Pancreatic-Derived Factor Promotes Lipogenesis in the Mouse Liver: Role of the Forkhead Box 1 Signaling Pathway
Pancreatic-Derived Factor Promotes Lipogenesis in the Mouse Liver: Role of the Forkhead Box 1 Signaling Pathway
复制标题
胰源性因子促进小鼠肝脏脂肪生成：Forkhead Box 1 信号通路的作用
DOI：
10.1002/hep.24295
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发表时间：
2011-06-01
期刊：
影响因子：
13.5
通讯作者：
Guan, Youfei
中科院分区：
文献类型：
--
作者：
Li, Jing;Chi, Yujing;Guan, Youfei
胰源性因子（PANDER）是一种胰岛特异性细胞因子，与胰岛素共分泌，对β细胞功能很重要。在这里，我们发现PANDER在肝细胞中组成性表达，并且在糖尿病胰岛素抵抗db/db小鼠和高脂肪饮食小鼠的脂肪变性肝脏中其表达显著增加。PANDER在C57Bl/6小鼠肝脏中过表达促进脂肪生成，Forkhead box 1 （FOXO1）表达增加，而小干扰rna介导的肝脏PANDER敲低显著减轻脂肪变性，db/db小鼠FOXO1表达降低。肝PANDER沉默也可减轻db/db小鼠的胰岛素抵抗和高血糖。在培养的肝细胞中，PANDER过表达诱导脂质沉积，增加FOXO1表达，抑制胰岛素刺激的Akt激活和FOXO1失活。此外，FOXO1过表达增加了培养肝细胞和小鼠肝脏中PANDER的表达。结论：PANDER通过增加FOXO1活性促进肝脏脂肪生成并破坏胰岛素信号。PANDER可能是治疗脂肪肝和胰岛素抵抗的潜在治疗靶点。(肝脏病学53:1906 2011;1916)
Pancreatic-derived factor (PANDER) is a pancreatic islet-specific cytokine that cosecretes with insulin and is important for beta cell function. Here, we show that PANDER is constitutively expressed in hepatocytes, and its expression is significantly increased in steatotic livers of diabetic insulin-resistant db/db mice and mice fed a high-fat diet. Overexpression of PANDER in the livers of C57Bl/6 mice promoted lipogenesis, with increased Forkhead box 1 (FOXO1) expression, whereas small interfering RNA-mediated knockdown of hepatic PANDER significantly attenuated steatosis, with reduced FOXO1 expression in db/db mice. Hepatic PANDER silencing also attenuated insulin resistance and hyperglycemia in db/db mice. In cultured hepatocytes, PANDER overexpression induced lipid deposition, increased FOXO1 expression, and suppressed insulin-stimulated Akt activation and FOXO1 inactivation. Moreover, FOXO1 overexpression increased PANDER expression in cultured hepatocytes and mouse livers. Conclusion: PANDER promotes lipogenesis and compromises insulin signaling in the liver by increasing FOXO1 activity. PANDER may represent a potential therapeutic target for the treatment of fatty liver and insulin resistance. (HEPATOLOGY 2011;53:1906-1916)