Pardo Virginia, González-Rodríguez Águeda, Guijas Carlos, Balsinde Jesús, Valverde Ángela M
From the Instituto de Investigaciones Biomédicas Alberto Sols (Consejo Superior de Investigaciones Científicas/Universidad Autónoma de Madrid), 28029 Madrid, Spain, the Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III, 28029 Madrid, Spain, and.
From the Instituto de Investigaciones Biomédicas Alberto Sols (Consejo Superior de Investigaciones Científicas/Universidad Autónoma de Madrid), 28029 Madrid, Spain, the Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III, 28029 Madrid, Spain, and
J Biol Chem. 2015 May 1;290(18):11663-77. doi: 10.1074/jbc.M115.649483. Epub 2015 Mar 19.
Chronic low grade inflammation in adipose tissue during obesity is associated with an impairment of the insulin signaling cascade. In this study, we have evaluated the impact of palmitate or oleate overload of macrophage/Kupffer cells in triggering stress-mediated signaling pathways, in lipoapoptosis, and in the cross-talk with insulin signaling in hepatocytes. RAW 264.7 macrophages or Kupffer cells were stimulated with oleate or palmitate, and levels of M1/M2 polarization markers and the lipidomic profile of eicosanoids were analyzed. Whereas proinflammatory cytokines and total eicosanoids were elevated in macrophages/Kupffer cells stimulated with palmitate, enhanced arginase 1 and lower leukotriene B4 (LTB4) levels were detected in macrophages stimulated with oleate. When hepatocytes were pretreated with conditioned medium (CM) from RAW 264.7 or Kupffer cells loaded with palmitate (CM-P), phosphorylation of stress kinases and endoplasmic reticulum stress signaling was increased, insulin signaling was impaired, and lipoapoptosis was detected. Conversely, enhanced insulin receptor-mediated signaling and reduced levels of the phosphatases protein tyrosine phosphatase 1B (PTP1B) and phosphatase and tensin homolog (PTEN) were found in hepatocytes treated with CM from macrophages stimulated with oleate (CM-O). Supplementation of CM-O with LTB4 suppressed insulin sensitization and increased PTP1B and PTEN. Furthermore, LTB4 decreased insulin receptor tyrosine phosphorylation in hepatocytes, activated the NFκB pathway, and up-regulated PTP1B and PTEN, these effects being mediated by LTB4 receptor BTL1. In conclusion, oleate and palmitate elicit an opposite cross-talk between macrophages/Kupffer cells and hepatocytes. Whereas CM-P interferes at the early steps of insulin signaling, CM-O increases insulin sensitization, possibly by reducing LTB4.
肥胖期间脂肪组织中的慢性低度炎症与胰岛素信号级联受损有关。在本研究中，我们评估了巨噬细胞/库普弗细胞中棕榈酸酯或油酸酯过载对触发应激介导的信号通路、脂肪细胞凋亡以及与肝细胞中胰岛素信号相互作用的影响。用油酸酯或棕榈酸酯刺激RAW 264.7巨噬细胞或库普弗细胞，并分析M1/M2极化标志物水平和类花生酸的脂质组学特征。在用棕榈酸酯刺激的巨噬细胞/库普弗细胞中促炎细胞因子和总类花生酸升高，而在用油酸酯刺激的巨噬细胞中检测到精氨酸酶1增强和白三烯B4（LTB4）水平降低。当用来自负载棕榈酸酯的RAW 264.7或库普弗细胞的条件培养基（CM）预处理肝细胞时，应激激酶的磷酸化和内质网应激信号增强，胰岛素信号受损，并检测到脂肪细胞凋亡。相反，在用来自用油酸酯刺激的巨噬细胞的CM（CM-O）处理的肝细胞中发现胰岛素受体介导的信号增强，并且磷酸酶蛋白酪氨酸磷酸酶1B（PTP1B）和磷酸酶及张力蛋白同源物（PTEN）水平降低。用LTB4补充CM-O可抑制胰岛素敏感性并增加PTP1B和PTEN。此外，LTB4降低肝细胞中胰岛素受体酪氨酸磷酸化，激活NFκB途径，并上调PTP1B和PTEN，这些作用由LTB4受体BTL1介导。总之，油酸酯和棕榈酸酯在巨噬细胞/库普弗细胞和肝细胞之间引发相反的相互作用。CM-P在胰岛素信号传导的早期步骤进行干扰，而CM-O可能通过降低LTB4来增加胰岛素敏感性。
