ABSTRACT
Peroxisomal 3-ketoacyl-CoA thiolase B (Thb) catalyzes the final step in the peroxisomal ß-oxidation of straight-chain acyl-CoAs and is under the transcription control of the nuclear hormone receptor PPARα. PPARα binds to and is activated by the synthetic compound Wy14,643 (Wy). Here, we show that the magnitude of Wy-mediated induction of peroxisomal ß-oxidation of radiolabeled (1-(14)C) palmitate was significantly reduced in mice deficient for Thb. In contrast, mitochondrial ß-oxidation was unaltered in Thb(-/-) mice. Given that Wy-treatment induced Acox1 and MFP-1/-2 activity at a similar level in both genotypes, we concluded that the thiolase step alone was responsible for the reduced peroxisomal ß-oxidation of fatty acids. Electron microscopic analysis and cytochemical localization of catalase indicated that peroxisome proliferation in the liver after Wy-treatment was normal in Thb(-/-) mice. Intriguingly, micro-array analysis revealed that mRNA levels of genes encoding cholesterol biosynthesis enzymes were upregulated by Wy in Wild-Type (WT) mice but not in Thb(-/-) mice, which was confirmed at the protein level for the selected genes. The non-induction of genes encoding cholesterol biosynthesis enzymes by Wy in Thb(-/-) mice appeared to be unrelated to defective SREBP-2 or PPARα signaling. No difference was observed in the plasma lathosterol/cholesterol ratio (a marker for de novo cholesterol biosynthesis) between Wy-treated WT and Thb(-/-) mice, suggesting functional compensation. Overall, we conclude that ThA and SCPx/SCP2 thiolases cannot fully compensate for the absence of ThB. In addition, our data indicate that ThB is involved in the regulation of genes encoding cholesterol biosynthesis enzymes in the liver, suggesting that the peroxisome could be a promising candidate for the correction of cholesterol imbalance in dyslipidemia.
Subject(s)
Acetyl-CoA C-Acyltransferase/metabolism , Liver/enzymology , PPAR alpha/metabolism , Sterol Regulatory Element Binding Protein 2/metabolism , Up-Regulation , Acetyl-CoA C-Acyltransferase/genetics , Animals , Cholesterol/genetics , Cholesterol/metabolism , Gene Deletion , Gene Expression Regulation , Hepatomegaly/genetics , Hepatomegaly/pathology , Humans , Lipid Metabolism/genetics , Liver/pathology , Male , Mice , Mice, Knockout , Mitochondria/metabolism , Oxidation-Reduction , Palmitates/metabolism , Peroxisome Proliferators/pharmacology , Peroxisomes/metabolism , Pyrimidines/pharmacology , Signal TransductionABSTRACT
Defects in the formation of the cerebral cortex and the cerebellum are a prominent feature of the peroxisome biogenesis disorder Zellweger syndrome and in mouse models for this disease. The aim of the present study was to investigate the impact of liver and brain peroxisomes on neurodevelopment by analyzing mice with tissue-selective elimination of peroxisomes. To this end, Pex5-loxP mice were bred with albumin/alpha-fetoprotein (Alfp)-Cre and nestin (Nes)-Cre mice. Local elimination of peroxisomes from the brain in Nes-Pex5 knockout mice caused a delay of cortical neuronal migration and of the formation of cerebellar folia and fissures. Migration of granule cells from the external granular layer was retarded, as was the polarization and branching of Purkinje cells, resulting in a less complex branching pattern and a smaller dendritic tree at P21. The Alfp-Pex5 knockout mice were affected differently, displaying a partial arrest of neuronal migration in the cerebral neopallium in the postnatal period despite of the incomplete elimination of peroxisomes from liver during embryonic development. Major abnormalities were seen in the formation of the cerebellum of these liver knockout mice, including hypotrophy, impaired foliation, a delay of granule cell migration, increased cell death, and stunted Purkinje cell arborization. In conclusion, these data demonstrate that absence of peroxisomal function both from liver and brain impairs cortical neuronal migration and maturation of the cerebellum, but different pathogenic mechanisms might be involved.
