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首页> 外文期刊>Hepatology: Official Journal of the American Association for the Study of Liver Diseases >The Novel Intracellular Protein CREG Inhibits Hepatic Steatosis, Obesity, and Insulin Resistance
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The Novel Intracellular Protein CREG Inhibits Hepatic Steatosis, Obesity, and Insulin Resistance

机译：新型细胞内蛋白质creg抑制肝脏脂肪变性，肥胖和胰岛素抵抗力

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摘要

Cellular repressor of E1A-stimulated genes (CREG), a novel cellular glycoprotein, has been identified as a suppressor of various cardiovascular diseases because of its capacity to reduce hyperplasia, maintain vascular homeostasis, and promote endothelial restoration. However, the effects and mechanism of CREG in metabolic disorder and hepatic steatosis remain unknown. Here, we report that hepatocyte-specific CREG deletion dramatically exacerbates high-fat diet and leptin deficiency-induced (ob/ob) adverse effects such as obesity, hepatic steatosis, and metabolic disorders, whereas a beneficial effect is conferred by CREG overexpression. Additional experiments demonstrated that c-Jun N-terminal kinase 1 (JNK1) but not JNK2 is largely responsible for the protective effect of CREG on the aforementioned pathologies. Notably, JNK1 inhibition strongly prevents the adverse effects of CREG deletion on steatosis and related metabolic disorders. Mechanistically, CREG interacts directly with apoptosis signal-regulating kinase 1 (ASK1) and inhibits its phosphorylation, thereby blocking the downstream MKK4/7-JNK1 signaling pathway and leading to significantly alleviated obesity, insulin resistance, and hepatic steatosis. Importantly, dramatically reduced CREG expression and hyperactivated JNK1 signaling was observed in the livers of nonalcoholic fatty liver disease (NAFLD) patients, suggesting that CREG might be a promising therapeutic target for NAFLD and related metabolic diseases. Conclusion: The results of our study provides evidence that CREG is a robust suppressor of hepatic steatosis and metabolic disorders through its direct interaction with ASK1 and the resultant inactivation of ASK1-JNK1 signaling. This study offers insights into NAFLD pathogenesis and its complicated pathologies, such as obesity and insulin resistance, and paves the way for disease treatment through targeting CREG.
机译：E1A刺激基因（Creg）的细胞阻遏物，一种新型细胞糖蛋白，已被鉴定为各种心血管疾病的抑制因素，因为它可以减少增生，维持血管稳态和促进内皮修复物的能力。然而，Creg在代谢紊乱和肝脏脂肪变性中的效果和机制仍然未知。在这里，我们报告说，肝细胞特异性的Creg缺失显着加剧了高脂饮食和瘦素缺乏诱导的（OB / OB）不良反应，例如肥胖症，肝脏脂肪变性和代谢紊乱，而Creg过表达赋予有益效果。另外的实验证明C-JUM N-末端激酶1（JNK1）但不是JNK2在很大程度上负责Creg对上述病理的保护作用。值得注意的是，JNK1抑制强烈地防止了Creg缺失对脂肪变性和相关代谢障碍的不利影响。机械地，Creg直接用凋亡信号调节激酶1（ASK1）相互作用并抑制其磷酸化，从而阻塞下游MKK4 / 7-JNK1信号通路，并导致显着减轻肥胖，胰岛素抵抗和肝脏脂肪变性。重要的是，在非酒精性脂肪肝疾病（NAFLD）患者的肝脏中观察到显着减少的Creg表达和超动诱变的JNK1信号传导，表明Creg可能是NAFLD和相关代谢疾病的有希望的治疗目标。结论：我们的研究结果提供了通过与ASK1的直接相互作用和Ask1-JNK1信号传导的直接相互作用，Creg是一种肝脏脂肪变性和代谢障碍的稳健抑制。本研究提供了对NAFLD发病机制的见解及其复杂的病理学，例如肥胖症和胰岛素抵抗，并通过靶向加勒格铺平疾病治疗方法。

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