Docosahexaenoic Acid Deficit Is Not a Major Pathogenic Factor in Peroxisome-Deficient Mice

Janssen, Ann; Baes, Myriam; Gressèns, Pierre; Mannaerts, Guy P.; Declercq, Peter; Veldhoven, Paul P. Van

doi:10.1038/labinvest.3780005

Cited by 55 publications

(35 citation statements)

References 19 publications

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“…This requires one peroxisomal β-oxidation cycle explaining the reduced levels of DHA in plasma of Zellweger patients [135] and in liver of Pex5 knockout mice [83,136]. The molecular impact of this deficit on hepatocyte function is unknown but clinical improvements were reported when supplementing this poly-unsaturated fatty acid to patients (see below).…”

Section: Other Peroxisomal Metabolites and Hepatocyte Dysfunctionmentioning

confidence: 92%

Hepatic dysfunction in peroxisomal disorders

Baes

Veldhoven

2016

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

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The peroxisomal compartment in hepatocytes hosts several essential metabolic conversions. These are defective in peroxisomal disorders that are either caused by failure to import the enzymes in the organelle or by mutations in the enzymes or in transporters needed to transfer the substrates across the peroxisomal membrane. Hepatic pathology is one of the cardinal features in disorders of peroxisome biogenesis and peroxisomal β-oxidation although it only rarely determines the clinical fate. In mouse models of these diseases liver pathologies also occur, although these are not always concordant with the human phenotype which might be due to differences in diet, expression of enzymes and backup mechanisms. Besides the morphological changes, we overview the impact of peroxisome malfunction on other cellular compartments including mitochondria and the ER. We further focus on the metabolic pathways that are affected such as bile acid formation, and dicarboxylic acid and branched chain fatty acid degradation. It appears that the association between deregulated metabolites and pathological events remains unclear.

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Section: Other Peroxisomal Metabolites and Hepatocyte Dysfunctionmentioning

confidence: 92%

Hepatic dysfunction in peroxisomal disorders

Baes

Veldhoven

2016

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

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“…The content of DHA in the phospholipid fraction was determined by GC analysis as previously described. 29 Phytanic, pristanic acid, and C 26:0 were quantified by GC-MS analysis in phospholipids and neutral lipids. 20 …”

Section: Lipid Analysismentioning

confidence: 99%

Peroxisomal Multifunctional Protein-2 Deficiency Causes Motor Deficits and Glial Lesions in the Adult Central Nervous System

Huyghe

Schmalbruch

Hulshagen

et al. 2006

The American Journal of Pathology

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In humans, mutations inactivating multifunctional protein-2 (MFP-2), and thus peroxisomal ␤-oxidation, cause neuronal heterotopia and demyelination, which is clinically reflected by hypotonia, seizures, and death within the first year of life. In contrast, our recently generated MFP-2-deficient mice did not show neurodevelopmental abnormalities but exhibited aberrations in bile acid metabolism and one of three of them died early postnatally. In the postweaning period, all survivors developed progressive motor deficits, including abnormal cramping reflexes of the limbs and loss of mobility, with death at 6 months. During the last decades it has been clearly established that peroxisomes are ubiquitously present in mammalian tissues. These organelles are involved in multiple processes such as the catabolism and synthesis of lipids and sterols and the degradation of hydrogen peroxide. Peroxisomal ␤-oxidation, in which multifunctional protein-2 (MFP-2) plays a pivotal role, is crucial for the breakdown of very-long-chain fatty acids, branched chain fatty acids, and cholesterol.

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“…Lipids were further separated in neutral lipids, fatty acids, and phospholipids by ion exchange chromatography (Bond Elut NH 2 , 500 mg, Varian). The fractions containing phospholipids were subjected to acidic methanolysis in the presence of internal standards (heptadecanoic acid and heptacosanoic acid) followed by gas chromatography of the fatty acid methyl esters on a BPX70 column (40). Triglycerides were isolated from the fractions containing neutral lipids by TLC (solvent heptane/ diethylether/acetic acid, 70:30:1, v/v/v), eluted with chloroform/methanol (41), transmethylated, and analyzed by gas chromatography.…”

Section: Construction Of the Targeting Vector And Generation Of Mfp-2mentioning

confidence: 99%

Inactivation of the Peroxisomal Multifunctional Protein-2 in Mice Impedes the Degradation of Not Only 2-Methyl-branched Fatty Acids and Bile Acid Intermediates but Also of Very Long Chain Fatty Acids

Baes¹,

Huyghe²,

Carmeliet³

et al. 2000

Journal of Biological Chemistry

176

145

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According to current views, peroxisomal ␤-oxidation is organized as two parallel pathways: the classical pathway that is responsible for the degradation of straight chain fatty acids and a more recently identified pathway that degrades branched chain fatty acids and bile acid intermediates. Multifunctional protein-2 (MFP-2), also called D-bifunctional protein, catalyzes the second (hydration) and third (dehydrogenation) reactions of the latter pathway. In order to further clarify the physiological role of this enzyme in the degradation of fatty carboxylates, MFP-2 knockout mice were generated. MFP-2 deficiency caused a severe growth retardation during the first weeks of life, resulting in the premature death of one-third of the MFP-2 ؊/؊ mice. Furthermore, MFP-2-deficient mice accumulated VLCFA in brain and liver phospholipids, immature C 27 bile acids in bile, and, after supplementation with phytol, pristanic and phytanic acid in liver triacylglycerols. These changes correlated with a severe impairment of peroxisomal ␤-oxidation of very long straight chain fatty acids (C 24 ), 2-methyl-branched chain fatty acids, and the bile acid intermediate trihydroxycoprostanic acid in fibroblast cultures or liver homogenates derived from the MFP-2 knockout mice. In contrast, peroxisomal ␤-oxidation of long straight chain fatty acids (C 16 ) was enhanced in liver tissue from MFP-2 ؊/؊ mice, due to the up-regulation of the enzymes of the classical peroxisomal ␤-oxidation pathway. The present data indicate that MFP-2 is not only essential for the degradation of 2-methyl-branched fatty acids and the bile acid intermediates di-and trihydroxycoprostanic acid but also for the breakdown of very long chain fatty acids.

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Docosahexaenoic Acid Deficit Is Not a Major Pathogenic Factor in Peroxisome-Deficient Mice

Cited by 55 publications

References 19 publications

Hepatic dysfunction in peroxisomal disorders

Hepatic dysfunction in peroxisomal disorders

Peroxisomal Multifunctional Protein-2 Deficiency Causes Motor Deficits and Glial Lesions in the Adult Central Nervous System

Inactivation of the Peroxisomal Multifunctional Protein-2 in Mice Impedes the Degradation of Not Only 2-Methyl-branched Fatty Acids and Bile Acid Intermediates but Also of Very Long Chain Fatty Acids

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