A Synthetic Peptide Designed to Neutralize Lipopolysaccharides Attenuates Metaflammation and Diet-Induced Metabolic Derangements in Mice.
A Synthetic Peptide Designed to Neutralize Lipopolysaccharides Attenuates Metaflammation and Diet-Induced Metabolic Derangements in Mice.
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DOI：
10.3389/fimmu.2021.701275
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发表时间：
2021
影响因子：
7.3
通讯作者：
Thiemermann C
中科院分区：
文献类型：
--
作者：
Mohammad S;Al Zoubi S;Collotta D;Krieg N;Wissuwa B;Ferreira Alves G;Purvis GSD;Norata GD;Baragetti A;Catapano AL;Solito E;Zechendorf E;Schürholz T;Correa-Vargas W;Brandenburg K;Coldewey SM;Collino M;Yaqoob MM;Martin L;Thiemermann C
代谢性内毒素血症被认为在代谢、胰岛素抵抗和最终的2型糖尿病(T2 DM)的病理生理学中起作用。内源性抗菌肽(AMPs)在T2 DM中的作用尚不清楚，如长春新碱LL-37。我们在这里首次报道，与健康志愿者相比，T2 DM患者的血浆IL-37水平升高。在反向翻译的方法中，我们研究了AMP，肽19-2.5，在高脂饮食(HFD)诱导的胰岛素抵抗、脂肪性肝炎和T2 DM小鼠模型中的作用。饲喂HFD 12周的小鼠出现肥胖、血糖调节障碍、高胆固醇血症、微量蛋白尿和脂肪性肝炎，所有这些都被多肽19-2.5缓解。高脂饮食引起的小鼠肝脏脂肪变性可导致活化B细胞核因子-ĸB(核因子-ĸB)的激活(kappa-β激酶抑制因子I-LRRB的磷酸化，p65转位到细胞核)，表达依赖于核因子的诱导型一氧化氮合酶(INOS)，并激活NOD、LRRRRRP3和含有NOD、LRR和PYRP3结构域的炎性小体，这些作用均被多肽19-2.5抑制。喂饲小鼠，HFD还导致脂质清道夫受体分化簇36(CD36)的表达增强，继而激活细胞外信号调节蛋白(ERK)1/2，这两种受体都被肽19-2.5取消。综上所述，这些结果表明AMP，19-2.5肽可以降低胰岛素抵抗、脂肪性肝炎和蛋白尿。这些作用至少部分是由于阻止了CD36的表达，并可能为代谢性内毒素血症在代谢和最终T2 DM发病机制中的作用提供进一步的证据。观察到T2 DM患者内源性AMP LL-37水平的升高可能有助于限制疾病的严重程度。
Metabolic endotoxemia has been suggested to play a role in the pathophysiology of metaflammation, insulin-resistance and ultimately type-2 diabetes mellitus (T2DM). The role of endogenous antimicrobial peptides (AMPs), such as the cathelicidin LL-37, in T2DM is unknown. We report here for the first time that patients with T2DM compared to healthy volunteers have elevated plasma levels of LL-37. In a reverse-translational approach, we have investigated the effects of the AMP, peptide 19-2.5, in a murine model of high-fat diet (HFD)-induced insulin-resistance, steatohepatitis and T2DM. HFD-fed mice for 12 weeks caused obesity, an impairment in glycemic regulations, hypercholesterolemia, microalbuminuria and steatohepatitis, all of which were attenuated by Peptide 19-2.5. The liver steatosis caused by feeding mice a HFD resulted in the activation of nuclear factor kappa light chain enhancer of activated B cells (NF-ĸB) (phosphorylation of inhibitor of kappa beta kinase (IKK)α/β, IκBα, translocation of p65 to the nucleus), expression of NF-ĸB-dependent protein inducible nitric oxide synthase (iNOS) and activation of the NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome, all of which were reduced by Peptide 19-2.5. Feeding mice, a HFD also resulted in an enhanced expression of the lipid scavenger receptor cluster of differentiation 36 (CD36) secondary to activation of extracellular signal-regulated kinases (ERK)1/2, both of which were abolished by Peptide 19-2.5. Taken together, these results demonstrate that the AMP, Peptide 19-2.5 reduces insulin-resistance, steatohepatitis and proteinuria. These effects are, at least in part, due to prevention of the expression of CD36 and may provide further evidence for a role of metabolic endotoxemia in the pathogenesis of metaflammation and ultimately T2DM. The observed increase in the levels of the endogenous AMP LL-37 in patients with T2DM may serve to limit the severity of the disease.
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影响因子：
7.7
作者：
Cani, Patrice D.;Amar, Jacques;Burcelin, Remy
通讯作者：
Burcelin, Remy
影响因子：
9.3
作者：
Al-Attas OS;Al-Daghri NM;Al-Rubeaan K;da Silva NF;Sabico SL;Kumar S;McTernan PG;Harte AL
通讯作者：
Harte AL
影响因子：
4.2
作者：
Awad WA;Hess C;Hess M
通讯作者：
Hess M
影响因子：
1.8
作者：
Fukumoto, K;Nagaoka, I;Miyano, T
通讯作者：
Miyano, T
影响因子：
8.2
作者：
Davies, Melanie J.;D'Alessio, David A.;Buse, John B.
通讯作者：
Buse, John B.