Licht- und Elektronenmikroskopische Leberbefunde beim Cerebro-Hepato-Renalen Syndrom nach Zellweger (Peroxisomen-Defizienz)

Pfeifer, U; Sandhage, K

doi:10.1007/bf00428229

Cited by 43 publications

(18 citation statements)

References 18 publications

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“…In particular, peroxisomes seem to be necessary for the maintenance of the integrity of the inner mitochondrial membrane, a finding that confirms previous observations in patients 4,[6][7][8][9] and other mouse models. 13,36,37 Some of the presently observed ultrastructural changes at the inner mitochondrial membrane were similar to the alterations in Zellweger patients.…”

Section: Discussionsupporting

confidence: 89%

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Absence of peroxisomes in mouse hepatocytes causes mitochondrial and ER abnormalities†

et al. 2005

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Peroxisome deficiency in men causes severe pathology in several organs, particularly in the brain and liver, but it is still unknown how metabolic abnormalities trigger these defects. In the present study, a mouse model with hepatocyte-selective elimination of peroxisomes was generated by inbreeding Pex5-loxP and albumin-Cre mice to investigate the consequences of peroxisome deletion on the functioning of hepatocytes. Besides the absence of catalase-positive peroxisomes, multiple ultrastructural alterations were noticed, including hepatocyte hypertrophy and hyperplasia, smooth endoplasmic reticulum proliferation, and accumulation of lipid droplets and lysosomes. Most prominent was the abnormal structure of the inner mitochondrial membrane, which bore some similarities with changes observed in Zellweger patients. This was accompanied by severely reduced activities of complex I, III, and V and a collapse of the mitochondrial inner membrane potential. Surprisingly, these abnormalities provoked no significant disturbances of adenosine triphosphate (ATP) levels and redox state of the liver. However, a compensatory increase of glycolysis as an alternative source of ATP and mitochondrial proliferation were observed. No evidence of oxidative damage to proteins or lipids nor elevation of oxidative stress defence mechanisms were found. Altered expression of peroxisome proliferator-activated receptor alpha (PPAR-␣) regulated genes indicated that PPAR-␣ is activated in the peroxisomedeficient cells. In conclusion, the absence of peroxisomes from mouse hepatocytes has an impact on several other subcellular compartments and metabolic pathways but is not detrimental to the function of the liver parenchyma. Supplementary material for this article can be found on the HEPATOLOGY website (http://interscience.wiley.com/jpages/0270-9139/suppmat/index.html). P eroxisomes are indispensable in cellular metabolism, because they harbor enzymes essential for the degradation of very long chain and branched chain fatty acids, for the conversion of cholesterol in bile acids and for the synthesis of ether phospholipids and polyunsaturated fatty acids. They also participate in the catabolism of purines, polyamines, and pipecolic acid. 1 The importance of peroxisomes is stressed by the existence of a group of genetic disorders in which one or more peroxisomal functions are impaired. The most severe is the cerebrohepatorenal syndrome of Zellweger, a peroxisome assembly disorder characterized by the absence of functional peroxisomes due to a disturbance in the peroxisomal protein import machinery. 2 At birth, Zellweger syndrome patients suffer from neurological and eye abnormalities, hypotonia, characteristic craniofacial dysmorphism, and renal cysts. 2 Hepatic pathology develops in the postnatal period, including hepatomegaly, fibrosis, micronodular cirrhosis, cholestasis, hyperbilirubinemia, and elevation of aminotransferases. 2,3 The biochemical hallmarks of this syndrome include the accumulation of very long chain and branched chain fatty aci...

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Section: Discussionsupporting

confidence: 89%

“…These changes were highly variable but included alterations at the inner mitochondrial membrane with twisted or irregular cristae, dense matrix and crystalline inclusions, [4][5][6][7][8][9] and a reduction of the activities of complex I and II of the respiratory chain. 10 No abberant mitochondrial morphology was found in other Zellweger patients.…”

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confidence: 99%

Absence of peroxisomes in mouse hepatocytes causes mitochondrial and ER abnormalities†

et al. 2005

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“…A single enzymatic defect might explain some of these conditions; however, in the Zellweger syndrome the whole organelle would be missing, perhaps reflecting the deficit of a protein essential for the assembly of peroxisomes. Consequently, as already suggested (14,(19)(20)(21)(22)(23)(24), this pathologic condition would constitute a unique example of a genetic disorder expressed as absence of a cell organelle involved in cell metabolism.…”

mentioning

confidence: 67%

“…With the procedures employed, no evidence was found of a major particle-bound catalase fraction in Zellweger fibroblasts. In three independent experiments, after mild sonication, 23.4% ± 4.8% of the catalase present in IMR-90 fibroblasts was released, whereas, in Zellweger fibroblasts, 93.6% ± 11.1% was found in the supernatant, after centrifugation for 30 min at 100,000 x g. Therefore, the observations after nitrogen pressurization followed by Teflon/glass homogenization, after disruption with the all-glass Dounce homogenizer, and after mild sonication are all consistent with the hypothesis of cytosolic localization for most, if not all, of the activity of the peroxisomal enzymes in Zellweger fibroblasts.…”

Section: Methodsmentioning

confidence: 99%

Peroxisomal organization in normal and cerebrohepatorenal (Zellweger) syndrome fibroblasts.

Santos¹,

Ojeda²,

Garrido³

et al. 1985

Proc. Natl. Acad. Sci. U.S.A.

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The reported absence of morphologicafly detectable peroxisomes in liver and kidney tissue cells from patients affected by the autosomic recessive, inherited metabolic disease known as cerebrohepatorenal, or Zeflweger, syndrome was studied in fibroblasts, assuming it to be a generalized defect.Normal cultured fibroblasts were shown to contain peroxisomes according to morphological, biochemical, and subcellular fractionation criteria: particle-bound catalase and fatty acyl-CoA oxidase copurify in subcellular fractionation by differential centrifugation or isopycnic equilibrium in continuous density gradients and peroxidase-positive organelles of =O.1 ,um in diameter are detected in the cytoplasm. In Zellweger cultured fibroblasts, these peroxisomal enzymes are present; however, they behave as cytosolic enzymes in the different subcellular fractionation procedures employed and peroxisomes are not detected cytochemically. These rindings support the hypothesis that the lack of peroxisomes in this genetic disease is the consequence of a defect in the assembly of the peroxisomal constituents. Furthermore, the value offibroblasts for subcellular analysis of peroxisomal defects is illustrated.Recent evidence supports the hypothesis that in some inherited metabolic disorders, defects in peroxisomal function are pathogenic. The initial observation that peroxisomes are absent in liver and kidney from children affected with the cerebrohepatorenal (Zellweger) syndrome (1) later correlated with the greatly reduced plasmalogen content found in their tissues (2), a phenomenon attributed to a lack of peroxisomal enzymes involved in plasmalogen biosynthesis (2, 3). It has also been correlated with the accumulation in fibroblasts of very long-chain fatty acids (4), supposedly the consequence of a defect in the peroxisomal fatty acid oxidation system capable of oxidizing very long-chain fatty acids (5, 6). The lack of peroxisomes would also explain the increased blood level of bile acid precursors (7,8) and possibly of pipecolic acid (9), assuming it reflects a deficiency in glutaryl-CoA oxidation (10). Adrenoleukodystrophy constitutes another hereditary disorder in which the accumulation of very longchain fatty acids (11) and also myelin degeneration (12, 13) apparently reflect a peroxisomal defect. As new findings increase the scope of the possible peroxisomal involvement in metabolic inherited disorders, their participation is being considered for hyperpipecolatemia (8,14), glutaric aciduria (10), dicarboxylic aciduria (15, 16), hyperoxaluria (14, 17), glycinuria (17), testicular feminization (18), and cerebrotendinous xanthomatosis (8,14). A single enzymatic defect might explain some of these conditions; however, in the Zellweger syndrome the whole organelle would be missing, perhaps reflecting the deficit of a protein essential for the assembly of peroxisomes. Consequently, as already suggested (14, 19-24), this pathologic condition would constitute a unique example of a genetic disorder expressed as absence of a cell o...

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“…In patients between 8 and 20 weeks of age fibrosis and distortion of liver architecture was found to be more severe. In almost all patients who were 20 weeks of age or older, there was severe fibrosis and micronodular cirrhosis (Passarge and McAdams 1967;Punnett and Kirkpatrick 1968;Gomez et al 1974;Gilchrist et al 1976;de Le6n et al 1977;Carlson and Weinberg 1978;Pfeiffer and Sandhage 1979;Hong et al 1981;Arneson et al 1982;Sarnat et al 1983). …”

Section: Biogenesis Of Peroxisomesmentioning

confidence: 99%

Peroxisomal disorders in neurology

Wanders

Heymans

Schutgens

et al. 1988

Journal of the Neurological Sciences

171

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SUMMARYAlthough peroxisomes were initially believed to play only a minor role in mammalian metabolism, it is now clear that they catalyse essential reactions in a number of different metabolic pathways and thus play an indispensable role in intermediary metabolism. The metabolic pathways in which peroxisomes are involved include the biosynthesis of ether phospholipids and bile acids, the oxidation of very long chain fatty acids, prostaglandins and unsaturated long chain fatty acids and the catabolism of phytanate and (in man) pipecolate and glyoxylate.The importance of peroxisomes in cellular metabolism is stressed by the existence of a group of inherited diseases, the peroxisomal disorders, caused by an impairment in one or more peroxisomal functions. In the last decade our knowledge about peroxisomes and peroxisomal disorders has progressed enormously and has been the subject of several reviews. New developments include the identification of several additional peroxisomal disorders, the discovery of the primary defect in several of these peroxisomal disorders, the recognition of novel peroxisomal functions and the application of complementation analysis to obtain information on the genetic relationship between the different peroxisomal disorders.The peroxisomal disorders recognized at present comprise 12 different diseases, with neurological involvement in 10 of them. These diseases include: (1) those in which peroxisomes are virtually absent leading to a generalized impairment of peroxisomal functions (the cerebro-hepato-renal syndrome of Zellweger, neonatal adrenoleukodystrophy, infantile Refsum disease and hyperpipecolic acidaemia); (2) those in which peroxisomes are present and several peroxisomal functions are impaired (the rhizomelic form of chondrodysplasia punctata, combined peroxisomal fl-oxidation enzyme protein deficiency); and (3)those in which peroxisomes are present and only a single peroxisomal function is impaired (X-linked adrenoleukodystrophy, peroxisomal thiolase deficiency (pseudo-Zellweger syndrome), acyl-CoA oxidase deficiency (pseudoneonatal adrenoleukodystrophy) and probably, the classic form of Refsum disease.

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Licht- und Elektronenmikroskopische Leberbefunde beim Cerebro-Hepato-Renalen Syndrom nach Zellweger (Peroxisomen-Defizienz)

Cited by 43 publications

References 18 publications

Absence of peroxisomes in mouse hepatocytes causes mitochondrial and ER abnormalities†

Absence of peroxisomes in mouse hepatocytes causes mitochondrial and ER abnormalities†

Peroxisomal organization in normal and cerebrohepatorenal (Zellweger) syndrome fibroblasts.

Peroxisomal disorders in neurology

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