Zeigerer Anja, Bogorad Roman L, Sharma Kirti, Gilleron Jerome, Seifert Sarah, Sales Susanne, Berndt Nikolaus, Bulik Sascha, Marsico Giovanni, D'Souza Rochelle C J, Lakshmanaperumal Naharajan, Meganathan Kesavan, Natarajan Karthick, Sachinidis Agapios, Dahl Andreas, Holzhütter Hermann-Georg, Shevchenko Andrej, Mann Matthias, Koteliansky Victor, Zerial Marino
Max Planck Institute of Molecular Cell Biology and Genetics, 01307 Dresden, Germany.
David H. Koch Institute for Integrative Cancer Research, MIT, Cambridge, MA 02139, USA.
Cell Rep. 2015 May 12;11(6):884-892. doi: 10.1016/j.celrep.2015.04.018. Epub 2015 Apr 30.
The liver maintains glucose and lipid homeostasis by adapting its metabolic activity to the energy needs of the organism. Communication between hepatocytes and extracellular environment via endocytosis is key to such homeostasis. Here, we addressed the question of whether endosomes are required for gluconeogenic gene expression. We took advantage of the loss of endosomes in the mouse liver upon Rab5 silencing. Strikingly, we found hepatomegaly and severe metabolic defects such as hypoglycemia, hypercholesterolemia, hyperlipidemia, and glycogen accumulation that phenocopied those found in von Gierke's disease, a glucose-6-phosphatase (G6Pase) deficiency. G6Pase deficiency alone can account for the reduction in hepatic glucose output and glycogen accumulation as determined by mathematical modeling. Interestingly, we uncovered functional alterations in the transcription factors, which regulate G6Pase expression. Our data highlight a requirement of Rab5 and the endosomal system for the regulation of gluconeogenic gene expression that has important implications for metabolic diseases.
肝脏通过调整其代谢活动以适应机体的能量需求来维持葡萄糖和脂质稳态。肝细胞与细胞外环境之间通过内吞作用进行的通讯是这种稳态的关键。在此，我们探讨了内体是否是糖异生基因表达所必需的这一问题。我们利用了Rab5沉默后小鼠肝脏内体缺失这一情况。令人惊讶的是，我们发现了肝肿大以及严重的代谢缺陷，如低血糖、高胆固醇血症、高脂血症和糖原积累，这些症状与在葡萄糖-6-磷酸酶（G6Pase）缺乏的冯·吉尔克病中发现的症状相似。通过数学建模确定，仅G6Pase缺乏就可以解释肝脏葡萄糖输出减少和糖原积累的现象。有趣的是，我们发现了调节G6Pase表达的转录因子的功能改变。我们的数据突出了Rab5和内体系统对糖异生基因表达调控的需求，这对代谢疾病具有重要意义。
