Department of Endocrinology and Metabolism, Dokkyo University School of Medicine, Mibu, Tochigi 321-0293, Japan.
Metabolism. 2011 Apr;60(4):513-22. doi: 10.1016/j.metabol.2010.04.020. Epub 2010 Jun 26.
The Fenofibrate Intervention and Event Lowering in Diabetes study demonstrated that treatment with fenofibrate in individuals with type 2 diabetes mellitus not only reduced nonfatal coronary events but also diminished the need for laser treatment of diabetic retinopathy and delayed the progression of diabetic nephropathy. However, the mechanism by which fenofibrate may have altered the microvasculature remains unclear. We thus investigated the effect of fenofibrate on human glomerular microvascular endothelial cells (HGMEC). Treatment of HGMEC with fenofibrate resulted in transient activation of adenosine monophosphate-activated protein kinase (AMPK), thereby inducing the phosphorylation of Akt and endothelial nitric oxide synthase, leading to nitric oxide production. We compared AMPK activation induced by bezafibrate and WY14643 with that induced by fenofibrate in HGMEC as well as HepG2 cells. Only fenofibrate activated AMPK in HGMEC. Fenofibrate also inhibited nuclear factor-κB activation by advanced glycation end-products, thereby suppressing the expression of various adhesion molecule genes in HGMEC. Suppression of fenofibrate-induced inhibition of nuclear factor-κB activation was observed in cells treated with AMPK small interfering RNA or compound C. Furthermore, fenofibrate was observed to significantly suppress apoptosis of HGMEC in hyperglycemic culture medium. Treatment with compound C or Nw-nitro-L-arginine methyl ester (L-NAME) abolished the suppressive effect of fenofibrate on HGMEC apoptosis. Our findings suggest that fenofibrate might exert a protective effect on the microvasculature by suppressing inflammation and apoptosis through AMPK activation beyond its lipid-lowering actions.
非诺贝特干预和糖尿病事件降低研究表明，在 2 型糖尿病患者中使用非诺贝特治疗不仅降低了非致死性冠状动脉事件的发生，还减少了糖尿病视网膜病变的激光治疗需求，并延缓了糖尿病肾病的进展。然而，非诺贝特改变微血管的机制尚不清楚。因此，我们研究了非诺贝特对人肾小球微血管内皮细胞（HGMEC）的影响。用非诺贝特处理 HGMEC 会导致 AMPK 短暂激活，从而诱导 Akt 和内皮型一氧化氮合酶的磷酸化，导致一氧化氮的产生。我们比较了 bezafibrate 和 WY14643 诱导的 AMPK 激活与非诺贝特在 HGMEC 以及 HepG2 细胞中诱导的 AMPK 激活。只有非诺贝特能在 HGMEC 中激活 AMPK。非诺贝特还能抑制晚期糖基化终产物诱导的核因子-κB 激活，从而抑制 HGMEC 中各种粘附分子基因的表达。在用 AMPK 小干扰 RNA 或化合物 C 处理的细胞中观察到对非诺贝特诱导的核因子-κB 激活抑制的抑制作用。此外，我们观察到非诺贝特能显著抑制高糖培养基中 HGMEC 的凋亡。用化合物 C 或 Nw-硝基-L-精氨酸甲酯（L-NAME）处理可消除非诺贝特对 HGMEC 凋亡的抑制作用。我们的研究结果表明，非诺贝特可能通过抑制炎症和凋亡来发挥对微血管的保护作用，其作用超出了其降脂作用，通过 AMPK 激活。
