Division of Gastroenterology and Hepatology, Department of Medical Sciences, University of Turin, Turin, Italy.
Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus, Denmark.
J Hepatol. 2019 Nov;71(5):1012-1021. doi: 10.1016/j.jhep.2019.06.031. Epub 2019 Jul 10.
BACKGROUND & AIMS: The pathogenesis of non-alcoholic fatty liver disease (NAFLD) and steatohepatitis (NASH) is likely due to the interaction between a deranged metabolic milieu and local mediators of hepatic inflammation and fibrosis. We undertook this study to elucidate the interplay between macrophage activation, insulin resistance (IR) in target organs/tissues and hepatic damage.
In 40 non-diabetic patients with biopsy-proven NAFLD we assessed: i) endogenous glucose production (EGP), glucose clearance and indexes of IR in the adipose tissue (Adipo-IR and Lipo-IR) and in the liver (Hep-IR) by tracer infusion ([6,6-2H2]glucose and [2H5]glycerol); ii) macrophage activity (by soluble sCD163) and iii) hepatic expression of CD163 (hCD163).
We found that sCD163 levels paralleled both the plasma free fatty acid (FFA) levels and lipolysis from adipose tissue. Consistently, sCD163 significantly correlated with adipose tissue IR (Adipo-IR: r = 0.32, p = 0.042; Lipo-IR: r = 0.39, p = 0.012). At multiple regression analysis, sCD163 levels were associated with FFA levels (r = 0.35, p = 0.026). In vitro exposure of human monocyte-derived macrophages to palmitate enhanced sCD163 secretion. Conversely, sCD163 did not correlate with EGP or with Hep-IR. In the liver, hCD163 positively correlated with sCD163 (r = 0.58, p = 0.007) and the degree of steatosis (r = 0.34, p = 0.048), but not with EGP or Hep-IR (r = -0.27 and r = 0.11, respectively, p >0.10, both).
Our findings suggest a link between deranged metabolism in the adipose tissue and activation of hepatic macrophages in patients with NAFLD, possibly in response to FFA overflow and independent of obesity and diabetes. Conversely, our findings do not support a link between activated hepatic macrophages and glucose metabolism (EGP or Hep-IR). The relationship between adipose tissue IR and hepatic macrophages should be considered to define therapeutic targets for NAFLD.
The pathogenesis of non-alcoholic fatty liver disease (NAFLD) and steatohepatitis (NASH) is likely due to the interaction between a deranged metabolic milieu and local mediators of hepatic inflammation and fibrosis in the insulin resistant state. This study provides in vivo support for a possible link between deranged metabolism in the adipose tissue and activation of hepatic macrophages in patients with NAFLD, most likely in response to free fatty acid overflow and independent of obesity and diabetes.
非酒精性脂肪性肝病（NAFLD）和脂肪性肝炎（NASH）的发病机制可能是由于代谢环境紊乱与肝内炎症和纤维化的局部介质之间的相互作用。我们进行这项研究旨在阐明巨噬细胞激活、靶器官/组织胰岛素抵抗（IR）与肝损伤之间的相互关系。
在 40 名经活检证实的 NAFLD 非糖尿病患者中，我们评估了以下内容：i）通过示踪剂输注（[6,6-2H2]葡萄糖和[2H5]甘油）评估内源性葡萄糖生成（EGP）、葡萄糖清除率和脂肪组织（Adipo-IR 和 Lipo-IR）和肝脏（Hep-IR）中的 IR 指数；ii）巨噬细胞活性（通过可溶性 sCD163）；iii）肝内 CD163 表达（hCD163）。
我们发现 sCD163 水平与血浆游离脂肪酸（FFA）水平和脂肪组织的脂肪分解平行。一致地，sCD163 与脂肪组织 IR 显著相关（Adipo-IR：r=0.32，p=0.042；Lipo-IR：r=0.39，p=0.012）。多元回归分析显示，sCD163 水平与 FFA 水平相关（r=0.35，p=0.026）。体外培养人单核细胞衍生的巨噬细胞暴露于棕榈酸可增强 sCD163 的分泌。相反，sCD163 与 EGP 或 Hep-IR 均无相关性。在肝脏中，hCD163 与 sCD163 呈正相关（r=0.58，p=0.007），与脂肪变性程度呈正相关（r=0.34，p=0.048），但与 EGP 或 Hep-IR 无相关性（r=-0.27 和 r=0.11，p>0.10，均）。
我们的研究结果表明，在 NAFLD 患者中，脂肪组织代谢紊乱与肝巨噬细胞激活之间存在关联，这可能是对游离脂肪酸溢出的反应，与肥胖和糖尿病无关。相反，我们的研究结果不支持肝巨噬细胞激活与葡萄糖代谢（EGP 或 Hep-IR）之间存在关联。脂肪组织 IR 与肝巨噬细胞之间的关系值得进一步研究，以确定 NAFLD 的治疗靶点。
非酒精性脂肪性肝病（NAFLD）和脂肪性肝炎（NASH）的发病机制可能是由于代谢紊乱与胰岛素抵抗状态下肝内炎症和纤维化的局部介质之间的相互作用。本研究为脂肪组织代谢紊乱与 NAFLD 患者肝巨噬细胞激活之间可能存在的联系提供了体内证据，这很可能是对游离脂肪酸溢出的反应，与肥胖和糖尿病无关。
