IL-17 signaling accelerates the progression of nonalcoholic fatty liver disease in mice.
IL-17 signaling accelerates the progression of nonalcoholic fatty liver disease in mice.
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DOI：
10.1002/hep.26746
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发表时间：
2014-05
期刊：
影响因子：
13.5
通讯作者：
Divanovic, Senad
中科院分区：
文献类型：
--
作者：
Harley, Isaac T. W.;Stankiewicz, Traci E.;Giles, Daniel A.;Softic, Samir;Flick, Leah M.;Cappelletti, Monica;Sheridan, Rachel;Xanthakos, Stavra A.;Steinbrecher, Kris A.;Sartor, R. Balfour;Kohli, Rohit;Karp, Christopher L.;Divanovic, Senad
炎症在肥胖的有害代谢和终末器官后遗症中起着重要的致病作用。在这些后遗症中，非酒精性脂肪性肝病（NAFLD）已成为发达国家最常见的慢性肝病。肥胖与白细胞介素（IL）-17轴的激活增加相关，并且该轴可以在不同情况下调节肝损伤，这一孪生观察促使我们解决IL-17 RA信号传导在NAFLD进展中的作用。我们进一步研究了微生物驱动的IL-17 A是否调节NAFLD的发展和进展。我们在这里表明，IL-17 RA −/−小鼠对高脂饮食应激的反应比野生型对照组显著更大的体重增加，内脏肥胖和肝脏脂肪变性。然而，在IL-17 RA −/−小鼠中，肥胖驱动的脂质蓄积与其终末器官后果脱钩，表现出脂肪性肝炎、烟酰胺腺嘌呤二核苷酸磷酸（NADPH）氧化酶表达和肝细胞损伤减少。IL-17 A的中和显著降低了野生型小鼠中肥胖驱动的肝细胞损伤。此外，用分节丝状细菌（SFB）（一种诱导IL-17 A产生的细菌）定殖小鼠，加剧了肥胖诱导的肝细胞损伤。相反，SFB耗竭保护免于肥胖诱导的肝细胞损伤。结论：这些数据表明，肥胖驱动的IL-17轴激活是NAFLD发展和进展为脂肪性肝炎的核心，并将IL-17途径确定为这种疾病的新治疗靶点。（肝病学2014;59：1830-1839）
Inflammation plays a central pathogenic role in the pernicious metabolic and end-organ sequelae of obesity. Among these sequelae, nonalcoholic fatty liver disease (NAFLD) has become the most common chronic liver disease in the developed world. The twinned observations that obesity is associated with increased activation of the interleukin (IL)-17 axis and that this axis can regulate liver damage in diverse contexts prompted us to address the role of IL-17RA signaling in the progression of NAFLD. We further examined whether microbe-driven IL-17A regulated NAFLD development and progression. We show here that IL-17RA−/− mice respond to high-fat diet stress with significantly greater weight gain, visceral adiposity, and hepatic steatosis than wild-type controls. However, obesity-driven lipid accumulation was uncoupled from its end-organ consequences in IL-17RA−/− mice, which exhibited decreased steatohepatitis, nicotinamide adenine dinucleotide phosphate (NADPH)-oxidase enzyme expression, and hepatocellular damage. Neutralization of IL-17A significantly reduced obesity-driven hepatocellular damage in wild-type mice. Further, colonization of mice with segmented filamentous bacteria (SFB), a commensal that induces IL-17A production, exacerbated obesity-induced hepatocellular damage. In contrast, SFB depletion protected from obesity-induced hepatocellular damage. Conclusion: These data indicate that obesity-driven activation of the IL-17 axis is central to the development and progression of NAFLD to steatohepatitis and identify the IL-17 pathway as a novel therapeutic target in this condition. (Hepatology 2014;59:1830–1839)
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影响因子：
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作者：
Cani, Patrice D.;Amar, Jacques;Burcelin, Remy
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Burcelin, Remy
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Whitfield, John B.
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Kisseleva T
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作者：
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Hara, Michio