Canal Frédéric, Charawi Sara, Grimber Gisèle, Houbron Christophe, Drouet Valérie, Colnot Sabine, Terris Benoit, Cavard Catherine, Perret Christine
Inserm, U1016, Institut Cochin, 75014 Paris, France.
Cnrs, UMR8104, 75014 Paris, France.
PLoS One. 2016 Mar 14;11(3):e0150997. doi: 10.1371/journal.pone.0150997. eCollection 2016.
Fine tuning of the Wnt/β-catenin signaling pathway is essential for the proper development and function of the liver. Aberrant activation of this pathway is observed in 20%-40% of hepatocellular carcinomas (HCC). Notum encodes a secreted Wnt deacylase that inhibits Wnt activity and thereby restricts the zone of activation of Wnt/β-catenin signaling. An important role of NOTUM has been described in development in drosophila, planaria and zebrafish, but its role in the mammalian liver is unknown. Notum is required for spatial control of the Wnt/β-catenin signaling in several animal models and the Wnt/β-catenin pathway contributes to liver patterning involved in metabolic zonation. Therefore, Notum may be involved in the liver patterning induced by the Wnt/β-catenin signaling during the adult stage.
METHODOLOGY/PRINCIPAL FINDINGS: We generated a conditional Notum knockout mouse mutant to study the effect of the deletion of Notum in the liver. We show that Notum is a direct target of the Wnt/β-catenin signaling in the liver. Liver-specific deletion of Notum did not modify liver zonation, but Notum deletion had a long-term effect on mouse physiology. In particular, male mutant mice developed metabolic disorders.
We show that Notum is not a key actor of Wnt/β-catenin-dependent liver patterning of adult mice, but has role in liver glucose homeostasis. Male mice deficient in Notum specifically in the liver develop metabolic dysfunctions implicating Notum in the development of Type 2 diabetes.
Wnt/β-连环蛋白信号通路的精细调节对于肝脏的正常发育和功能至关重要。在20%-40%的肝细胞癌（HCC）中观察到该通路的异常激活。Notum编码一种分泌型Wnt去酰基酶，可抑制Wnt活性，从而限制Wnt/β-连环蛋白信号的激活区域。Notum在果蝇、涡虫和斑马鱼的发育过程中发挥了重要作用，但其在哺乳动物肝脏中的作用尚不清楚。在几种动物模型中，Notum是Wnt/β-连环蛋白信号空间控制所必需的，并且Wnt/β-连环蛋白通路有助于参与代谢分区的肝脏模式形成。因此，Notum可能参与成年期由Wnt/β-连环蛋白信号诱导的肝脏模式形成。
方法/主要发现：我们生成了一个条件性Notum敲除小鼠突变体，以研究肝脏中Notum缺失的影响。我们表明Notum是肝脏中Wnt/β-连环蛋白信号的直接靶点。肝脏特异性Notum缺失并未改变肝脏分区，但Notum缺失对小鼠生理学有长期影响。特别是，雄性突变小鼠出现了代谢紊乱。
我们表明Notum不是成年小鼠Wnt/β-连环蛋白依赖性肝脏模式形成的关键因素，但在肝脏葡萄糖稳态中发挥作用。肝脏中特异性缺乏Notum的雄性小鼠发生代谢功能障碍，这表明Notum参与2型糖尿病的发展。
