Exercise inhibits JNK pathway activation and lipotoxicity via macrophage migration inhibitory factor in nonalcoholic fatty liver disease.
Exercise inhibits JNK pathway activation and lipotoxicity via macrophage migration inhibitory factor in nonalcoholic fatty liver disease.
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运动通过巨噬细胞迁移抑制因子抑制JNK途径的激活和脂肪毒性。
DOI：
10.3389/fendo.2022.961231
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发表时间：
2022
影响因子：
5.2
通讯作者：
中科院分区：
文献类型：
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肝细胞中表达的巨噬细胞迁移抑制因子（MIF）可以限制肥胖期间的脂肪变性。非酒精性脂肪肝的脂毒性部分是由应激激酶 JNK 的激活介导的，但 MIF 是否调节 JNK 的脂毒性尚不清楚。在这项研究中，我们研究了同步运动治疗期间 MIF 在调节 JNK 激活和高脂肪促进的肝脏脂毒性中的作用。 15只小鼠平均分为三组：正常饮食组、高脂饮食组、高脂运动组。长期高脂喂养会引起小鼠明显的高脂血症、肝脏脂肪变性和细胞凋亡，并抑制 MIF 并激活下游 MAPK 激酶 4 磷酸化和 JNK。这些效应在规定的游泳运动后被逆转，表明运动的出现可以预防脂质超载引起的肝脏脂毒性，并可能与调节 MIF 及其下游 JNK 通路的作用相关。在体外 HepG2 细胞棕榈酸处理中观察到类似的脂毒性有害作用。抑制 JNK 通过调节 BCL 家族来降低肝细胞脂毒性，并且过量的 JNK 激活也可以通过补充 MIF 来减弱或通过 MIF siRNA 施用来加剧。研究结果表明，运动可通过调节 NAFLD 中的内源性肝 MIF 来降低脂毒性并抑制 JNK 激活。这些发现对于预防和干预饮食不节诱发 NAFLD 患者具有临床意义。
The macrophage migration inhibitory factor (MIF) expressed in hepatocytes can limit steatosis during obesity. Lipotoxicity in nonalcoholic fatty liver disease is mediated in part by the activation of the stress kinase JNK, but whether MIF modulates JNK in lipotoxicity is unknown. In this study, we investigated the role of MIF in regulating JNK activation and high-fat fostered liver lipotoxicity during simultaneous exercise treatment. Fifteen mice were equally divided into three groups: normal diet, high-fat diet, and high-fat and exercise groups. High-fat feeding for extended periods elicited evident hyperlipemia, liver steatosis, and cell apoptosis in mice, with inhibited MIF and activated downstream MAPK kinase 4 phosphorylation and JNK. These effects were then reversed following prescribed swimming exercise, indicating that the advent of exercise could prevent liver lipotoxicity induced by lipid overload and might correlate to the action of modulating MIF and its downstream JNK pathway. Similar detrimental effects of lipotoxicity were observed in in vitro HepG2 cells palmitic acid treatment. Suppressed JNK reduced the hepatocyte lipotoxicity by regulating the BCL family, and the excess JNK activation could also be attenuated through MIF supplementation or exacerbated by MIF siRNA administration. The results found suggest that exercise reduces lipotoxicity and inhibits JNK activation by modulating endogenous hepatic MIF in NAFLD. These findings have clinical implications for the prevention and intervention of patients with immoderate diet evoked NAFLD.