Ogata Masaki, Tsujita Maki, Hossain Mohammad Anwar, Akita Nobukatsu, Gonzalez Frank J, Staels Bart, Suzuki Shogo, Fukutomi Tatsuya, Kimura Genjiro, Yokoyama Shinji
Nagoya City University Graduate School of Medical Sciences, Japan.
Atherosclerosis. 2009 Aug;205(2):413-9. doi: 10.1016/j.atherosclerosis.2009.01.008. Epub 2009 Jan 19.
Expression of ATP binding cassette transporter A1 (ABCA1), a major regulator of high density lipoprotein (HDL) biogenesis, is known to be up-regulated by the transcription factor liver X receptor (LXR) alpha, and expression is further enhanced by activation of the peroxisome proliferator activated receptors (PPARs). We investigated this complex regulatory network using specific PPAR agonists: four fibrates (fenofibrate, bezafibrate, gemfibrozil and LY518674), a PPAR delta agonist (GW501516) and a PPAR gamma agonist (pioglitazone). All of these compounds increased the expression of LXRs, PPARs and ABCA1 mRNAs, and associated apoA-I-mediated lipid release in THP-1 macrophage, WI38 fibroblast and mouse fibroblast. When mouse fibroblasts lacking expression of PPAR alpha were examined, the effects of fenofibrate and LY518674 were markedly diminished while induction by other ligands were retained. The PPAR alpha promoter was activated by all of these compounds in an LXR alpha-dependent manner, and partially in a PPAR alpha-dependent manner, in mouse fibroblast. The LXR responsive element (LXRE)-luciferase activity was enhanced by all the compounds in an LXR alpha-dependent manner in mouse fibroblast. This activation was exclusively PPAR alpha-dependent by fenofibrate and LY518674, but nonexclusively by the others. We conclude that PPARs and LXRs are involved in the regulation of ABCA1 expression and HDL biogenesis in a cooperative signal transduction pathway.
ATP结合盒转运蛋白A1（ABCA1）是高密度脂蛋白（HDL）生物合成的主要调节因子，已知其表达受转录因子肝X受体（LXR）α上调，而过氧化物酶体增殖物激活受体（PPARs）的激活可进一步增强其表达。我们使用特异性PPAR激动剂研究了这一复杂的调控网络：四种贝特类药物（非诺贝特、苯扎贝特、吉非贝齐和LY518674）、一种PPARδ激动剂（GW501516）和一种PPARγ激动剂（吡格列酮）。所有这些化合物均增加了THP-1巨噬细胞、WI38成纤维细胞和小鼠成纤维细胞中LXRs、PPARs和ABCA1 mRNA的表达以及载脂蛋白A-I介导的脂质释放。当检测缺乏PPARα表达的小鼠成纤维细胞时，非诺贝特和LY518674的作用明显减弱，而其他配体的诱导作用得以保留。在小鼠成纤维细胞中，所有这些化合物均以LXRα依赖的方式激活PPARα启动子，部分以PPARα依赖的方式激活。在小鼠成纤维细胞中，所有化合物均以LXRα依赖的方式增强LXR反应元件（LXRE）-荧光素酶活性。非诺贝特和LY518674对这种激活是完全PPARα依赖的，而其他化合物则不是。我们得出结论，PPARs和LXRs在协同信号转导途径中参与ABCA1表达和HDL生物合成的调控。
