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加速巨噬细胞中磷酯酰胆碱的转化可促进肥胖症脂肪组织炎症。

Accelerated phosphatidylcholine turnover in macrophages promotes adipose tissue inflammation in obesity.

机构信息

University of Cambridge Metabolic Research Laboratories, Institute of Metabolic Science, MDU MRC, Cambridge, United Kingdom.

Clinical Bioinformatics Area, Fundación Progreso y Salud, CDCA, Hospital Virgen del Rocio, Sevilla, Spain.

出版信息

Elife. 2019 Aug 16;8:e47990. doi: 10.7554/eLife.47990.

DOI:10.7554/eLife.47990
PMID:31418690
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC6748830/
Abstract

White adipose tissue (WAT) inflammation contributes to the development of insulin resistance in obesity. While the role of adipose tissue macrophage (ATM) pro-inflammatory signalling in the development of insulin resistance has been established, it is less clear how WAT inflammation is initiated. Here, we show that ATMs isolated from obese mice and humans exhibit markers of increased rate of de novo phosphatidylcholine (PC) biosynthesis. Macrophage-specific knockout of phosphocholine cytidylyltransferase A (CCTα), the rate-limiting enzyme of de novo PC biosynthesis pathway, alleviated obesity-induced WAT inflammation and insulin resistance. Mechanistically, CCTα-deficient macrophages showed reduced ER stress and inflammation in response to palmitate. Surprisingly, this was not due to lower exogenous palmitate incorporation into cellular PCs. Instead, CCTα-null macrophages had lower membrane PC turnover, leading to elevated membrane polyunsaturated fatty acid levels that negated the pro-inflammatory effects of palmitate. Our results reveal a causal link between obesity-associated increase in de novo PC synthesis, accelerated PC turnover and pro-inflammatory activation of ATMs.

摘要

白色脂肪组织（WAT）炎症会导致肥胖患者出现胰岛素抵抗。虽然脂肪组织巨噬细胞（ATM）促炎信号在胰岛素抵抗的发展中作用已得到证实，但脂肪组织炎症是如何引发的还不太清楚。在这里，我们发现，从肥胖小鼠和人类中分离出的 ATMs 表现出新生磷脂酰胆碱（PC）生物合成速率增加的标志物。巨噬细胞特异性敲除磷酸胆碱胞苷转移酶 A（CCTα），即新生 PC 生物合成途径的限速酶，可减轻肥胖引起的 WAT 炎症和胰岛素抵抗。从机制上讲，CCTα 缺陷型巨噬细胞在应对软脂酸时表现出较低的内质网应激和炎症。令人惊讶的是，这并不是由于外源性软脂酸掺入细胞 PC 减少所致。相反，CCTα 缺失型巨噬细胞的膜 PC 周转率较低，导致膜多不饱和脂肪酸水平升高，抵消了软脂酸的促炎作用。我们的研究结果揭示了肥胖相关的新生 PC 合成增加、PC 周转率加快与 ATM 促炎激活之间的因果关系。

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