在肥胖症中由肝细胞分泌的DPP4促进脂肪炎症和胰岛素抵抗
Devram S Ghorpade1, Lale Ozcan1, Ze Zheng1
1Department of Medicine, Columbia University Medical Center, New York, New York 10032, USA.
Nature
|March 22, 2018
概括
肥胖会促进肝细胞的二甲酶4 (DPP4) 的分泌,这与Xa因子一起,会引起内脏脂肪组织巨细胞 (ATM) 的炎症,并导致胰岛素抵抗. 除了口服DPP4抑制剂之外,针对这种途径提供了明显的代谢益处.
科学领域:
- 代谢疾病
- 肥胖研究
- 脂肪组织生物学
背景情况:
- 肥胖引起的代谢疾病涉及复杂的器官交叉声,特别是肝脏和内脏脂肪组织 (VAT) 之间的交叉声.
- 由脂肪组织巨细胞 (ATM) 驱动的VAT炎症与肥胖症中的胰岛素抵抗相关.
- 了解促进病态脂肪组织炎症的机制至关重要.
研究的目的:
- 在肥胖引起的代谢功能障碍中调查肝脏和VAT之间的交叉声.
- 确定将肝细胞功能与ATM炎症和胰岛素抵抗联系起来的分子媒介.
主要方法:
- 在肥胖小鼠中研究了双基酶4 (DPP4) 的肝细胞合成和分泌.
- 研究了DPP4和血XA因子在ATM激活和VAT炎症中的作用.
- 在肝细胞中使用DPP4和ATM中使用卡韦林-1/PAR2的基因沉默技术.
- 评估这些干预措施对VAT炎症和胰岛素敏感性的影响.
- 将肝细胞DPP4抑制与口服DPP4抑制 (西塔格利平) 的效果进行比较.
主要成果:
- 肥胖刺激肝细胞分泌DPP4,与XA因子一起促进ATM炎症.
- 抑制肝细胞DPP4的表达可以改善肥胖小鼠的VAT炎症和胰岛素抵抗.
- 在ATM中向卡韦林-1或PAR2也可以抑制炎症和胰岛素抵抗.
- 口服DPP4抑制 (西塔利普丁) 没有产生类似的代谢益处.
结论:
- 在肥胖期间,肝细胞衍生的DPP4在促进VAT炎症和胰岛素抵抗方面发挥着重要作用.
- 针对肝细胞DPP4-ATM通路提供了一种新的代谢疾病治疗策略.
- 与全身DPP4抑制相比,这种途径的调节具有明显的代谢益处.
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