Lemotte P K, Keidel S, Apfel C M
Department of Dermatology, F. Hoffmann-La Roche Ltd, Basel, Switzerland.
Eur J Biochem. 1996 Feb 15;236(1):328-33. doi: 10.1111/j.1432-1033.1996.00328.x.
Metabolic defects in phytanic acid catabolism have been shown to be connected with a number of human diseases which can lead to lethal defects of the nervous system and other organs. These effects are probably a result of the very high accumulation of phytanic acid in tissues throughout the body, due to defects in phytanic acid oxidation, the peroxisome being a major site for this process. The nuclear hormone receptors peroxisome proliferator-activated receptor and retinoid X receptor (RXR) have been shown to function as transcription factors in the control of the peroxisomal enzyme expression. Known activators of peroxisome proliferator-activated receptor include polyunsaturated fatty acids and, for RXR, the 9-cis isomer of retinoic acid. Here we report that phytanic acid is also a natural ligand for RXR alpha, being able to activate a RXR-responsive promoter. We present evidence that phytanic acid binds to RXR alpha, promotes formation of an RXR alpha/RXR response element complex (as detected by gel retardation), and induces a RXR alpha conformational change similar to that induced by 9-cis-retinoic acid (as detected by protease sensitivity). These results suggest an involvement of RXR alpha in the control of fatty acid metabolism and could imply that RXRs have a role in the disease effects resulting from defective phytanic acid catabolism.
植烷酸分解代谢中的代谢缺陷已被证明与许多人类疾病相关，这些疾病可导致神经系统和其他器官的致命缺陷。这些影响可能是由于植烷酸氧化缺陷导致植烷酸在全身组织中大量蓄积的结果，过氧化物酶体是这一过程的主要场所。核激素受体过氧化物酶体增殖物激活受体（PPAR）和视黄酸X受体（RXR）已被证明在过氧化物酶体酶表达的控制中作为转录因子发挥作用。已知的PPAR激活剂包括多不饱和脂肪酸，而对于RXR来说，视黄酸的9-顺式异构体是其激活剂。在此我们报告，植烷酸也是RXRα的天然配体，能够激活RXR反应性启动子。我们提供的证据表明，植烷酸与RXRα结合，促进RXRα/RXR反应元件复合物的形成（通过凝胶阻滞检测），并诱导类似于9-顺式视黄酸诱导的RXRα构象变化（通过蛋白酶敏感性检测）。这些结果表明RXRα参与脂肪酸代谢的控制，并且可能意味着RXR在植烷酸分解代谢缺陷导致的疾病影响中发挥作用。
