Inhibition of Ubiquitin Ligase F-box and WD Repeat Domain-containing 7α (Fbw7α) Causes Hepatosteatosis through Kruppel-like Factor 5 (KLF5)/Peroxisome Proliferator-activated Receptor γ2 (PPARγ2) Pathway but Not SREBP-1c Protein in Mice
Inhibition of Ubiquitin Ligase F-box and WD Repeat Domain-containing 7α (Fbw7α) Causes Hepatosteatosis through Kruppel-like Factor 5 (KLF5)/Peroxisome Proliferator-activated Receptor γ2 (PPARγ2) Pathway but Not SREBP-1c Protein in Mice
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DOI：
10.1074/jbc.m111.235283
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发表时间：
2011-11-25
影响因子：
4.8
通讯作者：
Shimano, Hitoshi
中科院分区：
文献类型：
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作者：
Kumadaki, Shin;Karasawa, Tadayoshi;Shimano, Hitoshi
包含F-box和WD重复结构域的7 α（Ebw 7 α）是泛素连接酶的底物识别组分，其控制参与细胞生长的因子（包括c-Myc、细胞周期蛋白E和c-Jun）的降解。此外，Fbw 7 α降解固醇调节元件结合蛋白（SREBP）-1a的核形式，所述固醇调节元件结合蛋白（SREBP）-1a是脂质合成的全局调节剂，特别是在培养细胞的有丝分裂期间。本研究探讨了Ebw 7 alpha在肝脏脂质代谢中的体内作用。在小鼠中Ebw 7 α的siRNA敲低引起显著的脂肪肝，伴随甘油三酯的积累。然而，Ebw 7 α的抑制并没有改变核SREBP-1蛋白的水平或参与脂肪酸合成和氧化的基因的表达。Fbw 7 α功能获得和丧失的体内实验表明，Fbw 7 α调节过氧化物酶体增殖物激活受体（PPAR）γ 2及其参与脂肪酸摄取和甘油三酯合成的靶基因的表达。这些基因包括脂肪酸转运蛋白Cd 36、二酰基甘油酰基转移酶1（Dgatl）和脂肪特异性蛋白27（Cidec）。Fbw 7 α对PPAR γ 2的调节至少部分是由PPAR γ 2表达上游的Krtippel样因子5（KI. F5）蛋白的直接降解介导的。肝脏Fbw 7 α有助于正常的脂肪酸和甘油三酯代谢，这些功能代表了这种细胞生长调节剂的新方面。
F-box and WD repeat domain-containing 7 alpha (Ebw7 alpha) is the substrate recognition component of a ubiquitin ligase that controls the degradation of factors involved in cellular growth, including c-Myc, cyclin E, and c-Jun. In addition, Fbw7 alpha degrades the nuclear form of sterol regulatory element-binding protein (SREBP)-1a, a global regulator of lipid synthesis, particularly during mitosis in cultured cells. This study investigated the in vivo role of Ebw7 alpha in hepatic lipid metabolism. siRNA knockdown of Ebw7 alpha in mice caused marked hepatosteatosis with the accumulation of triglycerides. However, inhibition of Ebw7 alpha did not change the level of nuclear SREBP-1 protein or the expression of genes involved in fatty acid synthesis and oxidation. In vivo experiments on the gain and loss of Fbw7 alpha function indicated that Fbw7 alpha regulated the expression of peroxisome proliferator-activated receptor (PPAR) gamma 2 and its target genes involved in fatty acid uptake and triglyceride synthesis. These genes included fatty acid transporter Cd36, diacylglycerol acyltransferase 1 (Dgatl), and fat-specific protein 27 (Cidec). The regulation of PPAR gamma 2 by Fbw7 alpha was mediated, at least in part, by the direct degradation of the Krtippel-like factor 5 (KI.F5) protein, upstream of PPAR gamma 2 expression. Hepatic Fbw7 alpha contributes to normal fatty acid and triglyceride metabolism, functions that represent novel aspects of this cell growth regulator.