Phytanic acid activates the peroxisome proliferator-activated receptor α (PPARα) in sterol carrier protein 2- sterol carrier protein x-deficient mice
Phytanic acid activates the peroxisome proliferator-activated receptor α (PPARα) in sterol carrier protein 2- sterol carrier protein x-deficient mice
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DOI：
10.1074/jbc.274.5.2766
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发表时间：
1999-01-29
影响因子：
4.8
通讯作者：
Seedorf, U
中科院分区：
文献类型：
--
作者：
Ellinghaus, P;Wolfrum, C;Seedorf, U
我们最近发现，小鼠甾醇载体蛋白2-/甾醇载体蛋白x基因（Scp2）的靶向零突变导致3,7,11,15-四甲基六酸（植物酸）的过氧化物酶体分解代谢缺陷，过氧化物酶体增殖，低血脂，以及肝脏中一些基因的表达增强，这些基因已被证明是由过氧化物酶体增殖物激活受体α (PPAR α)转录调节的。由于多种脂肪酸在体外激活PPAR α，我们研究了后者的作用是否可能是因为植酸诱导了该转录因子的激活。通过添加叶绿醇调节C57B1/6和Scp2（-/-）小鼠体内植酸浓度。我们发现血清植酸浓度与编码过氧化物酶体β -氧化酶和肝脏脂肪酸结合蛋白的基因表达密切相关，这些基因都被证明在其启动子区域含有功能活跃的过氧化物酶体增殖反应元件。根据这些发现，植酸对大鼠肝癌细胞系MH1C1孵育后也观察到对酰基辅酶a氧化酶基因表达的刺激作用。此外，报告基因研究表明，植酸诱导过氧化物酶体增殖因子反应元件驱动的氯霉素转移酶报告基因的表达，与强过氧化物酶体增殖因子相当。此外，植酸作为PPAR α依赖基因表达的诱导剂的能力与这种膳食支链脂肪酸与重组PPAR α的高亲和力结合相对应。我们得出结论，植酸可以被认为是小鼠PPAR α的真正的生理配体。
We showed recently that a targeted null mutation in the murine sterol carrier protein 2-/sterol carrier protein x-gene (Scp2) leads to defective peroxisomal catabolism of 3,7,11,15-tetramethylhexadecanoic acid (phytanic acid), peroxisome proliferation, hypolipidemia, and enhanced hepatic expression of several genes that have been demonstrated to be transcriptionally regulated by the peroxisome proliferator-activated receptor alpha (PPAR alpha), As a broad range of fatty acids activates PPAR alpha in vitro, we examined whether the latter effects could be because of phytanic acid-induced activation of this transcription factor. Dietary phytol supplementation was used to modulate the concentration of phytanic acid in C57B1/6 and Scp2 (-/-) mice. We found that the serum concentrations of phytanic acid correlated well with the expression of genes encoding peroxisomal beta-oxidation enzymes and liver fatty acid-binding protein, who have all been demonstrated to contain functionally active peroxisome proliferator response elements in their promoter regions. In accordance with these findings, a stimulating effect on acyl-CoA oxidase gene expression was also observed after incubation of the rat hepatoma cell line MH1C1 with phytanic acid. Moreover, reporter gene studies revealed that phytanic acid induces the expression of a peroxisome proliferator response element-driven chloramphenicol transferase reporter gene comparable with strong peroxisome proliferators, In addition, the ability of phytanic acid to act as an inductor of PPAR alpha-dependent gene expression corresponded with high affinity binding of this dietary branched chain fatty acid to recombinant PPAR alpha, We conclude that phytanic acid can be considered as a bona fide physiological ligand of murine PPAR alpha.