Hennige Anita M, Staiger Harald, Wicke Corinna, Machicao Fausto, Fritsche Andreas, Häring Hans-Ulrich, Stefan Norbert
Department of Internal Medicine, Division of Endocrinology, Nephrology, Vascular Disease and Clinical Chemistry, University of Tübingen, Tübingen, Germany.
PLoS One. 2008 Mar 12;3(3):e1765. doi: 10.1371/journal.pone.0001765.
The secreted liver protein fetuin-A (AHSG) is up-regulated in hepatic steatosis and the metabolic syndrome. These states are strongly associated with low-grade inflammation and hypoadiponectinemia. We, therefore, hypothesized that fetuin-A may play a role in the regulation of cytokine expression, the modulation of adipose tissue expression and plasma concentration of the insulin-sensitizing and atheroprotective adipokine adiponectin.
Human monocytic THP1 cells and human in vitro differenttiated adipocytes as well as C57BL/6 mice were treated with fetuin-A. mRNA expression of the genes encoding inflammatory cytokines and the adipokine adiponectin (ADIPOQ) was assessed by real-time RT-PCR. In 122 subjects, plasma levels of fetuin-A, adiponectin and, in a subgroup, the multimeric forms of adiponectin were determined. Fetuin-A treatment induced TNF and IL1B mRNA expression in THP1 cells (p<0.05). Treatment of mice with fetuin-A, analogously, resulted in a marked increase in adipose tissue Tnf mRNA as well as Il6 expression (27- and 174-fold, respectively). These effects were accompanied by a decrease in adipose tissue Adipoq mRNA expression and lower circulating adiponectin levels (p<0.05, both). Furthermore, fetuin-A repressed ADIPOQ mRNA expression of human in vitro differentiated adipocytes (p<0.02) and induced inflammatory cytokine expression. In humans in plasma, fetuin-A correlated positively with high-sensitivity C-reactive protein, a marker of subclinical inflammation (r = 0.26, p = 0.01), and negatively with total- (r = -0.28, p = 0.02) and, particularly, high molecular weight adiponectin (r = -0.36, p = 0.01).
We provide novel evidence that the secreted liver protein fetuin-A induces low-grade inflammation and represses adiponectin production in animals and in humans. These data suggest an important role of fatty liver in the pathophysiology of insulin resistance and atherosclerosis.
分泌型肝脏蛋白胎球蛋白-A（AHSG）在肝脂肪变性和代谢综合征中表达上调。这些状态与低度炎症和低脂联素血症密切相关。因此，我们推测胎球蛋白-A可能在细胞因子表达调节、脂肪组织表达调控以及胰岛素增敏和抗动脉粥样硬化脂肪因子脂联素的血浆浓度调节中发挥作用。
用人单核细胞THP1细胞、人体外分化脂肪细胞以及C57BL/6小鼠进行胎球蛋白-A处理。通过实时逆转录聚合酶链反应评估编码炎性细胞因子和脂肪因子脂联素（ADIPOQ）的基因的mRNA表达。在122名受试者中，测定了胎球蛋白-A、脂联素的血浆水平，并且在一个亚组中测定了脂联素的多聚体形式。胎球蛋白-A处理诱导THP1细胞中TNF和IL1B mRNA表达（p<0.05）。类似地，用胎球蛋白-A处理小鼠导致脂肪组织Tnf mRNA以及Il6表达显著增加（分别为27倍和174倍）。这些作用伴随着脂肪组织Adipoq mRNA表达降低和循环脂联素水平降低（两者均p<0.05）。此外，胎球蛋白-A抑制人体外分化脂肪细胞的ADIPOQ mRNA表达（p<0.02）并诱导炎性细胞因子表达。在人类血浆中，胎球蛋白-A与亚临床炎症标志物高敏C反应蛋白呈正相关（r = 0.26，p = 0.01），与总脂联素（r = -0.28，p = 0.02），特别是高分子量脂联素呈负相关（r = -0.36，p = 0.01）。
我们提供了新的证据，表明分泌型肝脏蛋白胎球蛋白-A在动物和人类中诱导低度炎症并抑制脂联素产生。这些数据表明脂肪肝在胰岛素抵抗和动脉粥样硬化的病理生理学中起重要作用。
