The Novel Intracellular Protein CREG Inhibits Hepatic Steatosis, Obesity, and Insulin Resistance
The Novel Intracellular Protein CREG Inhibits Hepatic Steatosis, Obesity, and Insulin Resistance
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新型细胞内蛋白 CREG 抑制肝脂肪变性、肥胖和胰岛素抵抗
DOI：
10.1002/hep.29257
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发表时间：
2017-09-01
期刊：
影响因子：
13.5
通讯作者：
Han, Ya-Ling
中科院分区：
文献类型：
--
作者：
Zhang, Quan-Yu;Zhao, Ling-Ping;Han, Ya-Ling
E1 A刺激基因的细胞阻遏物（Cellular repressor of E1 A-stimulated genes，CREG）是一种新型的细胞糖蛋白，具有抑制血管增生、维持血管内环境稳定、促进内皮细胞修复等作用，被认为是多种心血管疾病的抑制因子。然而，CREG在代谢紊乱和肝脂肪变性中的作用和机制尚不清楚。在这里，我们报告说，肝细胞特异性CREG缺失显着加剧高脂饮食和瘦素缺乏诱导（ob/ob）的不良反应，如肥胖，肝脂肪变性和代谢紊乱，而有益的效果是由CREG过表达。另外的实验表明，c-Jun N-末端激酶1（JNK 1）而不是JNK 2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，JNK 1抑制强烈防止CREG缺失对脂肪变性和相关代谢紊乱的不利影响。在机制上，CREG直接与凋亡信号调节激酶1（ASK 1）相互作用并抑制其磷酸化，从而阻断下游MKK 4/7-JNK 1信号通路并导致肥胖、胰岛素抵抗和肝脂肪变性显著减轻。重要的是，在非酒精性脂肪性肝病（NAFLD）患者的肝脏中观察到CREG表达显著降低和JNK 1信号过度活化，表明CREG可能是NAFLD和相关代谢疾病的有希望的治疗靶点。结论：我们的研究结果提供了证据表明，CREG是一个强大的肝脏脂肪变性和代谢紊乱的抑制剂，通过其与ASK 1的直接相互作用和ASK 1-JNK 1信号转导的结果失活。这项研究提供了对NAFLD发病机制及其复杂病理学的见解，如肥胖和胰岛素抵抗，并为通过靶向CREG治疗疾病铺平了道路。
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.