Lawrence J W, Foxworthy P S, Perry D N, Jensen C B, Giera D D, Meador V P, Eacho P I
Lilly Research Laboratory, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA.
Biochem Pharmacol. 1995 Mar 30;49(7):915-9. doi: 10.1016/0006-2952(95)00002-h.
Induction of peroxisome proliferator responsive genes is thought to be mediated through binding of a peroxisome proliferator-activated receptor (PPAR) to specific peroxisome proliferator response elements in the upstream region of these genes. Binding of PPAR to the acyl-CoA oxidase promoter requires heterodimerization with the retinoid X receptor (RXR), and subsequent transactivation is strongest when ligands for both PPAR and RXR are present. Therefore, we hypothesized that depletion of ligand for the retinoid receptor would limit the induction of peroxisome proliferation in rats. Hepatic retinol content was reduced by more than 90% by feeding weanling rats a vitamin A deficient (VAD) diet for approximately 3 months. Nafenopin treatment for 7 days induced peroxisomal beta-oxidation 18-fold in VAD rats compared with 16-fold in rats fed a vitamin A sufficient (VAS) diet. Nafenopin induced microsomal laurate hydroxylase and mitochondrial beta-oxidation to comparable rates of specific activity in both VAD and VAS rats. However, the activities in VAD controls were significantly lower than in VAS controls, so the magnitude of the nafenopin-induced increases was greater in the VAD rats. Relative liver weights were increased nearly 2-fold in both VAS and VAD rats treated with nafenopin. Ultrastructural examination of the livers demonstrated that nafenopin increased the number and size of peroxisomes in both VAD and VAS rats. These data demonstrate that rats with severely depleted vitamin A stores remained responsive to the peroxisome proliferator nafenopin. Whether critical retinoid pools that supply RXR ligand (9-cis-retinoic acid) are spared in the vitamin A deficient rats remains to be determined.
过氧化物酶体增殖物反应基因的诱导被认为是通过过氧化物酶体增殖物激活受体（PPAR）与这些基因上游区域的特定过氧化物酶体增殖物反应元件结合来介导的。PPAR与酰基辅酶A氧化酶启动子的结合需要与视黄酸X受体（RXR）形成异二聚体，并且当PPAR和RXR的配体都存在时，随后的反式激活最强。因此，我们假设视黄酸受体配体的耗竭会限制大鼠过氧化物酶体增殖的诱导。通过给断奶大鼠喂食维生素A缺乏（VAD）饮食约3个月，肝脏视黄醇含量降低了90%以上。与喂食维生素A充足（VAS）饮食的大鼠相比，萘酚平治疗7天可使VAD大鼠的过氧化物酶体β氧化增加18倍，而VAS大鼠增加16倍。萘酚平在VAD和VAS大鼠中诱导微粒体月桂酸羟化酶和线粒体β氧化至相当的比活性速率。然而，VAD对照组的活性明显低于VAS对照组，因此萘酚平诱导的增加幅度在VAD大鼠中更大。用萘酚平治疗的VAS和VAD大鼠的相对肝脏重量均增加了近2倍。肝脏的超微结构检查表明，萘酚平增加了VAD和VAS大鼠过氧化物酶体的数量和大小。这些数据表明，维生素A储备严重耗尽的大鼠对视黄酸受体配体的过氧化物酶体增殖剂萘酚平仍然有反应。供应RXR配体（9-顺式视黄酸）的关键视黄酸池在维生素A缺乏的大鼠中是否保留还有待确定。
