Peroxisomal and mitochondrial fatty acid β-oxidation in mice nullizygous for both peroxisome proliferator-activated receptor α and peroxisomal fatty Acyl-CoA oxidase -: Genotype correlation with fatty liver phenotype
Peroxisomal and mitochondrial fatty acid β-oxidation in mice nullizygous for both peroxisome proliferator-activated receptor α and peroxisomal fatty Acyl-CoA oxidase -: Genotype correlation with fatty liver phenotype
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DOI：
10.1074/jbc.274.27.19228
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发表时间：
1999-07-02
影响因子：
4.8
通讯作者：
Reddy, JK
中科院分区：
文献类型：
--
作者：
Hashimoto, T;Fujita, T;Reddy, JK
脂肪酸β-氧化发生在线粒体和过氧化物酶体中。长链脂肪酸也被细胞色素 P450 CYP4A omega 氧化酶代谢为有毒二羧酸 (DCA)，作为过氧化物酶体 β 氧化的底物。合成的过氧化物酶体增殖剂与过氧化物酶体增殖剂激活受体 α (PPAR α) 相互作用，转录激活参与过氧化物酶体、微粒体和线粒体脂肪酸氧化的基因。缺乏 PPAR α (PPAR α(-/-)) 的小鼠无法对过氧化物酶体增殖剂的诱导作用做出反应，而缺乏脂酰辅酶 A 氧化酶 (AOX(-/-))（过氧化物酶体 β 氧化系统的第一种酶）的小鼠则表现出广泛的微泡性脂肪性肝炎，导致肝细胞再生和大量过氧化物酶体增殖，这意味着天然药物对 PPAR α 的持续激活。配体。我们现在报道，PPAR α和AOX（PPAR α(-/-) AOX(-/-)）均无效的小鼠未能表现出自发的过氧化物酶体增殖，也未能通过在缺乏AOX的情况下未代谢的生物配体诱导PPAR α调节基因。在 AOX-/- 小鼠中，PPAR α 的过度活跃通过诱导产生 DCA 的 CYP4A 家族蛋白来增强脂肪变性的严重程度，并且由于它们在没有过氧化物酶体 β-氧化的情况下不会被代谢，因此会损害线粒体，导致脂肪变性。微泡脂肪变性仅限于 PPAR α(-/-) AOX(-/-) 小鼠门静脉周围区域的少数肝细胞，其钝化表明 PPAR α 诱导基因，尤其是 CYP4A 家族成员，在确定过氧化物酶体 β-氧化缺陷肝脏脂肪变性的严重程度中发挥作用。在年龄匹配的 PPAR α(-/-) 小鼠中，组成性线粒体 β-氧化和完整的组成性过氧化物酶体 β-氧化系统的减少导致仅限于小叶中心肝细胞的大液滴脂肪变化。这些数据明确了 PPAR α 和 AOX 在肝脏脂质代谢和特定脂肪肝表型发病机制中的关键作用。
Fatty acid beta-oxidation occurs in both mitochondria and peroxisomes. Long chain fatty acids are also metabolized by the cytochrome P450 CYP4A omega-oxidation enzymes to toxic dicarboxylic acids (DCAs) that serve as substrates for peroxisomal beta-oxidation. Synthetic peroxisome proliferators interact with peroxisome proliferator activated receptor alpha (PPAR alpha) to transcriptionally activate genes that participate in peroxisomal, microsomal, and mitochondrial fatty acid oxidation. Mice lacking PPAR alpha (PPAR alpha(-/-)) fail to respond to the inductive effects of peroxisome proliferators, whereas those lacking fatty acyl-CoA oxidase (AOX(-/-)), the first enzyme of the peroxisomal beta-oxidation system, exhibit extensive microvesicular steatohepatitis, leading to hepatocellular regeneration and massive peroxisome proliferation, implying sustained activation of PPAR alpha by natural ligands. We now report that mice nullizygous for both PPAR alpha and AOX (PPAR alpha(-/-) AOX(-/-)) failed to exhibit spontaneous peroxisome proliferation and induction of PPAR alpha-regulated genes by biological ligands unmetabolized in the absence of AOX. In AOX-/- mice, the hyperactivity of PPAR alpha enhances the severity of steatosis by inducing CYP4A family proteins that generate DCAs and since they are not metabolized in the absence of peroxisomal beta-oxidation, they damage mitochondria leading to steatosis. Blunting of microvesicular steatosis, which is restricted to few liver cells in periportal regions in PPAR alpha(-/-) AOX(-/-) mice, suggests a role for PPAR alpha-induced genes, especially members of CYP4A family, in determining the severity of steatosis in livers with defective peroxisomal beta-oxidation. In age-matched PPAR alpha(-/-) mice, a decrease in constitutive mitochondrial beta-oxidation with intact constitutive peroxisomal beta-oxidation system contributes to large droplet fatty change that is restricted to centrilobular hepatocytes. These data define a critical role for both PPAR alpha and AOX in hepatic lipid metabolism and in the pathogenesis of specific fatty liver phenotype.