THE PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR RETINOID-X RECEPTOR HETERODIMER IS ACTIVATED BY FATTY-ACIDS AND FIBRATE HYPOLIPEMIC DRUGS
THE PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR RETINOID-X RECEPTOR HETERODIMER IS ACTIVATED BY FATTY-ACIDS AND FIBRATE HYPOLIPEMIC DRUGS
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DOI：
10.1677/jme.0.0110037
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发表时间：
1993-08-01
影响因子：
3.5
通讯作者：
GREEN, S
中科院分区：
文献类型：
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作者：
ISSEMANN, I;PRINCE, RA;GREEN, S
过氧化物酶体增殖物激活受体（PPAR）是类固醇激素受体超家族的一员，可被多种被统称为过氧化物酶体增殖物的降血脂药物和非遗传毒性啮齿动物肝癌物质激活。过氧化物酶体增殖作用的一个关键标志是过氧化物酶体酰基辅酶A氧化酶，它在治疗过的啮齿动物肝脏中升高约10倍。我们之前已经证明过氧化物酶体增殖反应元件（PPRE）位于大鼠过氧化物酶体酰基辅酶a氧化酶基因上游570bp处，PPAR与它结合。我们在这里表明，PPAR与PPRE结合需要类视黄酸受体（RXR），而RXR配体9-顺式视黄酸可增强PPAR的作用。因此，类维甲酸可能调节过氧化物酶体增殖体的作用，而PPAR可能干扰类维甲酸的作用，这可能为解释过氧化物酶体增殖体的毒性提供了一种机制。我们还发现多种降血脂药物和脂肪酸可以激活PPAR。这支持了PPAR的生理作用是调节脂肪酸稳态的观点，并进一步证明PPAR是贝特类降血脂药物的靶点。最后，我们证明了一种代谢稳定的脂肪酸是一种有效的PPAR激活剂，这表明脂肪酸或其酰基辅酶a衍生物可能是PPAR的天然配体。
The peroxisome proliferator-activated receptor (PPAR) is a member of the steroid hormone receptor superfamily and is activated by a variety of fibrate hypolipidaemic drugs and non-genotoxic rodent hepatocarcinogens that are collectively termed peroxisome proliferators. A key marker of peroxisome proliferator action is the peroxisomal enzyme acyl CoA oxidase, which is elevated about tenfold in the livers of treated rodents. We have previously shown that a peroxisome proliferator response element (PPRE) is located 570 bp upstream of the rat peroxisomal acyl CoA oxidase gene and that PPAR binds to it. We show here that the retinoid X receptor (RXR) is required for PPAR to bind to the PPRE, and that the RXR ligand, 9-cis retinoic acid, enhances PPAR action. Retinoids may therefore modulate the action of peroxisome proliferators and PPAR may interfere with retinoid action, perhaps providing one mechanism to explain the toxicity of peroxisome proliferators. We have also shown that a variety of hypolipidaemic drugs and fatty acids can activate PPAR. This supports the suggestion that the physiological role of PPAR is to regulate fatty acid homeostasis, and provides further evidence that PPAR is the target of the fibrate class of hypolipidaemic drugs. Finally, we have demonstrated that a metabolically stabilized fatty acid is a potent PPAR activator, suggesting that fatty acids, or their acyl CoA derivatives, may be the natural ligands of PPAR.