Polysome profiling in liver identifies dynamic regulation of endoplasmic reticulum translatome by obesity and fasting.
Polysome profiling in liver identifies dynamic regulation of endoplasmic reticulum translatome by obesity and fasting.
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DOI：
10.1371/journal.pgen.1002902
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发表时间：
2012-08
期刊：
影响因子：
4.5
通讯作者：
Hotamisligil GS
中科院分区：
文献类型：
--
作者：
Fu S;Fan J;Blanco J;Gimenez-Cassina A;Danial NN;Watkins SM;Hotamisligil GS
肥胖相关的代谢并发症通常被认为是由碳水化合物和脂质代谢异常引起的，而蛋白质代谢的状况尚未得到很好的研究。在这里，我们进行了比较多体和相关转录谱分析，以研究肥胖和营养剥夺条件下小鼠肝脏内质网（ER）相关蛋白合成的动力学和功能意义。我们发现肥胖小鼠肝脏的内质网显示出蛋白质合成的普遍减少，对多体结合转录本的综合分析显示，肥胖翻译体中蛋白质合成机制、线粒体成分和胆汁酸代谢的广泛下调。营养可利用性在瘦和肥胖小鼠肝脏内质网翻译组的重塑中也起着重要但独特的作用。肥胖小鼠的禁食部分逆转了瘦小鼠和肥胖非禁食对照组之间的整体翻译差异，而瘦小鼠的禁食模仿了肥胖发展引起的许多翻译变化。这种调控最明显的例子是参与胆汁酸代谢的分子Cyp7b1和Slco1a1的减少。外源表达任一基因均可显著降低血糖水平，改善肝脏脂肪变性，但也可引起胆汁淤滞，表明胆汁酸在调节代谢和健康方面发挥着微妙的平衡作用。总之，我们的工作定义了肥胖和营养可用性对肝翻译组的动态调节，并确定了胆汁酸代谢在肥胖相关代谢异常发病机制中的新作用。包括肥胖和相关代谢异常在内的慢性疾病已成为世界范围内人类健康的最大威胁。代谢器官和细胞器如何适应营养波动，或不能这样做，仍然不完全清楚。为了探索这些问题，我们开发了一个新的平台来探索肝脏的翻译反应，肝脏是代谢稳态的关键器官。在这个翻译平台上，我们整合了多聚体分析和多聚体相关mrna的全局分析，以系统地量化肥胖和禁食期间每个转录本上的蛋白质合成。我们的分析首次证明，肥胖肝脏中的蛋白质合成逐渐受到抑制，肥胖肝脏的整体翻译组谱与禁食瘦小鼠明显相似，特别是在线粒体功能和胆汁代谢方面。我们还研究了这些改变的生理影响，并得出结论，肥胖肝脏中异常的胆酸代谢代表了导致高血糖和持续体重增加的新机制。总之，我们的工作揭示了异常的翻译调节是肥胖的一个新方面，可能影响代谢性疾病治疗的未来方向，我们相信翻译组分析代表了一种揭示调节细胞功能和疾病病理的复杂机制的新方法。
Obesity-associated metabolic complications are generally considered to emerge from abnormalities in carbohydrate and lipid metabolism, whereas the status of protein metabolism is not well studied. Here, we performed comparative polysome and associated transcriptional profiling analyses to study the dynamics and functional implications of endoplasmic reticulum (ER)–associated protein synthesis in the mouse liver under conditions of obesity and nutrient deprivation. We discovered that ER from livers of obese mice exhibits a general reduction in protein synthesis, and comprehensive analysis of polysome-bound transcripts revealed extensive down-regulation of protein synthesis machinery, mitochondrial components, and bile acid metabolism in the obese translatome. Nutrient availability also plays an important but distinct role in remodeling the hepatic ER translatome in lean and obese mice. Fasting in obese mice partially reversed the overall translatomic differences between lean and obese nonfasted controls, whereas fasting of the lean mice mimicked many of the translatomic changes induced by the development of obesity. The strongest examples of such regulations were the reduction in Cyp7b1 and Slco1a1, molecules involved in bile acid metabolism. Exogenous expression of either gene significantly lowered plasma glucose levels, improved hepatic steatosis, but also caused cholestasis, indicating the fine balance bile acids play in regulating metabolism and health. Together, our work defines dynamic regulation of the liver translatome by obesity and nutrient availability, and it identifies a novel role for bile acid metabolism in the pathogenesis of metabolic abnormalities associated with obesity. Chronic diseases including obesity and associated metabolic abnormalities have become the greatest threat to human health worldwide. How metabolic organs and organelles adapt to nutritional fluctuations, or fail to do so, remains incompletely understood. To explore these issues, we developed a new platform to explore translational responses in the liver, a critical organ for metabolic homeostasis. In this translatomic platform, we integrated polysome profiling and global analysis of polysome-associated mRNAs to systematically quantify protein synthesis on each transcript in obesity and during fasting. Our analysis demonstrated for the first time that protein synthesis is progressively suppressed in the obese liver and that the overall translatome profile of obese liver markedly resembles that of fasting lean mice, particularly in mitochondrial function and bile metabolism. We also examined the physiological impact of some of these alterations and concluded that aberrant bile acid metabolism in the obese liver represents a novel mechanism contributing to hyperglycemia and continuous weight gain. Together, our work reveals abnormal translational regulation as a novel aspect of obesity that could impact future directions in metabolic disease treatment, and we believe translatome profiling represents a new approach to unravel complex mechanisms regulating cellular function and disease pathology.
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影响因子：
56.9
作者：
FLECK, A;SHEPHERD, J;MUNRO, HN
通讯作者：
MUNRO, HN
影响因子：
64.8
作者：
Fu, Suneng;Yang, Ling;Li, Ping;Hofmann, Oliver;Dicker, Lee;Hide, Winston;Lin, Xihong;Watkins, Steven M.;Ivanov, Alexander R.;Hotamisligil, Goekhan S.
通讯作者：
Hotamisligil, Goekhan S.
影响因子：
7.7
作者：
Gregor MF;Yang L;Fabbrini E;Mohammed BS;Eagon JC;Hotamisligil GS;Klein S
通讯作者：
Klein S
影响因子：
7.7
作者：
Harding, HP;Ron, D
通讯作者：
Ron, D
影响因子：
14.8
作者：
Huang, Da Wei;Sherman, Brad T.;Lempicki, Richard A.
通讯作者：
Lempicki, Richard A.