Severe plasmalogen deficiency in tissues of infants without peroxisomes (Zellweger syndrome)

Heymans, H. S. A.; Schutgens, R. B. H.; Tan, Ru Yu; Bosch, H. van den; Borst, Piet

doi:10.1038/306069a0

Cited by 319 publications

(151 citation statements)

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“…However, the general consensus is that this peroxisomal pathway is solely for the biosynthesis of ether lipids (13). This assumption is based on the fact that there is a deficiency of ether lipids, but not other glycerolipids, in the tissues of patients suffering from congenital peroxisomal disorders (47), where there is also a deficiency of DHAPAT (48). On the other hand, a complete loss of GPD, in a mutant mouse strain does not affect the animal's physiological functions (49).…”

Section: Discussionmentioning

confidence: 99%

Induction of the Peroxisomal Glycerolipid-synthesizing Enzymes during Differentiation of 3T3-L1 Adipocytes

Hajra¹,

Larkins²,

Das³

et al. 2000

Journal of Biological Chemistry

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The glycerophosphate backbone for triglyceride synthesis is commonly believed to be created through the conversion of dihydroxyacetone phosphate (DHAP) by glycerophosphate dehydrogenase (GPD) to sn-glycerol 3-phosphate (GP), which is then converted by glycerophosphate acyltransferase (GPAT) to 1-acyl-GP. Consistent with this, GPD and GPAT are highly induced during differentiation of mouse 3T3-L1 preadipocytes. While the acyl dihydroxyacetone phosphate (acyl-DHAP) pathway for glycerolipid synthesis is commonly believed to be involved only in glycerol ether lipid synthesis, we report here that during conversion of 3T3-L1 preadipocytes to adipocytes, the specific activity of peroxisomal DHAP acyltransferase (DHAPAT) is increased by 9-fold in 6 days, while acyl-DHAP:NADPH reductase is induced by 5-fold. A parallel increase in the catalase (the peroxisomal marker enzyme) activity is also seen. In contrast, the specific activity of alkyl-DHAP synthase, the enzyme catalyzing the synthesis of the ether bond, is decreased by 60% during the same period. Unlike microsomal GPAT, the induced DHAPAT is found to have high activity at pH 5.5 and is resistant to inhibition by sulfhydryl agents, heat, and proteolysis. On subcellular fractionation, DHAPAT is found to be associated with microperoxisomes whereas GPAT activity is mainly present in microsomes. Northern blot analyses reveal that induction of DHAPAT can be largely explained through increases in DHAPAT mRNA. A comparison of microsomal and peroxisomal glycerolipid synthetic pathways, using Preadipocyte cell lines (1) have been widely used to study the induction of a number of enzymes and receptors and also the mechanism of differentiation at the genetic level (2, 3). The fibroblast-like mouse 3T3-L1 cells differentiate in response to high concentrations of insulin and other agents to cells that synthesize large amounts of triglycerides and are morphologically similar to adipose cells (4). A similar cell line (3T3-F442A), on transplantation in mice has been reported to develop into adipose tissue (5). During differentiation, lipogenic enzymes of the triglyceride biosynthetic pathway, as well as the ancillary enzymes needed for the formation of substrates and cofactors are induced (6). As outlined in Fig. 1, enzymes starting from the cytosolic glycerophosphate dehydrogenase (GPD), 1 catalyzing the biosynthesis of sn-glycerol 3-phosphate (GP) followed by the glycerophosphate acyltransferase (GPAT), 1-acyl-GP acyltransferase, and diacylglycerol acyltransferase (DAGAT) are highly induced during differentiation (7-9). Coleman and Bell (10) reported that due to nonspecificity of microsomal GPAT, which catalyzes the acylation of both GP and DHAP, DHAPAT activity is also induced during differentiation of these cells. All animal cells, however, have been shown to contain a specific peroxisomal DHAPAT which does not contain GPAT activity (11,12). This DHAPAT, co-localized in peroxisomes with acyl/alkyl DHAP:NADPH reductase and alkyl-DHAP synthase, is generally believed to be involve...

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Section: Discussionmentioning

confidence: 99%

Induction of the Peroxisomal Glycerolipid-synthesizing Enzymes during Differentiation of 3T3-L1 Adipocytes

Hajra¹,

Larkins²,

Das³

et al. 2000

Journal of Biological Chemistry

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“…It is characterized by a reduced number or absence of peroxisomes (3) and regarded as the prototype of peroxisomal deficiency disorders. Multiple peroxisomal biochemical processes are defective, including @-oxidation of very long chain fatty acids (4), phytanic acid oxidation (5,6), pipecolic acid oxidation (7), plasmalogen biosynthesis (8), and bile acid metabolism (9).…”

mentioning

confidence: 99%

The 22-kD Peroxisomal Integral Membrane Protein in Zellweger Syndrome—Presence, Abundance, and Association with a Peroxisomal Thiolase Precursor Protein

et al. 1991

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ABSTRACT. The primary genetic defect of Zellweger syndrome may be related to defective synthesis or impaired import of peroxisomal proteins. We analyzed the presence and measured the abundance of the 22-kD peroxisomal integral membrane protein (PMP) in patients with Zellweger syndrome. We determined the intracellular localization of the 22-kD PMP and compared it with the localization of a peroxisomal 44-kD thiolase precursor protein.The 22-kD P M P was quantified by immunoblot analyses in liver tissue (n = 7 patients). Immunoblot signals were evaluated using transmission photometry. The intracellular localization of the 22-kD P M P and the peroxisomal 44-kD thiolase precursor protein were determined by immunoblot analyses on fibroblast subcellular fractions prepared by Nycodenz (n = 5 patients) or sucrose density gradient centrifugation (n = 2 patients). The 22-kD P M P was present and associated with membrane fractions in all patients. Its abundance varied in patients as compared with normal human liver controls. The 22-kD P M P was located in subcellular membrane fractions having a lower density than normal peroxisomes or mitochondria. Using two different gradient techniques, the 22-kD P M P and the peroxisomal 44-kD thiolase precursor protein were found in the same low-density gradient fractions. These results suggest that in Zellweger syndrome peroxisome-like elements containing both the 22-kD P M P and a 44-kD thiolase precursor protein are formed.

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“…4 The absence of functional peroxisomes in patients with a PBD leads to a number of biochemical abnormalities: (i) PBD patients have an impaired synthesis of plasmalogens, due to a deficiency of the two enzymes dihydroxyacetonephosphate acyltransferase (DHAPAT) and alkyl-dihydroxyacetonephosphate synthase (alkyl-DHAP-synthase). 5,6 (ii) Peroxisomal fatty acid b-oxidation is defective, leading to the accumulation of very-longchain fatty acids (VLCFAs), notably C26:0, the branchedchain fatty acid pristanic acid and the bile acid intermediates di-and trihydroxycholestanoic acid (DHCA and THCA). 1 (iii) Phytanic acid a-oxidation and L-pipecolic acid oxidation are impaired.…”

Section: Introductionmentioning

confidence: 99%

Novel mutations in the PEX12 gene of patients with a peroxisome biogenesis disorder

et al. 2003

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Severe plasmalogen deficiency in tissues of infants without peroxisomes (Zellweger syndrome)

Cited by 319 publications

References 19 publications

Induction of the Peroxisomal Glycerolipid-synthesizing Enzymes during Differentiation of 3T3-L1 Adipocytes

Induction of the Peroxisomal Glycerolipid-synthesizing Enzymes during Differentiation of 3T3-L1 Adipocytes

The 22-kD Peroxisomal Integral Membrane Protein in Zellweger Syndrome—Presence, Abundance, and Association with a Peroxisomal Thiolase Precursor Protein

Novel mutations in the PEX12 gene of patients with a peroxisome biogenesis disorder

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