Insulin signaling as a potential natural killer cell checkpoint in fatty liver disease.
Insulin signaling as a potential natural killer cell checkpoint in fatty liver disease.
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DOI：
10.1002/hep4.1146
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发表时间：
2018-03
影响因子：
5.1
通讯作者：
Safadi R
中科院分区：
文献类型：
--
作者：
Amer J;Salhab A;Noureddin M;Doron S;Abu-Tair L;Ghantous R;Mahamid M;Safadi R
胰岛素抵抗是非酒精性脂肪性肝病（NAFLD）进展的关键危险因素，并可能导致肝纤维化。自然杀伤（NK）细胞被认为通过杀死活化的肝星状细胞（HSC）发挥抗纤维化作用。在这里，我们研究了NK细胞和HSC之间的相互作用是如何被NAFLD中的胰岛素抵抗所改变的。从22名健康成人和72名目前未服用任何药物且无代谢综合征体征的NAFLD患者中收集新鲜外周血NK细胞（分化簇[CD] 56 dim，CD 16+）。当在具有HSC的培养基中培养时，评估NK细胞的胰岛素受体表达和细胞毒活性。NAFLD患者的纤维化程度与血清促炎细胞因子表达升高和胰岛素抵抗程度呈线性相关。与此同时，纤维化严重程度与NK细胞上的胰岛素受体表达以及通过流式细胞术通过CD 107 a测定的细胞毒性活性呈负相关。来自表现出严重纤维化和胰岛素抵抗的供体的NK细胞表现出显著的哺乳动物雷帕霉素靶标和细胞外信号调节激酶耗竭（通过NK细胞蛋白质印迹定量），细胞凋亡增加，并且未能减弱体外HSC活化。当暴露于胰岛素刺激健康NK细胞的细胞毒性活性时，雷帕霉素阻止了这种作用并降低了NK胰岛素受体的表达。结论：F1和F2纤维化中升高的胰岛素水平增强了NK细胞对HSC的细胞毒性活性，并通过胰岛素受体和雷帕霉素下游哺乳动物靶标以及细胞外信号调节激酶途径阻止纤维化进展。在胰岛素抵抗的更晚期阶段（F3和F4纤维化），源于胰岛素受体表达低和/或血清胰岛素水平低的NK细胞活性受损可能会进一步恶化纤维化，并可能导致肝硬化的发展。（Hepatology Communications 2018;2：285 - 298）
Insulin resistance is a key risk factor in the progression of nonalcoholic fatty liver disease (NAFLD) and may lead to liver fibrosis. Natural killer (NK) cells are thought to exert an antifibrotic effect through their killing of activated hepatic stellate cells (HSCs). Here, we investigated how the interplay between NK cells and HSCs are modified by insulin resistance in NAFLD. Fresh peripheral blood NK cells (clusters of differentiation [CD]56dim, CD16+) were collected from 22 healthy adults and 72 patients with NAFLD not currently taking any medications and without signs of metabolic syndrome. NK cells were assessed for insulin receptor expressions and cytotoxic activity when cultured in medium with HSCs. Fibrosis severities in patients with NAFLD were correlated linearly with elevated serum proinflammatory cytokine expression and insulin resistance severity. At the same time, fibrosis severities inversely correlated with insulin receptor expressions on NK cells as well as with their cytotoxic activities determined by CD107a by flow cytometry. NK cells from donors exhibiting severe fibrosis and insulin resistance exhibited significant mammalian target of rapamycin and extracellular signal‐regulated kinase depletion (through NK cell western blot quantitation), increased apoptosis, and failure to attenuate HSC activation in vitro. While exposure to insulin stimulated the cytotoxic activity of healthy NK cells, rapamycin prevented this effect and reduced NK insulin receptor expressions. Conclusion: Elevated insulin levels in F1 and F2 fibrosis enhances NK cell cytotoxic activity toward HSCs and prevents fibrosis progression by insulin receptors and downstream mammalian target of rapamycin and extracellular signal‐regulated kinase pathways. At more advanced stages of insulin resistance (F3 and F4 fibrosis), impaired NK cell activity rooted in low insulin receptor expression and or low serum insulin levels could further deteriorate fibrosis and may likely lead to cirrhosis development. (Hepatology Communications 2018;2:285‐298)
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影响因子：
7.3
作者：
Fasbender F;Widera A;Hengstler JG;Watzl C
通讯作者：
Watzl C
影响因子：
5.1
作者：
Kleiner DE;Makhlouf HR
通讯作者：
Makhlouf HR
影响因子：
82.9
作者：
Arkan, MC;Hevener, AL;Karin, M
通讯作者：
Karin, M
DOI：
10.1056/nejmoa0907929
发表时间：
2010-05-06
期刊：
The New England journal of medicine
影响因子：
--
作者：
Sanyal AJ;Chalasani N;Kowdley KV;McCullough A;Diehl AM;Bass NM;Neuschwander-Tetri BA;Lavine JE;Tonascia J;Unalp A;Van Natta M;Clark J;Brunt EM;Kleiner DE;Hoofnagle JH;Robuck PR;NASH CRN
通讯作者：
NASH CRN
影响因子：
3.9
作者：
Destefano MA;Jacinto E
通讯作者：
Jacinto E