The Critical Role of AKT2 in Hepatic Steatosis Induced by PTEN Loss
The Critical Role of AKT2 in Hepatic Steatosis Induced by PTEN Loss
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DOI：
10.2353/ajpath.2010.090931
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发表时间：
2010-05-01
影响因子：
6
通讯作者：
Stiles, Bangyan L.
中科院分区：
文献类型：
--
作者：
He, Lina;Hou, Xiaogang;Stiles, Bangyan L.
肝脏中的胰岛素信号传导导致磷脂酰肌醇（3，4，5）-三磷酸（PIP 3）的积累。磷酸酶Pten（10号染色体上缺失的磷酸酶和张力蛋白同源物）的缺失降低了PIP 3水平并导致脂肪肝的发展。本研究的目的是使用肝脏Pten缺失小鼠研究由PIP 3积累引起的脂肪生成的潜在机制。为了探索AKT 2（主要的肝脏AKT同种型）在由Pten缺失诱导的脂肪变性中的作用，我们创建了肝细胞中缺乏Pten和Akt 2的小鼠，并比较了在双突变体中缺失Akt 2和Pten与单独Pten缺失小鼠的效果。与单独的Pten突变小鼠相比，缺乏PTEN和AKT 2的小鼠的肝脏脂质积累显著减少。这种效应是由于AKT 2在维持参与从头脂肪生成的基因表达中的作用。我们发现，在双突变肝细胞中的脂质积累被组成型活性FOXO 1的表达部分逆转，FOXO 1是AKT下游的一种转录因子，不依赖于非典型蛋白激酶C的抑制。总之，本研究通过显示AKT介导PIP 3积累（通过PTEN损失模拟）诱导的肝脏中的脂质沉积来描绘PI 3 K信号通路对脂质代谢的调节，并且为胰岛素调节的肝脏脂肪生成提供了重要的分子机制。(Am J Pathol 2010，176：2302-2308; DOI：10.2353/ajpath.2010.090931）
Insulin signaling in the liver leads to accumulation of phosphatidylinositol (3,4,5)-trisphosphate (PIP3). Deletion of the phosphatase Pten (phosphatase and tensin homologue deleted on chromosome 10) reduces PIP3 levels and leads to fatty liver development. The purpose of this study was to investigate the mechanisms underlying lipogenesis that result from PIP3 accumulation using liver Pten-deletion mice. To explore the role of AKT2, the major liver AKT isoform in steatosis induced by deletion of Pten, we created mice lacking both Pten and Akt2 in hepatocytes and compared the effect of deleting Akt2 and Pten in the double mutants to the Pten deletion mice alone. Hepatic lipid accumulation was significantly reduced in mice lacking both PTEN and AKT2, as compared with Pten mutant mice alone. This effect was due to the role of AKT2 in maintaining expression of genes involved in de novo lipogenesis. We showed that lipid accumulation in the double mutant hepatocytes was partially reversed by expression of constitutive active FOXO1, a transcription factor downstream of AKT not dependent on inhibition of atypical protein kinase C. In summary, this study delineated regulation of lipid metabolism by PI3K signaling pathway by showing that AKT mediates PIP3 accumulation (mimicked by PTEN loss) induced lipid deposition in the liver and provided an important molecular mechanism for insulin-regulated hepatic lipogenesis. (Am J Pathol 2010, 176:2302-2308; DOI: 10.2353/ajpath.2010.090931)