Mol Metab|Fiona C. McGillicuddy团队揭示水杨酸钠对肥胖患者受损RCT途径的影响

2022年8月3日 0条评论 246次阅读 0人点赞

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肥胖是一种复杂的多因素疾病，以慢性炎症为基础，并与许多并发症有关，这些并发症通常共同存在。胆固醇逆向转运（RCT）是一种动脉粥样硬化保护过程，通过该过程，外周细胞内的胆固醇可流入高密度脂蛋白（HDL）颗粒，并返回肝脏以排泄胆汁和粪便。高脂饮食（HFD）诱导的肥胖可通过RCT途径损害胆固醇清除，降低胆固醇和胆汁酸转运蛋白ABCG5/8/ABCB11在肝脏中的表达，并降低HDL的胆固醇流出能力（CEC）。因此，在肥胖患者中针对RCT通路进行治疗可能提供了一种重要的方式，以对抗该人群患有慢性心血管疾病的风险。

2021年12月24日，爱尔兰UCD医学院糖尿病并发症研究中心Fiona C. McGillicuddy团队在Molecular Metabolism上发表了题为“Sodium salicylate rewires hepatic metabolic pathways in obesity and attenuates IL-1β secretion from adipose tissue–implications for obesity-impaired reverse cholesterol transport”的研究论文。在本研究中，团队假设继发于脂肪组织功能障碍的肝脂肪变性发展会导致RCT受损，这种影响可通过使用抗炎药——水杨酸钠（NaS）来减轻。

研究中，团队通过对C57BL/6j小鼠喂食HFD±NaS或低脂饮食（LFD）24周，以构建实验模型，之后，进行葡萄糖和胰岛素耐受性测试，并在体内评估从巨噬细胞到粪便的³H-胆固醇运动；同时，体外测定HDL-CEC以及脂肪来源的基质血管部分（SVF）细胞因子的分泌。结果发现，NaS可延迟HFD诱导的小鼠体重增加，并缓解SVF中pro-IL-1β的启动，减弱胰岛素抵抗，防止肝脏异位脂肪积累；紧接着，团队进一步证明，肝脂肪变性的预防与PPAR-α/β-氧化蛋白、NaS表达增加以及LXR/RXR诱导蛋白（包括载脂蛋白）表达减少相吻合，而后一种效应反映在循环HDL蛋白质组中。

总之，团队的此项研究指出，NaS的心脏代谢保护机制可能归因于肝代谢途径的重编程，以在营养过剩的情况下增加脂肪酸利用。肝脏胆固醇水平降低，再加上LXR/RXR诱导蛋白的减少，可能是NaS拯救ABCG5/8表达的基础。

《Mol Metab|Fiona C. McGillicuddy团队揭示水杨酸钠对肥胖患者受损RCT途径的影响》

图本文图形摘要示意图。

期刊及DOI号

Mol Metab. 2021 Dec 24.

doi: 10.1016/j.molmet.2021.101425.

题目

Sodium salicylate rewires hepatic metabolic pathways in obesity and attenuates IL-1β secretion from adipose tissue–implications for obesity-impaired reverse cholesterol transport

摘要

介绍：High-fat diet (HFD)-induced obesity impairs clearance of cholesterol through the Reverse Cholesterol Transport (RCT) pathway, with downregulation in hepatic expression of cholesterol and bile acid transporters, ABCG5/8 and ABCB11, and reduced high-density lipoprotein (HDL) cholesterol efflux capacity (CEC). Within the current study we hypothesized that development of hepatosteatosis, secondary to adipose-tissue dysfunction, contributes to obesity-impaired RCT and such effects could be mitigated using the anti-inflammatory drug sodium salicylate (NaS).

材料和方法：C57BL/6j mice, fed HFD±NaS or low-fat diet (LFD) for 24 weeks, underwent glucose and insulin tolerance testing and ³H-cholesterol movement from macrophage-to-feces was assessed in vivo. HDL-CEC was determined ex vivo. Cytokine secretion from adipose-derived stromal vascular fraction (SVF) cells was measured ex vivo. Liver and HDL proteins were determined by mass spectrometry and analysed using Ingenuity Pathway Analysis.

结果：NaS delayed HFD-induced weight-gain, abrogated priming of pro-IL-1β in SVFs, attenuated insulin resistance and prevented ectopic fat accumulation in the liver. Prevention of hepatosteatosis coincided with increased expression of PPAR-alpha/beta-oxidation proteins with NaS and reduced expression of LXR/RXR-induced proteins including apolipoproteins; these latter effects were mirrored within the HDL proteome in circulation. Despite remarkable protection against steatosis, HFD-induced hypercholesterolemia and repression of the liver-to-bile cholesterol transporter ABCG5/8 were not rescued with NaS.

讨论/结论：The cardiometabolic health benefits of NaS are likely attributable to reprogramming of hepatic metabolic pathways to increase fatty acid utilization in the setting of nutritional overabundance. Reduced hepatic cholesterol levels, coupled with reduced LXR/RXR-induced proteins, may underlie lack of rescue of ABCG5/8 expression with NaS. This remarkable protection against HFD-induced hepatosteatosis did not translate to improvements in cholesterol homeostasis.