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首页> 外文期刊>Molecular and Cellular Biology >Hepatic Mitogen-Activated Protein Kinase Phosphatase 1 Selectively Regulates Glucose Metabolism and Energy Homeostasis
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Hepatic Mitogen-Activated Protein Kinase Phosphatase 1 Selectively Regulates Glucose Metabolism and Energy Homeostasis

机译：肝丝裂原激活的蛋白激酶磷酸酶1选择性调节葡萄糖代谢和能量稳态。

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The liver plays a critical role in glucose metabolism and communicates with peripheral tissues to maintain energy homeostasis. Obesity and insulin resistance are highly associated with nonalcoholic fatty liver disease (NAFLD). However, the precise molecular details of NAFLD remain incomplete. The p38 mitogen-activated protein kinase (MAPK) and c-Jun NH2-terminal kinase (JNK) regulate liver metabolism. However, the physiological contribution of MAPK phosphatase 1 (MKP-1) as a nuclear antagonist of both p38 MAPK and JNK in the liver is unknown. Here we show that hepatic MKP-1 becomes overexpressed following high-fat feeding. Liver-specific deletion of MKP-1 enhances gluconeogenesis and causes hepatic insulin resistance in chow-fed mice while selectively conferring protection from hepatosteatosis upon high-fat feeding. Further, hepatic MKP-1 regulates both interleukin-6 (IL-6) and fibroblast growth factor 21 (FGF21). Mice lacking hepatic MKP-1 exhibit reduced circulating IL-6 and FGF21 levels that were associated with impaired skeletal muscle mitochondrial oxidation and susceptibility to diet-induced obesity. Hence, hepatic MKP-1 serves as a selective regulator of MAPK-dependent signals that contributes to the maintenance of glucose homeostasis and peripheral tissue energy balance. These results also demonstrate that hepatic MKP-1 overexpression in obesity is causally linked to the promotion of hepatosteatosis.
机译：肝脏在葡萄糖代谢中起关键作用，并与周围组织沟通以维持能量稳态。肥胖和胰岛素抵抗与非酒精性脂肪肝疾病（NAFLD）高度相关。但是，NAFLD的确切分子细节仍然不完整。 p38丝裂原活化蛋白激酶（MAPK）和c-Jun NH 2 -末端激酶（JNK）调节肝脏代谢。但是，尚不知道MAPK磷酸酶1（MKP-1）作为肝脏p38 MAPK和JNK的核拮抗剂的生理作用。在这里，我们显示高脂喂养后肝MKP-1变得过表达。 MKP-1的肝脏特异性缺失增强了高脂饮食小鼠的糖异生，并引起肝胰岛素抵抗，同时在高脂喂养下选择性地赋予了对肝脂肪变性的保护作用。此外，肝MKP-1调节白介素6（IL-6）和成纤维细胞生长因子21（FGF21）。缺乏肝MKP-1的小鼠表现出降低的循环IL-6和FGF21水平，这与骨骼肌线粒体氧化受损和对饮食性肥胖症的敏感性有关。因此，肝MKP-1充当MAPK依赖性信号的选择性调节剂，有助于维持葡萄糖稳态和周围组织能量平衡。这些结果还表明，肥胖中肝脏MKP-1的过表达与促进肝脂肪变性有关。

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