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首页> 外文期刊>Life sciences >Unmetabolized fenofibrate, but not fenofibric acid, activates AMPK and inhibits the expression of phosphoenolpyruvate carboxykinase in hepatocytes.
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Unmetabolized fenofibrate, but not fenofibric acid, activates AMPK and inhibits the expression of phosphoenolpyruvate carboxykinase in hepatocytes.

机译：未代谢的非诺贝特而非非诺贝特酸可激活AMPK，并抑制肝细胞中磷酸烯醇丙酮酸羧化激酶的表达。

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摘要

AIMS: A lipid-lowering agent, fenofibrate, has been reported to reduce hepatic glucose production and the expression of phosphoenolpyruvate carboxykinase (PEPCK), a rate-limiting enzyme for gluconeogenesis in the liver. However, the precise mechanisms of these effects have remained unclear. MAIN METHODS: Rat hepatoma-derived H4IIE cells and murine myoblast-derived C2C12 cells were incubated with the ester form of fenofibrate and fenofibric acid, a metabolite of fenofibrate ester, and the phosphorylation of AMPK, acetyl-CoA carboxylase (ACC), PEPCK mRNA expression and glucose production were assessed. KEY FINDINGS: Incubation of H4IIE hepatoma cells with the ester form of fenofibrate increased the phosphorylation of AMPK and acetyl-CoA carboxylase (ACC) and decreased PEPCK mRNA expression and glucose production. Fenofibrate-induced reductions in PEPCK expression and glucose production were abrogated by compound C, a specific AMPK inhibitor. Fenofibric acid, a metabolite of fenofibrate ester, had no effects on AMPK phosphorylation, PEPCK gene expression, or glucose production in H4IIE cells. Fenofibrate-treated mice exhibited increases in AMPK phosphorylation and a decrease in PEPCK expression in the liver but not in skeletal muscles, suggesting that unmetabolized fenofibrate accumulated and affected AMPK only in the liver. SIGNIFICANCE: These results demonstrate that fenofibrate inhibits PEPCK gene expression and hepatic glucose production in the liver via AMPK activation, even though the metabolite loses its effects on AMPK and does not work in vivo in myocytes. This novel feature of fenofibrate may provide additional benefit for the treatment of patients with disorders of both lipid and glucose metabolism.
机译：目的：降脂剂非诺贝特，据报道可减少肝脏葡萄糖的产生和磷酸烯醇丙酮酸羧化激酶（PEPCK）的表达，该酶是肝脏糖异生的限速酶。但是，这些作用的确切机制仍不清楚。主要方法：将大鼠肝癌衍生的H4IIE细胞和鼠成肌细胞C2C12细胞与非诺贝特和非诺贝特酸的酯形式，非诺贝特酯的代谢产物以及AMPK的磷酸化，乙酰辅酶A羧化酶（ACC），PEPCK mRNA孵育评估表达和葡萄糖产生。主要发现：用非诺贝特酯形式孵育H4IIE肝癌细胞可增加AMPK和乙酰辅酶A羧化酶（ACC）的磷酸化，并降低PEPCK mRNA表达和葡萄糖生成。非诺贝特诱导的PEPCK表达减少和葡萄糖生成被化合物C（一种特定的AMPK抑制剂）废除。非诺贝特酸酯的代谢产物非诺贝酸对H4IIE细胞中的AMPK磷酸化，PEPCK基因表达或葡萄糖产生没有影响。用非诺贝特治疗的小鼠肝脏中AMPK磷酸化增强，而PEPCK表达降低，但骨骼肌中PCPCK表达没有降低，这表明未代谢的非诺贝特仅在肝脏中积累并影响AMPK。意义：这些结果表明非诺贝特通过AMPK激活抑制肝中PEPCK基因表达和肝葡萄糖生成，即使该代谢产物失去了对AMPK的作用并且在体内也不在肌细胞中起作用。非诺贝特的这一新颖功能可能为患有脂质和葡萄糖代谢异常的患者提供额外的益处。

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