Fbxw7 regulates lipid metabolism and cell fate decisions in the mouse liver
Fbxw7 regulates lipid metabolism and cell fate decisions in the mouse liver
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DOI：
10.1172/jci40725
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发表时间：
2011-01-01
影响因子：
15.9
通讯作者：
Nakayama, Keiichi I.
中科院分区：
文献类型：
--
作者：
Onoyama, Ichiro;Suzuki, Atsushi;Nakayama, Keiichi I.
E3泛素连接酶复合物的自洽场类型包括戒指盒1 (Rbx1) cullin 1(剔除),s阶段kinase-associated蛋白1 (Skp1),和一盒的蛋白质家族成员的身份盒的底物特异性蛋白决定了复杂盒家庭成员盒- - - WD重复domain-containing 7(也称为Fbw7 Fbxw7, SEL-10, hCdc4,和hAgo)目标降解蛋白质与广泛的功能,发现其体内作用已经十分艰难,使用两种不同的Cre-loxP系统（Mx1-Cre和Alb-Cre），我们产生了Fbxw7肝脏特异性零突变的小鼠。Fbxw7的肝脏消融导致肝脏肥大和脂肪性肝炎，并伴有大量甘油三酯沉积。在Fbxw7缺乏的肝脏中，细胞增殖和Fbxw7底物的丰度都增加了。长期的Fbxw7缺乏导致胆道系统的显著增殖和错构瘤的发展。Fbxw7缺乏也使肝干细胞在体外向胆管细胞谱系而不是肝细胞谱系分化Notch辅助因子RBP-J，提示Notch积累触发了胆道系统的异常增殖。综上所述，我们的研究结果表明Fbxw7在调节肝脏脂肪生成和细胞增殖分化方面发挥了关键作用
E3 ubiquitin ligase complexes of the SCF type consist of ring-box 1 (Rbx1), cullin 1 (Cull), S-phase kinase-associated protein 1 (Skp1), and a member of the F-box family of proteins The identity of the F-box protein determines the substrate specificity of the complex The F-box family member F-box- and WD repeat domain-containing 7 (Fbxw7, also known as Fbw7, SEL-10, hCdc4, and hAgo) targets for degradation proteins with wide-ranging functions, and uncovering its in vivo role has been difficult, because Fbzw7(-/-) embryos die m utero Using two different Cre-loxP systems (Mx1-Cre and Alb-Cre), we generated mice with liver-specific null mutations of Fbxw7 Hepatic ablation of Fbxw7 resulted m hepatomegaly and steatohepatitis, with massive deposition of triglyceride, a phenotype similar to that observed in humans with nonalcoholic steatohepatitis Both cell proliferation and the abundance of Fbxw7 substrates were increased in the Fbxw7-deficient liver Long-term Fbxw7 deficiency resulted m marked proliferation of the biliary system and the development of hamartomas Fbxw7 deficiency also skewed the differentiation of liver stem cells toward the cholangiocyte lineage rather than the hepatocyte lineage m vitro This bias was corrected by additional loss of the Notch cofactor RBP-J, suggesting that Notch accumulation triggered the abnormal proliferation of the biliary system Together, our results suggest that Fbxw7 plays key roles, regulating lipogenesis and cell proliferation and differentiation in the liver