Effects of peroxisome proliferator-activated receptor ligands, bezafibrate and fenofibrate, on adiponectin level
Effects of peroxisome proliferator-activated receptor ligands, bezafibrate and fenofibrate, on adiponectin level
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DOI：
10.1161/01.atv.0000256469.06782.d5
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发表时间：
2007-03-01
影响因子：
8.7
通讯作者：
Funahashi, Tohru
中科院分区：
文献类型：
--
作者：
Hiuge, Aki;Tenenbaum, Alexander;Funahashi, Tohru
目的：脂联素是一种脂肪特异性分泌蛋白，具有抗糖尿病和抗动脉粥样硬化的作用。我们先前在脂联素启动子区域发现了过氧化物酶体增殖物反应元件，提示过氧化物酶体增殖物激活受体(PPAR)配体使脂联素水平升高。贝特类是已知的PPARα配体，并被证明可以降低糖尿病和心血管疾病的风险。贝特类药物对脂联素的影响尚不清楚，但噻唑烷二酮类药物可促进脂联素的生成。因此，我们探索了贝贝特增强人、小鼠和细胞中脂联素的可能性和机制。方法和结果-在参加苯扎贝特脑梗塞预防研究的患者中，服用苯扎贝特的受试者的血清脂联素水平显著高于安慰剂组。较高的基线脂联素水平与新发糖尿病风险的降低密切相关。贝特、苯扎贝特和非诺贝特显著提高野生型小鼠和3T3-L1脂肪细胞的脂联素水平。在PPARα缺陷小鼠和脂肪细胞中没有观察到这种效应。当过氧化体增殖物反应元件发生点突变，内源性PPARα被PPARαRNA敲除时，贝特类药物激活了脂联素启动子，但不能增强其活性。结论：贝特类药物部分通过脂肪PPARα增强脂联素活性，脂联素测定可能是寻找糖尿病高危人群的有用工具。
Objective - Adiponectin is adipose-specific secretory protein and acts as anti-diabetic and anti-atherosclerotic molecule. We previously found peroxisome proliferators response element in adiponectin promoter region, suggesting that peroxisome proliferator-activated receptor (PPAR) ligands elevate adiponectin. Fibrates are known to be PPAR alpha ligands and were shown to reduce risks of diabetes and cardiovascular disease. Effect of fibrates on adiponectin has not been clarified, whereas thiazolidinediones enhance adiponectin. Thus, we explored the possibility and mechanism that fibrates enhance adiponectin in humans, mice, and cells.Methods and Results - Significant increase of serum adiponectin was observed in bezafibrate-treated subjects compared with placebo group in patients enrolled in The Bezafibrate Infarction Prevention study. Higher baseline adiponectin levels were strongly associated with reduced risk of new diabetes. Fibrates, bezafibrate and fenofibrate, significantly elevated adiponectin levels in wild-type mice and 3T3-L1 adipocytes. Such an effect was not observed in PPAR alpha-deficient mice and adipocytes. Fibrates activated adiponectin promoter but failed to enhance its activity when the point mutation occurred in peroxisome proliferators response element site and the endogenous PPAR alpha was knocked down by PPAR alpha-RNAi.Conclusions - Our results suggest that fibrates enhance adiponectin partly through adipose PPAR alpha and measurement of adiponectin might be a useful tool for searching subjects at high risk for diabetes.