Exendin-4和α1抗胰蛋白酶融合基因的流体动力传递控制肥胖和代谢性疾病。,Scientific Reports

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Exendin-4和α1抗胰蛋白酶融合基因的流体动力传递控制肥胖和代谢性疾病。
Scientific Reports ( IF 3.8 ) Pub Date : 2019-09-17 , DOI: 10.1038/s41598-019-49757-y
Mingming Gao ₁ , Dexi Liu ₁

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肥胖症和相关的代谢合并症代表了日益严重的公共卫生问题。在这项研究中，我们证明了新创建的exendin-4和α1-抗胰蛋白酶的融合基因在控制肥胖症和肥胖症相关的代谢性疾病中的应用，包括胰岛素抵抗，脂肪肝和高血糖症。该融合基因编码具有位于人α-1抗胰蛋白酶N末端的exendin-4肽的蛋白质，并被命名为EAT。饮食基因向小鼠的流体动力学转移可防止高脂饮食诱导的肥胖，胰岛素抵抗和脂肪肝的发展。在饮食诱导的肥胖小鼠中，EAT基因的表达可引起体重减轻，改善葡萄糖稳态，并减轻肝脂肪变性。在ob / ob小鼠中，EAT基因转移抑制体重增加，维持代谢稳态，并完全阻止脂肪肝的发育。EAT融合基因在健康小鼠中六个月的过度表达不会导致任何可检测到的毒性。机理研究表明，通过减少食物摄取和下调负责肝脏脂肪形成和脂质滴形成以及内脏脂肪慢性炎症的关键基因的转录，可以获得新的代谢益处。这些结果验证了基因疗法在多种病理情况下预防和恢复代谢稳态的可行性，并为支持控制肥胖症和相关代谢疾病的新策略提供了证据。机理研究表明，通过减少食物摄取和下调负责肝脏脂肪形成和脂质滴形成以及内脏脂肪慢性炎症的关键基因的转录，可以获得新的代谢益处。这些结果验证了基因疗法在多种病理情况下预防和恢复代谢稳态的可行性，并为支持控制肥胖症和相关代谢疾病的新策略提供了证据。机理研究表明，通过减少食物摄取和下调负责肝脏脂肪形成和脂质滴形成以及内脏脂肪慢性炎症的关键基因的转录，可以获得新的代谢益处。这些结果验证了基因疗法在多种病理情况下预防和恢复代谢稳态的可行性，并为支持控制肥胖症和相关代谢疾病的新策略提供了证据。

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Controlling Obesity and Metabolic Diseases by Hydrodynamic Delivery of a Fusion Gene of Exendin-4 and α1 Antitrypsin.

Obesity and associated metabolic comorbidities represent a growing public health problem. In this study, we demonstrate the use of a newly created fusion gene of exendin-4 and α1-antitrypsin to control obesity and obesity-associated metabolic disorders including insulin resistance, fatty liver and hyperglycemia. The fusion gene encodes a protein with exendin-4 peptide placed at the N-terminus of human α-1 antitrypsin, and is named EAT. Hydrodynamic transfer of the EAT gene to mice prevents high-fat diet-induced obesity, insulin resistance and fatty liver development. In diet-induced obese mice, expression of EAT gene induces weight loss, improves glucose homeostasis, and attenuates hepatic steatosis. In ob/ob mice, EAT gene transfer suppresses body weight gain, maintains metabolic homeostasis, and completely blocks fatty liver development. Six-month overexpression of the EAT fusion gene in healthy mice does not lead to any detectable toxicity. Mechanistic study reveals that the resulting metabolic benefits are achieved by a reduced food take and down-regulation of transcription of pivotal genes responsible for lipogenesis and lipid droplet formation in the liver and chronic inflammation in visceral fat. These results validate the feasibility of gene therapy in preventing and restoring metabolic homeostasis under diverse pathologic conditions, and provide evidence in support of a new strategy to control obesity and related metabolic diseases.

更新日期：2019-09-18

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