The polyol pathway is a crucial glucose sensor in Drosophila
The polyol pathway is a crucial glucose sensor in Drosophila
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DOI：
10.1101/2020.03.16.993170
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发表时间：
2020-03
期刊：
影响因子：
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通讯作者：
Hiroko Sano;A. Nakamura;Mariko Yamane;H. Niwa;Takashi Nishimura;M. Kojima
中科院分区：
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作者：
Hiroko Sano;A. Nakamura;Mariko Yamane;H. Niwa;Takashi Nishimura;M. Kojima
动物的主要营养来源是葡萄糖，它能诱导改变新陈代谢的转录反应。这种代谢适应应该适当地与摄入的葡萄糖水平相适应，而解耦会导致人类的代谢疾病。然而，将循环葡萄糖水平传递给转录机制的关键传感器代谢物的身份仍然难以捉摸。本研究表明，通过山梨醇将葡萄糖转化为果糖的多元醇途径是激活主要代谢调节剂Mondo （MondoA/ChREBP的果蝇同源物）所必需的。我们证明，在正常营养条件下，多元醇途径代谢物促进Mondo的核定位并引起代谢基因表达的全局变化。尽管糖酵解和戊糖磷酸途径完整，但多元醇途径突变体阻断了Mondo和Mondo介导的基因表达的核定位。我们的研究结果揭示了这一途径的正常生理功能，并为高果糖饮食对人类健康的不利影响提供了新的视角。
A major nutrient source for animals is glucose, which induces transcriptional responses that shift metabolism. Such metabolic adaptation should be appropriately scaled to the ingested glucose levels, and decoupling causes human metabolic diseases. However, the identity of the crucial sensor metabolite(s) that transmit circulating glucose levels to the transcriptional machinery remains elusive. Here we show that the polyol pathway, which converts glucose to fructose via sorbitol, is required for activation of the master metabolic regulator Mondo, the Drosophila homologue of MondoA/ChREBP. We demonstrate that under normal nutritional conditions polyol pathway metabolites promote Mondo’s nuclear localization and cause global changes in metabolic gene expression. Polyol pathway mutants block nuclear localization of Mondo and Mondo-mediated gene expression despite intact glycolytic and pentose phosphate pathways. Our results uncover the normal physiological function of this pathway and cast a new light on the adverse effects of high fructose diets in human health.