Coordinate regulation of lipid metabolism by novel nuclear receptor partnerships.
Coordinate regulation of lipid metabolism by novel nuclear receptor partnerships.
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DOI：
10.1371/journal.pgen.1002645
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发表时间：
2012
期刊：
影响因子：
4.5
通讯作者：
Van Gilst MR
中科院分区：
文献类型：
--
作者：
Pathare PP;Lin A;Bornfeldt KE;Taubert S;Van Gilst MR
哺乳动物核受体广泛影响代谢适应性，并成为开发治疗心血管疾病、肥胖和糖尿病药物的热门靶点。然而，控制脂质代谢的分子机制和调控途径仍然知之甚少。我们之前发现秀丽隐杆线虫核激素受体NHR-49调节脂肪酸β -氧化和去饱和途径中的多个基因。在这里，我们确定了额外的NHR-49靶点，包括鞘脂加工和脂质重塑基因。我们发现NHR-49通过与至少两个其他不同的核受体合作来调节其靶基因的不同亚群。基因表达谱表明，NHR-49与NHR-66共同调控鞘脂和脂质重塑基因，与NHR-80共同调控脂肪酸去饱和相关基因。此外，虽然我们没有发现NHR-49和NHR-13之间的直接物理相互作用，但我们证明NHR-13也调节参与去饱和酶途径的基因。与此一致的是，这些受体的基因敲除显示出一系列反映其基因表达谱的表型。我们的数据表明，NHR-80和NHR-13对NHR-49调节的脂肪酸去饱和酶基因的调节有助于NHR-49缺失突变动物的寿命缩短表型。此外，我们观察到nhr-49动物的线粒体形态和功能显著改变，这种表型的不同方面可归因于NHR-66和nhr- 80介导的活性缺陷。鉴定NHR-49的结合伙伴有助于精细解剖其在秀丽隐杆线虫中的无数调节作用。我们的发现也为哺乳动物脂感核受体HNF4α和PPARα的功能提供了进一步的见解。哺乳动物核受体是治疗一系列心血管疾病和肥胖的积极靶点。然而，有效的药物开发仍然依赖于对不同核受体在体内如何介导其不同生理作用的更详尽的描述。以秀丽隐杆线虫（Caenorhabditis elegans）为研究对象，采用遗传与生化相结合的方法，对核受体NHR-49的基因网络进行了表征，并探讨了不同靶基因对其生理的影响。这项工作已经确定了以前不知道由NHR-49调节的基因和途径。重要的是，我们确定了NHR-49辅助因子NHR-66和NHR-80，它们调节NHR-49靶基因的特定亚群，并有助于NHR-49动物的不同表型。综上所述，我们在秀丽隐杆线虫中的发现不仅为核受体转录网络如何协调调节脂质代谢提供了新的见解，而且揭示了它们对动物生理不同方面的影响的广度。
Mammalian nuclear receptors broadly influence metabolic fitness and serve as popular targets for developing drugs to treat cardiovascular disease, obesity, and diabetes. However, the molecular mechanisms and regulatory pathways that govern lipid metabolism remain poorly understood. We previously found that the Caenorhabditis elegans nuclear hormone receptor NHR-49 regulates multiple genes in the fatty acid beta-oxidation and desaturation pathways. Here, we identify additional NHR-49 targets that include sphingolipid processing and lipid remodeling genes. We show that NHR-49 regulates distinct subsets of its target genes by partnering with at least two other distinct nuclear receptors. Gene expression profiles suggest that NHR-49 partners with NHR-66 to regulate sphingolipid and lipid remodeling genes and with NHR-80 to regulate genes involved in fatty acid desaturation. In addition, although we did not detect a direct physical interaction between NHR-49 and NHR-13, we demonstrate that NHR-13 also regulates genes involved in the desaturase pathway. Consistent with this, gene knockouts of these receptors display a host of phenotypes that reflect their gene expression profile. Our data suggest that NHR-80 and NHR-13's modulation of NHR-49 regulated fatty acid desaturase genes contribute to the shortened lifespan phenotype of nhr-49 deletion mutant animals. In addition, we observed that nhr-49 animals had significantly altered mitochondrial morphology and function, and that distinct aspects of this phenotype can be ascribed to defects in NHR-66– and NHR-80–mediated activities. Identification of NHR-49's binding partners facilitates a fine-scale dissection of its myriad regulatory roles in C. elegans. Our findings also provide further insights into the functions of the mammalian lipid-sensing nuclear receptors HNF4α and PPARα. Mammalian nuclear receptors are actively targeted for treatment of a range of cardiovascular diseases and obesity. However, effective drug development still depends on a more exhaustive characterization of how different nuclear receptors mediate their different physiological effects in vivo. Taking advantage of the roundworm Caenorhabditis elegans, we used a combination of genetic and biochemical approaches to characterize the gene network of the nuclear receptor NHR-49 and to explore the impact of the different target genes on physiology. This work has identified genes and pathways that were not previously known to be regulated by NHR-49. Importantly, we identified NHR-49 co-factors NHR-66 and NHR-80 that regulate specific subsets of NHR-49 target genes and that contribute to distinct phenotypes of nhr-49 animals. Taken together, our findings in C. elegans not only provide novel insights into how nuclear receptor transcriptional networks coordinate to regulate lipid metabolism, but also reveal the breadth of their influence on different aspects of animal physiology.
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