The orphan nuclear receptor, RORα, regulates gene expression that controls lipid metabolism -: Staggerer (sg/sg) mice are resistant to diet-induced obesity
The orphan nuclear receptor, RORα, regulates gene expression that controls lipid metabolism -: Staggerer (sg/sg) mice are resistant to diet-induced obesity
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DOI：
10.1074/jbc.m710526200
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发表时间：
2008-06-27
影响因子：
4.8
通讯作者：
Muscat, George E. O.
中科院分区：
文献类型：
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作者：
Lau, Patrick;Fitzsimmons, Rebecca L.;Muscat, George E. O.
纯合子交错小鼠（sg/sg）显示出视黄酸受体相关孤儿受体α（ROR α）表达减少和功能障碍。我们观察到sg/sg小鼠血清（和肝脏）甘油三酯和总胆固醇和高密度脂蛋白血清胆固醇降低。此外，sg/sg小鼠的特征在于减少的肥胖（与减少的脂肪垫质量和脂肪细胞大小相关）。基于胆固醇的表达谱表明，sg/sg小鼠的血脂异常与SREBP-1c和胆固醇反向转运蛋白ABCA 1和ABCG 1的肝脏表达减少有关。这与血清脂质降低一致。其分子机制不涉及LXR和/或ChREBP的异常表达。然而，ChIP和转染分析显示，ROR α被募集到SREBP-1c启动子并调节其活性。此外，sg/sg小鼠中的瘦表型的特征还在于来自sg/sg小鼠的肝脏和白色和棕色脂肪组织中PGC-1 α、PGC-1 α和lipin 1 mRNA的表达显著增加。此外，我们观察到棕色脂肪组织中β 2-肾上腺素能受体mRNA显著增加4倍。最后，功能失调的ROR α表达可以防止饮食诱导的肥胖。经过10周的高脂饮食后，野生型小鼠（但sg/sg小鼠除外）的体重增加了20%，肝脏甘油三酯增加，以及显着的白色和棕色脂肪组织积聚。总之，代谢组织中基因表达（调节脂质稳态）的这些变化与sg/sg小鼠的肥胖减少和对饮食诱导的肥胖的抵抗有关，尽管有过食。总之，我们认为这种孤儿核受体是脂肪积累的关键调节剂，并且选择性ROR调节剂可能在肥胖症的治疗中具有实用性。
Homozygous staggerer mice (sg/sg) display decreased and dysfunctional retinoic acid receptor-related orphan receptor alpha (ROR alpha) expression. We observed decreases in serum (and liver) triglycerides and total and high density lipoprotein serum cholesterol in sg/sg mice. Moreover, the sg/sg mice were characterized by reduced adiposity (associated with decreased fat pad mass and adipocyte size). Candidate-based expression profiling demonstrated that the dyslipidemia in sg/sg mice is associated with decreased hepatic expression of SREBP-1c, and the reverse cholesterol transporters, ABCA1 and ABCG1. This is consistent with the reduced serum lipids. The molecular mechanism did not involve aberrant expression of LXR and/or ChREBP. However, ChIP and transfection analyses revealed that ROR alpha is recruited to and regulates the activity of the SREBP-1c promoter. Furthermore, the lean phenotype in sg/sg mice is also characterized by significantly increased expression of PGC-1 alpha, PGC-1 alpha, and lipin1 mRNA in liver and white and brown adipose tissue from sg/sg mice. In addition, we observed a significant 4-fold increase in beta(2)-adrenergic receptor mRNA in brown adipose tissue. Finally, dysfunctional ROR alpha expression protects against diet-induced obesity. Following a 10-week high fat diet, wild-type but not sg/sg mice exhibited a similar to 20% weight gain, increased hepatic triglycerides, and notable white and brown adipose tissue accumulation. In summary, these changes in gene expression (that modulate lipid homeostasis) in metabolic tissues are involved in decreased adiposity and resistance to diet-induced obesity in the sg/sg mice, despite hyperphagia. In conclusion, we suggest this orphan nuclear receptor is a key modulator of fat accumulation and that selective ROR modulators may have utility in the treatment of obesity.