Inhibition of ubiquitin ligase F-box and WD repeat domain-containing 7α (Fbw7α) causes hepatosteatosis through Krüppel-like factor 5 (KLF5)/peroxisome proliferator-activated receptor γ2 (PPARγ2) pathway but not SREBP-1c protein in mice

F-box and WD repeat domain-containing 7α (Fbw7α) 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, Fbw7α 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 Fbw7α in hepatic lipid metabolism. siRNA knockdown of Fbw7α in mice caused marked hepatosteatosis with the accumulation of triglycerides. However, inhibition of Fbw7α 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 Fbw7α function indicated that Fbw7α regulated the expression of peroxisome proliferator-activated receptor (PPAR) γ2 and its target genes involved in fatty acid uptake and triglyceride synthesis. These genes included fatty acid transporter Cd36, diacylglycerol acyltransferase 1 (Dgat1), and fat-specific protein 27 (Cidec). The regulation of PPARγ2 by Fbw7α was mediated, at least in part, by the direct degradation of the Krüppel-like factor 5 (KLF5) protein, upstream of PPARγ2 expression. Hepatic Fbw7α contributes to normal fatty acid and triglyceride metabolism, functions that represent novel aspects of this cell growth regulator.     

肝细胞中活化转录因子ATF6抑制SREBP1的转录活性

内质网膜定位的活化转录因子ATF6和SREBP1均是经过蛋白酶切水解激活,激活后的ATF6(N)和SREBP1(N)进入细胞核内,分别指导内质网膜未折叠蛋白聚集反应相关基因和脂肪酸合成相关基因的表达.研究发现,肝细胞内葡萄糖饥饿激活ATF6并抑制SREBP1的转录活性及其靶基因的表达.过表达ATF6(N)能够抑制SREBP1介导的转录及其下游基因的表达.免疫共沉淀实验显示,ATF6(N)在细胞核内结合SREBP1(N),这种结合在无糖状况下增强.不同功能区缺失分析表明,ATF6和SREBP1通过亮氨酸拉链(leucinezipper)功能区相互作用.在葡萄糖饥饿状况下,ATF6对SREBP1转录活性的抑制保证了细胞基本生命活动所需要的能量.