Biochemical Studies in the Liver and Muscle of Patients with Zellweger Syndrome

Trijbels, J. M. F.; Berden, J.A.; Monnens, L.A.H.; Willems, J. L.; Janssen, A.J.M.; Schutgens, R. B. H.; Essen, Martin Van

doi:10.1203/00006450-198306000-00018

Cited by 67 publications

(24 citation statements)

References 18 publications

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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%

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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mentioning

confidence: 67%

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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“…Previous studies demonstrated that mitochondria are abnormal in livers of Zellweger patients and mouse Zellweger models [17][18][19][20][21][22][23] and that bile acids may mediate mitochondrial toxicity. 24 Electron microscopy demonstrated mitochondrial abnormalities typically seen in peroxisomal disorders in both early postnatal and P36 untreated PEX2 mutant livers, and these defects persisted in all BA-fed PEX2 Ϫ/Ϫ mice (Fig.…”

Section: Resultsmentioning

confidence: 99%

Bile acid treatment alters hepatic disease and bile acid transport in peroxisome‐deficient PEX2 Zellweger mice†

et al. 2007

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The marked deficiency of peroxisomal organelle assembly in the PEX2 ؊/؊ mouse model for Zellweger syndrome provides a unique opportunity to developmentally and biochemically characterize hepatic disease progression and bile acid products. The postnatal survival of homozygous mutants enabled us to evaluate the response to bile acid replenishment in this disease state. PEX2 mutant liver has severe but transient intrahepatic cholestasis that abates in the early postnatal period and progresses to steatohepatitis by postnatal day 36. We confirmed the expected reduction of mature C24 bile acids, accumulation of C27-bile acid intermediates, and low total bile acid level in liver and bile from these mutant mice. Treating the PEX2 ؊/؊ mice with bile acids prolonged postnatal survival, alleviated intrahepatic cholestasis and intestinal malabsorption, reduced C27-bile acid intermediate production, and prevented older mutants from developing severe steatohepatitis. However, this therapy exacerbated the degree of hepatic steatosis and worsened the already severe mitochondrial and cellular damage in peroxisome-deficient liver. Both untreated and bile acid-fed PEX2 ؊/؊ mice accumulated high levels of predominantly unconjugated bile acids in plasma because of altered expression of hepatocyte bile acid transporters. Significant amounts of unconjugated bile acids were also found in the liver and bile of PEX2 mutants, indicating a generalized defect in bile acid conjugation. Conclusion: Peroxisome deficiency widely disturbs bile acid homeostasis and hepatic functioning in mice, and the high sensitivity of the peroxisome-deficient liver to bile acid toxicity limits the effectiveness of bile acid therapy for preventing hepatic disease. (HEPATOLOGY 2007;45:982-997.)

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“…Furthermore, steatosis and canalicular and cytoplasmic cholestasis develop with normal, deficient, or hyperplastic intrahepatic bile ducts. Another striking observation was the altered structure of mitochondria at the level of the inner membrane (5)(6)(7)(8)(9)(10). However, the precise consequences of these mitochondrial abnormalities remain largely unexplored.…”

mentioning

confidence: 99%

Carbohydrate Metabolism Is Perturbed in Peroxisome-deficient Hepatocytes Due to Mitochondrial Dysfunction, AMP-activated Protein Kinase (AMPK) Activation, and Peroxisome Proliferator-activated Receptor γ Coactivator 1α (PGC-1α) Suppression

Peeters

Fraisl

Berg

et al. 2011

Journal of Biological Chemistry

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Background:It is not known whether peroxisomes influence hepatic carbohydrate metabolism. Results: Carbohydrate metabolism is perturbed in peroxisome-deficient mouse liver through mitochondrial deficits, AMPK, and PGC-1␣. Conclusion: Dysfunctional peroxisome metabolism disrupts carbohydrate homeostasis by indirect mechanisms. Significance: The impact of peroxisome deficiency on liver metabolism is broader than expected.

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Biochemical Studies in the Liver and Muscle of Patients with Zellweger Syndrome

Cited by 67 publications

References 18 publications

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

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

Bile acid treatment alters hepatic disease and bile acid transport in peroxisome‐deficient PEX2 Zellweger mice†

Carbohydrate Metabolism Is Perturbed in Peroxisome-deficient Hepatocytes Due to Mitochondrial Dysfunction, AMP-activated Protein Kinase (AMPK) Activation, and Peroxisome Proliferator-activated Receptor γ Coactivator 1α (PGC-1α) Suppression

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