Ablation of PI3K p110-α prevents high-fat diet-induced liver steatosis.
Ablation of PI3K p110-α prevents high-fat diet-induced liver steatosis.
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作者：
Chattopadhyay M;Selinger ES;Ballou LM;Lin RZ
确定磷脂酰肌醇3-激酶（PI 3 K）催化亚基p110-α和p110-β是否在高脂饮食（HFD）诱导的肝脏脂肪变性中发挥作用。肝脏特异性p110-α和p110-β基因敲除小鼠和每组的对照动物喂食HFD或正常食物8周。生化分析和定量实时PCR用于测量甘油三酯，脂肪生成和脂肪生成基因的表达，以及肝脏裂解物中PI 3 K下游蛋白激酶的活性。在分离的肝细胞中评估脂肪酸摄取和掺入甘油三酯。喂食HFD的p110-α−/−小鼠的肝脏甘油三酯水平比p110-α+/+小鼠低84 ± 3%，而p110-β的缺失并未显著改变肝脏脂质蓄积。p110-α−/−肝脏也显示非典型蛋白激酶C活性降低，几种脂肪生成基因的mRNA和蛋白表达降低。与p110-α+/+细胞相比，从p110-α −/−小鼠中分离的肝细胞显示棕榈酸摄取减少和甘油三酯中脂肪酸掺入减少，与对照组相比，喂食HFD的p110-α−/−小鼠肝脏脂肪酸结合蛋白的肝脏表达较低。去除p110-α和p110-β都不能改善HFD诱导的葡萄糖耐受不良，并且在两种基因敲除动物的肝脏中，参与胚胎发生的基因都上调。在喂食HFD的小鼠中，PI 3 K p110-α而非p110-β促进肝脏脂肪变性。p110-α可能部分通过激活非典型蛋白激酶C、上调脂肪生成和增加脂肪酸摄取来发挥这种作用。
To determine whether the phosphoinositide 3-kinase (PI3K) catalytic subunits p110-α and p110-β play a role in liver steatosis induced by a high-fat diet (HFD). Liver-specific p110-α and p110-β knockout mice and control animals for each group were fed an HFD or normal chow for 8 weeks. Biochemical assays and quantitative real-time PCR were used to measure triglyceride, expression of lipogenic and gluconeogenic genes, and activity of protein kinases downstream of PI3K in liver lysates. Fatty acid uptake and incorporation into triglycerides were assessed in isolated hepatocytes. Hepatic triglyceride levels in HFD-fed p110-α−/− mice were 84 ± 3% lower than in p110-α+/+ mice, whereas the loss of p110-β did not significantly alter liver lipid accumulation. p110-α−/− livers also showed a reduction in atypical protein kinase C activity and decreased mRNA and protein expression of several lipogenic genes. Hepatocytes isolated from p110-α−/− mice exhibited decreased palmitate uptake and reduced fatty acid incorporation into triglycerides as compared with p110-α+/+ cells, and hepatic expression of liver fatty acid binding protein was lower in p110-α−/− mice fed the HFD as compared with controls. Ablation of neither p110-α nor p110-β ameliorated glucose intolerance induced by the HFD, and genes involved in gluconeogenesis were upregulated in the liver of both knockout animals. PI3K p110-α, and not p110-β, promotes liver steatosis in mice fed an HFD. p110-α might exert this effect in part through activation of atypical protein kinase C, upregulation of lipogenesis, and increased uptake of fatty acids.
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影响因子：
3.7
作者：
Oosterveer MH;van Dijk TH;Tietge UJ;Boer T;Havinga R;Stellaard F;Groen AK;Kuipers F;Reijngoud DJ
通讯作者：
Reijngoud DJ
DOI：
10.1016/j.jnutbio.2010.01.005
发表时间：
2010-11
期刊：
The Journal of nutritional biochemistry
影响因子：
--
作者：
Atshaves BP;Martin GG;Hostetler HA;McIntosh AL;Kier AB;Schroeder F
通讯作者：
Schroeder F
影响因子：
4.8
作者：
Fan, GF;Jiang, YP;Lin, RZ
通讯作者：
Lin, RZ
影响因子：
6.5
作者：
Sajan, Mini P.;Standaert, Mary L.;Farese, Robert V.
通讯作者：
Farese, Robert V.
DOI：
10.1073/pnas.0914798107
发表时间：
2010-02-23
影响因子：
11.1
作者：
Li, Shijie;Brown, Michael S.;Goldstein, Joseph L.
通讯作者：
Goldstein, Joseph L.