Fatty Acid Metabolites Combine with Reduced β Oxidation to Activate Th17 Inflammation in Human Type 2 Diabetes.
Fatty Acid Metabolites Combine with Reduced β Oxidation to Activate Th17 Inflammation in Human Type 2 Diabetes.
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DOI：
10.1016/j.cmet.2019.07.004
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发表时间：
2019-09-03
期刊：
影响因子：
29
通讯作者：
Nikolajczyk BS
中科院分区：
文献类型：
--
作者：
Nicholas DA;Proctor EA;Agrawal M;Belkina AC;Van Nostrand SC;Panneerseelan-Bharath L;Jones AR 4th;Raval F;Ip BC;Zhu M;Cacicedo JM;Habib C;Sainz-Rueda N;Persky L;Sullivan PG;Corkey BE;Apovian CM;Kern PA;Lauffenburger DA;Nikolajczyk BS
调节代谢产物和下游能量产生的机制是T细胞细胞因子产生的关键决定因素，但预测肥胖者代谢状态的Th17谱背后的过程尚未经过测试。Th17的功能需要脂肪酸摄取，我们的新数据表明，阻断CPT1A可以抑制2型糖尿病(T2D)患者细胞产生Th17相关细胞因子。在T2D受试者的免疫细胞中，CACT：CPT1A的低比率表明线粒体功能发生了变化，这与这些细胞倾向于通过糖酵解而不是脂肪酸氧化来产生ATP的偏好相一致。然而，糖酵解并不是Th17细胞因子的关键。相反，T细胞中的β氧化阻断或CACT被敲除以模拟T2D的特征，促进瘦受试者的细胞利用16C-脂肪酰卡尼汀来支持Th17型细胞因子。这些数据表明，长链酰肉碱与受损的β氧化相结合，可以促进人类T2D的疾病预见性炎症。虽然糖酵解通常会加剧炎症，但Nicholas、Proctor和Agrawal等人认为。报告说，来自2型糖尿病患者的PBMC使用一种不同的机制来支持慢性炎症，在很大程度上与燃料的利用无关。对健康受试者细胞进行的功能丧失和功能获得实验表明，线粒体变化和脂肪酸代谢产物的增加共同推动了慢性T2D样炎症。
Mechanisms that regulate metabolites and downstream energy generation are key determinants of T cell cytokine production, but the processes underlying the Th17 profile that predicts the metabolic status of people with obesity are untested. Th17 function requires fatty acid uptake, and our new data show that blockade of CPT1A inhibits Th17-associated cytokine production by cells from people with type 2 diabetes (T2D). A low CACT:CPT1A ratio in immune cells from T2D subjects indicates altered mitochondrial function and coincides with the preference of these cells to generate ATP through glycolysis rather than fatty acid oxidation. However, glycolysis was not critical for Th17 cytokines. Instead, β oxidation blockade or CACT knockdown in T cells to mimic characteristics of T2D promotes cells from lean subjects to utilize 16C-fatty acylcarnitine to support a Th17 cytokines. These data show long chain acylcarnitine combines with compromised β oxidation to promote disease-predictive inflammation in human T2D. Although glycolysis generally fuels inflammation, Nicholas, Proctor and Agrawal et al. report that PBMCs from subjects with type 2 diabetes use a different mechanism to support chronic inflammation largely independent of fuel utilization. Loss- and gain-of-function experiments in cells from healthy subjects show mitochondrial alterations combine with increases in fatty acid metabolites to drive chronic T2D-like inflammation.
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人白细胞介素17产生的细胞起源于CD161+ CD4+ T细胞前体。
影响因子：
15.3
作者：
Cosmi, Lorenzo;De Palma, Raffaele;Santarlasci, Veronica;Maggi, Laura;Capone, Manuela;Frosali, Francesca;Rodolico, Gabriella;Querci, Valentina;Abbate, Gianfranco;Angeli, Roberta;Berrino, Liberato;Fambrini, Massimiliano;Caproni, Marzia;Tonelli, Francesco;Lazzeri, Elena;Parronchi, Paola;Liotta, Francesco;Maggi, Enrico;Romagnani, Sergio;Annunziato, Francesco
通讯作者：
Annunziato, Francesco
DOI：
10.4049/jimmunol.1002615
发表时间：
2011-01-15
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Jagannathan-Bogdan M;McDonnell ME;Shin H;Rehman Q;Hasturk H;Apovian CM;Nikolajczyk BS
通讯作者：
Nikolajczyk BS
影响因子：
3.5
作者：
CARLING, D;ZAMMIT, VA;HARDIE, DG
通讯作者：
HARDIE, DG
DOI：
10.1073/pnas.1215840110
发表时间：
2013-03-26
影响因子：
11.1
作者：
DeFuria, Jason;Belkina, Anna C.;Nikolajczyk, Barbara S.
通讯作者：
Nikolajczyk, Barbara S.
影响因子：
32.4
作者：
De Rosa, Veronica;Procaccini, Claudio;Matarese, Giuseppe
通讯作者：
Matarese, Giuseppe