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首页> 外文期刊>Endocrinology >Pigment epithelium-derived factor (PEDF) suppresses IL-1β-mediated c-Jun N-terminal kinase (JNK) activation to improve hepatocyte insulin signaling
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Pigment epithelium-derived factor (PEDF) suppresses IL-1β-mediated c-Jun N-terminal kinase (JNK) activation to improve hepatocyte insulin signaling

机译：色素上皮衍生因子（PEDF）抑制IL-1β介导的c-Jun N末端激酶（JNK）活化以改善肝细胞胰岛素信号传导

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Pigment epithelium-derived factor (PEDF) is an antiinflammatory protein that circulates at high levels in the metabolic syndrome. Metabolic studies of PEDF knockout (KO) mice were conducted to investigate the relationship between PEDF, inflammatory markers, and metabolic homeostasis. Male PEDF KO mice demonstrated a phenotype consisting of increased adiposity, glucose intolerance, andelevated serum levels of metabolites associated with the metabolic syndrome.Genome expression analysis revealed an increase in IL-1β signaling in the livers of PEDF KO mice that was accompanied by impaired IRS and Akt signaling. In human hepatocytes, PEDF blocked the effects of an IL-1β challenge by suppressing activation of the inflammatory mediator c-Jun N-terminal kinase while restoring Akt signaling. RNA interference of PEDF in human hepatocytes was permissive for c-Jun N-terminal kinase activation and decreased Akt signaling. A metabolomics profile identified elevated circulating levels of tricarboxyclic acid cycle intermediates including succinate, an inducer of IL-1β, in PEDF KO mice. Succinate-dependent IL-1β expression was blocked by PEDF in PEDF KO, but not wild-type hepatocytes. In vivo, PEDF restoration reduced hyperglycemia and improved hepatic insulin signaling in PEDF KO mice. These findings identify elevated PEDF as a homeostatic mechanism in the human metabolic syndrome.
机译：色素上皮衍生因子（PEDF）是一种抗炎蛋白，在代谢综合征中以高水平循环。进行了PEDF基因敲除（KO）小鼠的代谢研究，以研究PEDF，炎症标志物和代谢稳态之间的关系。雄性PEDF KO小鼠表现出表型，包括与代谢综合征相关的肥胖症，葡萄糖耐量增加和血清代谢产物水平升高。基因组表达分析显示，PEDF KO小鼠肝脏中IL-1β信号转导增加，并伴有IRS受损。和Akt信令。在人肝细胞中，PEDF通过抑制炎症介质c-Jun N-末端激酶的激活，同时恢复Akt信号传导，从而阻断了IL-1β攻击的作用。 PEDF在人肝细胞中的RNA干扰允许c-Jun N端激酶激活并降低Akt信号传导。代谢组学分析确定了PEDF KO小鼠体内三羧酸循环中间体（包括琥珀酸酯，IL-1β的诱导剂）的循环水平升高。 PEDF KO中的PEDF阻止了琥珀酸依赖性IL-1β的表达，但野生型肝细胞却没有。在体内，PEDF恢复可降低PEDF KO小鼠的高血糖症并改善肝胰岛素信号传导。这些发现确定了升高的PEDF是人类代谢综合征中的体内平衡机制。

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