Endoplasmic reticulum stress, hepatocyte CD1d and NKT cell abnormalities in murine fatty livers
Endoplasmic reticulum stress, hepatocyte CD1d and NKT cell abnormalities in murine fatty livers
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DOI：
10.1038/labinvest.3700603
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发表时间：
2007-09-01
影响因子：
5
通讯作者：
Diehl, Anna Mae
中科院分区：
文献类型：
--
作者：
Yang, Liu;Jhaveri, Ravi;Diehl, Anna Mae
肝脏调节脂类平衡，富含对脂类抗原作出反应的自然杀伤T细胞(NKT)。NKT细胞的最佳成熟和激活需要它们与由抗原提呈细胞上的分化簇-1(CD-1)分子递呈的脂类抗原相互作用。肝细胞表达CD1d，并向NKT细胞递呈脂类抗原。脂肪肝小鼠会出现肝脏NKT细胞耗尽和调节失调。在此，我们评估脂肪变性肝细胞上CD1d含量降低是否导致脂肪肝相关的NKT细胞异常。我们发现，尽管肥胖/肥胖小鼠的脂肪肝细胞表达正常水平的CD1d，但与正常肝细胞相比，脂肪肝细胞质膜上的CD1d显著减少。这具有功能意义，因为ob/ob肝细胞在体外激活CD1d限制性T细胞反应的能力较弱，而ob/ob肝脏中CD1d反应的NKT细胞减少。内质网(ER)中的事件通常调节CD1d向质膜的运输。肝脏脂肪变性与内质网应激有关。为了确定内质网应激是否减少了CD-1在肝细胞上的积聚，我们评估了ob/ob小鼠的肝脏内质网应激，并用衣霉素处理培养的肝细胞和瘦小鼠来诱导内质网应激。Ob/ob和衣霉素处理的小鼠的肝脏中都出现了脂质堆积和内质网应激。衣霉素使肝细胞CD1d呈剂量依赖性下降，抑制肝细胞活化CD1d限制性T细胞反应，耗竭肝脏CD1d反应性NKT细胞群，促进肝脏细胞因子产生的Th-1极化。总之，内质网应激相关的肝细胞CD1d的减少是脂肪肝中NKT细胞失调的原因之一。
The liver regulates lipid homeostasis and is enriched with natural killer T (NKT) cells that respond to lipid antigens. Optimal maturation and activation of NKT cells requires their interaction with lipid antigens that are presented by cluster of differentiation-1 (CD-1) molecules on antigen-presenting cells. Hepatocytes express CD1d and present lipid antigens to NKT cells. Depletion and dysregulation of hepatic NKT cells occurs in mice with fatty livers. Herein, we assess whether reduced CD1d content on steatotic hepatocytes contributes to fatty liver-associated NKT cell abnormalities. We show that despite expressing normal levels of CD1d mRNA, fatty hepatocytes from ob/ob mice have significantly less CD1d on their plasma membranes than normal hepatocytes. This has functional significance because ob/ob hepatocytes are less able to activate CD1d-restricted T-cell responses in vitro, and CD1d-reactive NKT cells are reduced in ob/ob livers. Events in the endoplasmic reticulum (ER) normally regulate CD1d trafficking to plasma membranes. Hepatic steatosis has been associated with ER stress. To determine if ER stress reduces CD-1 accumulation on hepatocytes, we evaluated hepatic ER stress in ob/ob mice and treated cultured hepatocytes and lean mice with tunicamycin to induce ER stress. Lipid accumulation and ER stress occurred in the livers of both ob/ob and tunicamycin-treated mice. Tunicamycin caused dose-dependent decreases in hepatocyte CD1d, inhibited hepatocyte activation of CD1d-restricted T-cell responses, depleted liver populations of CD1d-reactive NKT cells and promoted Th-1 polarization of hepatic cytokine production. In conclusion, ER stress-related decreases in hepatocyte CD1d contribute to NKT cell dysregulation in fatty livers.