Inflammation. 2014 Feb;37(1):177-85. doi: 10.1007/s10753-013-9728-6.
Fenofibrate, as a lipid-lowering drug in clinic, participates in the regulation of inflammatory response. Recently, increasing studies have indicated that sirtuin1 (SIRT1), a NAD+-dependent deacetylase, has potential anti-inflammatory effect in endothelial cells. However, whether the regulatory effect of fenofibrate on inflammation response is mediated by SIRT1 remains unclear. The aim of this study was to investigate the effect of fenofibrate on the expressions of SIRT1 and pro-inflammatory cytokine CD40 in endothelial cells and explore the underlying mechanisms. The results showed that fenofibrate upregulated SIRT1 expression and inhibited CD40 expression in TNF-α-stimulated endothelial cells, but these effects were reversed by peroxisome proliferator-activated receptor-α (PPARα) antagonist GW6471. Furthermore, SIRT1 inhibitors sirtinol/nicotinamide (NAM) or SIRT1 knockdown could attenuate the effect of fenofibrate on CD40 expression in endothelial cells. Importantly, NF-κB inhibitor pyrrolidine dithiocarbamate (PDTC) augmented the effect of fenofibrate on CD40 expression. Further study found that fenofibrate decreased the expression of acetylated-NF-κB p65 (Ac-NF-κB p65) in TNF-α-stimulated endothelial cells, which was abolished by SIRT1 knockdown. These results indicate that fenofibrate has protective effect against TNF-α-induced CD40 expression through SIRT1-mediated deacetylation of the p65 subunit of NF-κB.
非诺贝特作为临床降脂药物，参与炎症反应的调节。最近，越来越多的研究表明，烟酰胺腺嘌呤二核苷酸（NAD+）依赖性去乙酰化酶 SIRT1，在内皮细胞中具有潜在的抗炎作用。然而，非诺贝特对炎症反应的调节作用是否通过 SIRT1 介导尚不清楚。本研究旨在探讨非诺贝特对 TNF-α刺激的内皮细胞中 SIRT1 和促炎细胞因子 CD40 表达的影响，并探讨其潜在机制。结果表明，非诺贝特上调了 TNF-α刺激的内皮细胞中 SIRT1 的表达，并抑制了 CD40 的表达，但这些作用被过氧化物酶体增殖物激活受体-α（PPARα）拮抗剂 GW6471 逆转。此外，SIRT1 抑制剂 sirtinol/烟酰胺（NAM）或 SIRT1 敲低可减弱非诺贝特对内皮细胞中 CD40 表达的影响。重要的是，NF-κB 抑制剂吡咯烷二硫代氨基甲酸盐（PDTC）增强了非诺贝特对 CD40 表达的影响。进一步的研究发现，非诺贝特降低了 TNF-α刺激的内皮细胞中乙酰化 NF-κB p65（Ac-NF-κB p65）的表达，而 SIRT1 敲低则消除了这种作用。这些结果表明，非诺贝特通过 SIRT1 介导的 NF-κB p65 亚基去乙酰化，对 TNF-α诱导的 CD40 表达具有保护作用。
