PPARγ信号转导通路在内脂素诱导泡沫细胞形成中的作用机制

PPARγ signal transduction pathway in the foam cell formation induced by visfatin

本文旨在观察过氧化物酶体增殖物激活受体γ(peroxisome proliferator-activated receptorγ,PPARγ)信号转导通路在内脂素(visfatin)调控人单核细胞株THP-1源性巨噬细胞ATP结合盒转运蛋白A1(ATP binding cassette transporter A1,ABCA1)和酰基辅酶A:胆固醇酰基转移酶1(acyl-CoA:cholesterol acyltransferase1,ACAT1)表达中的作用,探讨内脂素诱导泡沫细胞形成的机制和途径。THP-1单核细胞经佛波酯诱导分化为巨噬细胞,随机分组,给予不同浓度的内脂素和PPARγ激动剂罗格列酮(rosiglitazone)进行干预,分别运用RT-PCR和Western blot法检测各组细胞PPARγ、ABCA1及ACAT1 mRNA和蛋白表达,酶荧光学法检测细胞内总胆固醇(total cholesterol,TC)和游离胆固醇(free cholesterol,FC)含量,TC与FC之差为胆固醇酯(cholesterol ester,CE)含量。结果显示,内脂素呈浓度依赖性增加THP-1源性巨噬细胞内FC和CE含量,下调巨噬细胞PPARγ mRNA和蛋白的表达,同时下调其下游的靶基因ABCA1 mRNA和蛋白的表达,上调ACAT1 mRNA和蛋白的表达;而罗格列酮呈浓度依赖性地抑制内脂素所诱导的上述效应。上述结果提示,内脂素可能通过PPARγ信号转导通路下调ABCA1表达,上调ACAT1表达,使细胞内FC流出减少,CE合成增加,从而诱导泡沫细胞的形成。这为研究内脂素致动脉粥样硬化的机制提供了新的理论依据。

The aim of the present study was to investigate the role of peroxisome proliferator-activated receptor γ（PPARγ） signal transduction pathway in the expression of ATP binding cassette transporter A1（ABCA1） and acyl-CoA：cholesterol acyltransferase 1（ACAT1） induced by visfatin and to discuss the mechanism of foam cell formation induced by visfatin.THP-1 monocytes were induced into macrophages by 160 nmol/L phorbol myristate acetate（PMA） for 48 h,and then the macrophages were exposed to visfatin and PPARγ activator rosiglitazone,respectively.The expressions of PPAR？,ABCA1 and ACAT1 mRNA and protein were determined by RT-PCR and Western blot respectively.The contents of total cholesterol（TC） and free cholesterol（FC） were detected by enzyme fluorescence analysis.The content of cholesterol ester（CE） was calculated by the difference between TC and FC.The results showed that visfatin decreased the mRNA and protein expressions of PPARγ and ABCA1,increased the mRNA and protein expressions of ACAT1,and increased the contents of FC and CE in a concentration-dependent manner.These above effects of visfatin were inhibited by rosiglitazone in a concentration-dependent manner.These results suggest that visfatin may down-regulate the ABCA1 expression and up-regulate the ACAT1 expression via PPARγ signal transduction pathway,which decreases the outflow of FC,increases the content of CE,and then induces foam cell formation.