism restores metabolic homeostasis in HFD-fed liver-specific Rorα deficient mice. Our data indicate that RORα has a pivotal role in the regulation of hepatic lipid homeostasis. Therapeutic strategies designed to modulate RORα activity may be beneficial for the treatment of metabolic disorders. Hepatic steatosis development may result from dysregulation of lipid metabolism, which is finely tuned by several transcription factors including the PPAR family. Here Kim et al. show that the nuclear receptor RORα inhibits PPARγ-mediated transcriptional activity by interacting with HDAC3 and competing for the promoters of lipogenic genes.
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影响因子：
15.9
作者：
Kahn, BB;Flier, JS
通讯作者：
Flier, JS
影响因子：
4.8
作者：
Lau, Patrick;Fitzsimmons, Rebecca L.;Muscat, George E. O.
通讯作者：
Muscat, George E. O.
DOI：
10.1073/pnas.0508647102
发表时间：
2005-11-29
影响因子：
11.1
作者：
Hwang, D;Rust, AG;Bolouri, H
通讯作者：
Bolouri, H
影响因子：
8.2
作者：
Lau, P.;Fitzsimmons, R. L.;Pearen, M. A.;Watt, M. J.;Muscat, G. E. O.
通讯作者：
Muscat, G. E. O.
影响因子：
64.5
作者：
Bookout, Angie L.;Jeong, Yangsik;Mangelsdorf, David J.
通讯作者：
Mangelsdorf, David J.