肥胖和非酒精性脂肪性肝病患者的脂肪组织免疫学、炎症、外泌体与胰岛素敏感性的关系。
Associations Among Adipose Tissue Immunology, Inflammation, Exosomes and Insulin Sensitivity in People With Obesity and Nonalcoholic Fatty Liver Disease.
机构信息
Department of Surgery, Washington University School of Medicine, St. Louis, Missouri.
Center for Human Nutrition, Washington University School of Medicine, St. Louis, Missouri.
出版信息
Gastroenterology. 2021 Sep;161(3):968-981.e12. doi: 10.1053/j.gastro.2021.05.008. Epub 2021 May 15.
BACKGROUND AND AIMS
Insulin resistance is a key factor in the pathogenesis of nonalcoholic fatty liver disease (NAFLD). We evaluated the importance of subcutaneous abdominal adipose tissue (SAAT) inflammation and both plasma and SAAT-derived exosomes in regulating insulin sensitivity in people with obesity and NAFLD.
METHODS
Adipose tissue inflammation (macrophage and T-cell content and expression of proinflammatory cytokines), liver and whole-body insulin sensitivity (assessed using a hyperinsulinemic-euglycemic clamp and glucose tracer infusion), and 24-hour serial plasma cytokine concentrations were evaluated in 3 groups stratified by adiposity and intrahepatic triglyceride (IHTG) content: (1) lean with normal IHTG content (LEAN; N = 14); (2) obese with normal IHTG content (OB-NL; N = 28); and (3) obese with NAFLD (OB-NAFLD; N = 28). The effect of plasma and SAAT-derived exosomes on insulin-stimulated Akt phosphorylation in human skeletal muscle myotubes and mouse primary hepatocytes was assessed in a subset of participants.
RESULTS
Proinflammatory macrophages, proinflammatory CD4 and CD8 T-cell populations, and gene expression of several cytokines in SAAT were greater in the OB-NAFLD than the OB-NL and LEAN groups. However, with the exception of PAI-1, which was greater in the OB-NAFLD than the LEAN and OB-NL groups, 24-hour plasma cytokine concentration areas-under-the-curve were not different between groups. The percentage of proinflammatory macrophages and plasma PAI-1 concentration areas-under-the-curve were inversely correlated with both hepatic and whole-body insulin sensitivity. Compared with exosomes from OB-NL participants, plasma and SAAT-derived exosomes from the OB-NAFLD group decreased insulin signaling in myotubes and hepatocytes.
CONCLUSIONS
Systemic insulin resistance in people with obesity and NAFLD is associated with increased plasma PAI-1 concentrations and both plasma and SAAT-derived exosomes. ClinicalTrials.gov number: NCT02706262 (https://clinicaltrials.gov/ct2/show/NCT02706262).
背景和目的
胰岛素抵抗是非酒精性脂肪性肝病（NAFLD）发病机制中的一个关键因素。我们评估了皮下腹部脂肪组织（SAAT）炎症以及血浆和 SAAT 衍生的外泌体在调节肥胖和 NAFLD 人群胰岛素敏感性方面的重要性。
方法
根据肥胖和肝内甘油三酯（IHTG）含量将 3 组人群分层，评估脂肪组织炎症（巨噬细胞和 T 细胞含量以及促炎细胞因子的表达）、肝脏和全身胰岛素敏感性（通过高胰岛素-正葡萄糖钳夹和葡萄糖示踪剂输注评估）以及 24 小时连续血浆细胞因子浓度：（1）瘦且 IHTG 含量正常（LEAN；N=14）；（2）肥胖且 IHTG 含量正常（OB-NL；N=28）；和（3）肥胖伴 NAFLD（OB-NAFLD；N=28）。在一部分参与者中，评估了血浆和 SAAT 衍生的外泌体对人骨骼肌成肌细胞和小鼠原代肝细胞中胰岛素刺激的 Akt 磷酸化的影响。
结果
与 OB-NL 和 LEAN 组相比，OB-NAFLD 患者的 SAAT 中促炎巨噬细胞、促炎 CD4 和 CD8 T 细胞群以及几种细胞因子的基因表达更高。然而，除了 OB-NAFLD 组比 LEAN 和 OB-NL 组更高的 PAI-1 外，各组之间 24 小时血浆细胞因子浓度曲线下面积无差异。促炎巨噬细胞的百分比和血浆 PAI-1 浓度曲线下面积与肝脏和全身胰岛素敏感性呈负相关。与 OB-NL 参与者的外泌体相比，来自 OB-NAFLD 组的血浆和 SAAT 衍生的外泌体降低了成肌细胞和肝细胞中的胰岛素信号。
结论
肥胖和 NAFLD 患者的全身胰岛素抵抗与血浆 PAI-1 浓度升高以及血浆和 SAAT 衍生的外泌体有关。临床试验注册号：NCT02706262（https://clinicaltrials.gov/ct2/show/NCT02706262）。
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