Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, The Netherlands.
Metabolism. 2011 Jul;60(7):969-75. doi: 10.1016/j.metabol.2010.09.006. Epub 2010 Oct 30.
The metabolic syndrome is associated with nonalcoholic fatty liver disease (NAFLD) as well as with insulin resistance, inflammatory adipokines, endothelial dysfunction, and higher plasma levels of nonesterified fatty acids (NEFA), all of which may also affect the development of NAFLD. Therefore, we investigated to what extent the association between the metabolic syndrome and alanine aminotransferase (ALT, as a surrogate of NAFLD) can be explained by different metabolic intermediates of the metabolic syndrome. Cross-sectional analyses were performed in 434 subjects from the Cohort on Diabetes and Atherosclerosis Maastricht study (264 men; mean age, 59.5 ± 7.1 years). We used multiple linear regression analyses to investigate the association between the metabolic syndrome and ALT and the mediation role of potential mediators herein. The mediators considered were insulin resistance (homeostasis model assessment), an inflammatory adipokine score (based on interleukin-6, serum amyloid A, intercellular adhesion molecule, adiponectin, and leptin), an endothelial dysfunction score (based on E-selectin, vascular cell adhesion molecule, and von Willebrand factor), and plasma levels of NEFA. All analyses were adjusted for age, sex, smoking, alcohol consumption, and use of medication. Subjects with the metabolic syndrome (53.7%) had significantly higher levels of ALT (β = 0.67 SD [95% confidence interval, 0.49-0.85], P < .001). Adjustment for insulin resistance attenuated this difference by 77.3% (to 0.15 SD [-0.04 to 0.35]). Attenuation by adipose tissue-associated inflammation, endothelial dysfunction, and NEFA was more modest (20.7%, 13.1%, and 9.5%, respectively). Part of the attenuation by NEFA, but not of the other mediators, was additional to that of insulin resistance. Insulin resistance constitutes a key pathophysiological mechanism in the association between the metabolic syndrome and NAFLD (measured as ALT), which may operate through adipose tissue-associated inflammation and endothelial dysfunction and to a lesser extent through NEFA, which may have an independent role in the development of NAFLD in subjects with the metabolic syndrome.
代谢综合征与非酒精性脂肪性肝病（NAFLD）以及胰岛素抵抗、炎症性脂肪因子、内皮功能障碍和非酯化脂肪酸（NEFA）血浆水平升高有关，所有这些因素也可能影响 NAFLD 的发展。因此，我们研究了代谢综合征与丙氨酸氨基转移酶（ALT，作为 NAFLD 的替代指标）之间的关联在多大程度上可以用代谢综合征的不同代谢中间产物来解释。在马斯特里赫特糖尿病和动脉粥样硬化队列研究（Cohort on Diabetes and Atherosclerosis Maastricht study）的 434 名受试者中进行了横断面分析（264 名男性；平均年龄 59.5±7.1 岁）。我们使用多元线性回归分析来研究代谢综合征与 ALT 之间的关联，以及其中潜在介质的中介作用。考虑的介质包括胰岛素抵抗（稳态模型评估）、炎症性脂肪因子评分（基于白细胞介素-6、血清淀粉样蛋白 A、细胞间黏附分子、脂联素和瘦素）、内皮功能障碍评分（基于 E-选择素、血管细胞黏附分子和血管性血友病因子）和非酯化脂肪酸（NEFA）的血浆水平。所有分析均调整了年龄、性别、吸烟、饮酒和用药情况。患有代谢综合征（53.7%）的受试者的 ALT 水平明显更高（β=0.67 SD [95%置信区间，0.49-0.85]，P<0.001）。调整胰岛素抵抗后，这种差异降低了 77.3%（至 0.15 SD [-0.04 至 0.35]）。脂肪组织相关炎症、内皮功能障碍和 NEFA 的衰减程度较小（分别为 20.7%、13.1%和 9.5%）。NEFA 部分衰减，而不是其他介质，是胰岛素抵抗之外的因素。胰岛素抵抗是代谢综合征与 NAFLD（以 ALT 衡量）之间关联的关键病理生理机制，可能通过脂肪组织相关炎症和内皮功能障碍起作用，在代谢综合征患者中，通过 NEFA 的作用较小，而 NEFA 在代谢综合征患者的 NAFLD 发展中可能具有独立作用。
