Ultrastructure of the Liver in the Cerebrohepatorenal Syndrome of Zellweger

Wj, Mooi; Kp, Dingemans; Weerman, van den Bergh; Ac, Jöbsis; Hs, Heymans; Barth, P. G.

doi:10.3109/01913128309141833

Cited by 64 publications

(42 citation statements)

References 12 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: 79%

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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: 79%

“…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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“…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-deficientPEX2Zellweger 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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“…These organelles participate in a number of metabolic cellular processes-e.g., 13-oxidation of fatty acids (11,12), plasmalogen biosynthesis (13,14), and bile acid synthesis (15,16). Peroxisomes are decreased or absent in liver and kidney from patients with the Zellweger cerebrohepatorenal syndrome (17,18), which is characterized biochemically by accumulation ofVLCFA in plasma, tissues, and fibroblasts (19)(20)(21); decreased plasmalogen content of tissues (22,23); and accumulation of pipecolic acid (24,25) and bile acid synthesis intermediates (26)(27)(28) in tissues. The Zellweger syndrome is usually fatal within the first year of life (21), suggesting that peroxisomes play a vital role in normal cellular metabolism.…”

mentioning

confidence: 99%

Peroxisomal beta-oxidation enzyme proteins in adrenoleukodystrophy: distinction between X-linked adrenoleukodystrophy and neonatal adrenoleukodystrophy.

Chen

Watkins

Osumi

et al. 1987

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

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Very long chain fatty acids, which accumulate in plasma and tissues in X-linked adrenoleukodystrophy (ALD), neonatal ALD, and the Zellweger cerebrohepatorenal syndrome, are degraded by the peroxisomal ,8-oxidation pathway, consisting of acyl-CoA oxidase, the bifunctional enoylCoA hydratase/3-hydroxyacyl-CoA dehydrogenase, and 13-ketothiolase. A marked deficiency of all three enzyme proteins was reported in livers from patients with the Zellweger syndrome, a disorder in which peroxisomes are decreased or absent. Peroxisomes are not as markedly decreased in neonatal ALD and appear normal in X-linked ALD. Immunoblot analysis of the peroxisomal 13-oxidation enzymes revealed an almost complete lack of the bifunctional enzyme in neonatal ALD liver, similar to the finding in Zellweger tissue. In contrast, acyl-CoA oxidase and f3-ketothiolase were present in neonatal ALD liver, although the thiolase appeared to be in precursor form (2-3 kDa larger than the mature enzyme) in neonatal ALD. Unlike either neonatal ALD or Zellweger syndrome, all three peroxisomal 13-oxidation enzymes were present in X-linked ALD liver. Despite the absence in neonatal ALD liver of bifunctional enzyme protein, its mRNA was detected by RNA blot analysis in fibroblasts from these patients. These observations suggest that lack of bifunctional enzyme protein in neonatal ALD results from either abnormal translation of the mRNA or degradation of the enzyme prior to its entry into peroxisomes.

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Ultrastructure of the Liver in the Cerebrohepatorenal Syndrome of Zellweger

Cited by 64 publications

References 12 publications

Absence of peroxisomes in mouse hepatocytes causes mitochondrial and ER abnormalities

Absence of peroxisomes in mouse hepatocytes causes mitochondrial and ER abnormalities

Bile acid treatment alters hepatic disease and bile acid transport in peroxisome-deficientPEX2Zellweger mice

Peroxisomal beta-oxidation enzyme proteins in adrenoleukodystrophy: distinction between X-linked adrenoleukodystrophy and neonatal adrenoleukodystrophy.

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