Nuclear hormone receptor NHR-49 controls fat consumption and fatty acid composition in C. elegans.
Nuclear hormone receptor NHR-49 controls fat consumption and fatty acid composition in C. elegans.
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DOI：
10.1371/journal.pbio.0030053
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发表时间：
2005-02
期刊：
影响因子：
9.8
通讯作者：
Yamamoto KR
中科院分区：
文献类型：
--
作者：
Van Gilst MR;Hadjivassiliou H;Jolly A;Yamamoto KR
哺乳动物核激素受体（NHRs），如肝X受体、法尼醇X受体和过氧化物酶体增殖物激活受体（PPARs），精确地控制能量代谢。因此，这些受体是治疗代谢疾病，包括糖尿病和肥胖症的重要靶标。然而，由于缺乏遗传学上易于处理的实验系统，对NHR脂肪调控网络的深入了解受到限制。在这里，我们表明，删除秀丽隐杆线虫NHR基因nhr-49产生的蠕虫脂肪含量升高，寿命缩短。采用定量RT-PCR筛选，我们发现nhr-49影响了13个参与能量代谢的基因的表达。事实上，nhr-49是脂肪使用的关键调节剂，调节控制脂肪消耗和维持脂肪酸饱和度正常平衡的途径。我们发现nhr-49基因敲除的两种表型与不同的途径相关，并且是可分离的：高脂肪表型是由于脂肪酸β-氧化酶表达减少，而成年寿命缩短是由于硬脂酰辅酶A去饱和酶表达受损。尽管其与哺乳动物肝细胞核因子4受体的序列关系，nhr-49的生物活性是最相似的哺乳动物PPARs，这意味着进化保守的作用，NHRs在调节脂肪的消耗和组成。我们在C.线虫提供了新的见解如何NHR调节网络协调管理脂肪代谢。秀丽隐杆线虫基因nhr- 49的缺失会导致蠕虫积累脂肪并过早死亡;但这两种表型是不同且可分离的途径的结果
Mammalian nuclear hormone receptors (NHRs), such as liver X receptor, farnesoid X receptor, and peroxisome proliferator-activated receptors (PPARs), precisely control energy metabolism. Consequently, these receptors are important targets for the treatment of metabolic diseases, including diabetes and obesity. A thorough understanding of NHR fat regulatory networks has been limited, however, by a lack of genetically tractable experimental systems. Here we show that deletion of the Caenorhabditis elegans NHR gene nhr-49 yielded worms with elevated fat content and shortened life span. Employing a quantitative RT-PCR screen, we found that nhr-49 influenced the expression of 13 genes involved in energy metabolism. Indeed, nhr-49 served as a key regulator of fat usage, modulating pathways that control the consumption of fat and maintain a normal balance of fatty acid saturation. We found that the two phenotypes of the nhr-49 knockout were linked to distinct pathways and were separable: The high-fat phenotype was due to reduced expression of enzymes in fatty acid β-oxidation, and the shortened adult life span resulted from impaired expression of a stearoyl-CoA desaturase. Despite its sequence relationship with the mammalian hepatocyte nuclear factor 4 receptor, the biological activities of nhr-49 were most similar to those of the mammalian PPARs, implying an evolutionarily conserved role for NHRs in modulating fat consumption and composition. Our findings in C. elegans provide novel insights into how NHR regulatory networks are coordinated to govern fat metabolism. Deletion of the Caenorhabditis elegans gene nhr- 49 causes worms to accumulate fat and die younger; but these two phenotypes are a result of distinct and separable pathways