Altered constitutive expression of fatty acid-metabolizing enzymes in mice lacking the peroxisome proliferator-activated receptor α (PPARα)
Altered constitutive expression of fatty acid-metabolizing enzymes in mice lacking the peroxisome proliferator-activated receptor α (PPARα)
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DOI：
10.1074/jbc.273.10.5678
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发表时间：
1998-03-06
影响因子：
4.8
通讯作者：
Gonzalez, FJ
中科院分区：
文献类型：
--
作者：
Aoyama, T;Peters, JM;Gonzalez, FJ
过氧化物酶体增殖性激活受体α(PPARα)是类固醇/核受体超家族的一员，介导了过氧化物酶体增殖物的生物学和毒理学效应。为了确定PPARα在脂肪酸代谢中的生理作用，测定了PPARα缺失小鼠肝组织中过氧化物型和线粒体脂肪酸代谢酶的水平，发现PPARα缺失小鼠肝组织中长链脂肪酸棕榈酸的结构性氧化水平低于野生型小鼠，提示线粒体脂肪酸分解代谢存在缺陷。相反，超长链脂肪酸甘油酸的结构性氧化在野生型和PPARα缺失小鼠中没有区别，这表明参与过氧化物体β氧化的酶的结构性表达独立于PPARα。事实上，PPARα基因缺失的小鼠体内的过氧化物酰基辅酶A氧化酶、双功能蛋白(水合酶+3-羟基酰辅酶A脱氢酶)和硫解酶的表达水平正常，但D-型双功能蛋白(水合酶+3-羟基酰基辅酶A脱氢酶)的结构性表达较低，几种线粒体脂肪酸代谢酶包括超长链酰基辅酶A脱氢酶、长链酰辅酶A脱氢酶、短链特异性的3-酮酰辅酶A硫解酶和长链酰基辅酶A合成酶在未经处理的PPARα零基因小鼠中也有较低水平的表达，而其他脂肪酸代谢酶在未经处理的PPARα零基因小鼠中的表达水平与野生型小鼠没有什么不同。编码这些酶的mRNAs的组成表达也较低，这表明这种影响是由于基因表达的改变。在野生型小鼠中，过氧化物体增殖剂Wy-14,643诱导了过氧化物体酶和线粒体酶；在PPARα缺失的动物中没有观察到诱导，这些数据表明PPARα除了调节可诱导的线粒体和过氧体脂肪酸β氧化外，还调节编码几种线粒体脂肪酸分解代谢酶的基因的结构性表达，从而确立了受体在脂肪酸动态平衡中的作用。
Peroxisome proliferative-activated receptor alpha (PPAR alpha) is a member of the steroid/nuclear receptor superfamily and mediates the biological and toxicological effects of peroxisome proliferators. To determine the physiological role of PPAR alpha in fatty acid metabolism, levels of peroxisomal and mitochondrial fatty acid metabolizing enzymes were determined in the PPAR alpha null mouse, Constitutive liver beta-oxidation of the long chain fatty acid, palmitic acid, was lower in the PPAR alpha null mice as compared with wild type mice, indicating defective mitochondrial fatty acid catabolism. In contrast, constitutive oxidation of the very long chain fatty acid, lignoceric acid, was not different between wild type and PPAR alpha null mice, suggesting that constitutive expression of enzymes involved in peroxisomal beta-oxidation is independent of PPAR alpha. Indeed, the PPAR alpha null mice had normal levels of the peroxisomal acyl-CoA oxidase, bifunctional protein (hydratase + 3-hydroxyacyl-CoA dehydrogenase), and thiolase but lower constitutive expression of the D-type bifunctional protein (hydratase + 3-hydroxyacyl-CoA dehydrogenase), Several mitochondrial fatty acid metabolizing enzymes including very long chain acyl-CoA dehydrogenase, long chain acyl-CoA dehydrogenase, short chain-specific 3-ketoacyl-CoA thiolase, and long chain acyl-CoA synthetase are also expressed at lower levels in the untreated PPAR alpha null mice, whereas other fatty acid metabolizing enzymes were not different between the untreated null mice and wild type mice. A lower constitutive expression of mRNAs encoding these enzymes was also found, suggesting that the effect was due to altered gene expression. In wild type mice, both peroxisomal and mitochondrial enzymes were induced by the peroxisome proliferator Wy-14,643; induction was not observed in the PPAR alpha null animals, These data indicate that PPAR alpha modulates constitutive expression of genes encoding several mitochondrial fatty acid-catabolizing enzymes in addition to mediating inducible mitochondrial and peroxisomal fatty acid beta-oxidation, thus establishing a role for the receptor in fatty acid homeostasis.