A role for the human peroxisomal half-transporter ABCD3 in the oxidation of dicarboxylic acids

Roermund, C. W. T. van; IJlst, Lodewijk; Wagemans, Tom; Wanders, Ronald J. A.; Waterham, Hans R.

doi:10.1016/j.bbalip.2013.12.001

Cited by 85 publications

(100 citation statements)

References 35 publications

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“…Several other lines of evidence indicate that the import of DCA-CoA esters, which are formed in the ER, is mediated by the ABCD3 transporter. First, using a rescue expression system of human ABCD transporters in S. cerevisiae pxa1/pxa2 mutants, it was shown that DCA are preferentially taken up by ABCD3 [114]. Secondly, the ABCD3 transporter is upregulated by PPARα in the mouse, which facilitates uptake of the DCA across the peroxisomal membrane when fatty acid supply is increased [115].…”

Section: Peroxisomal β-Oxidation Deficiencies and Impairment Of Dca Mmentioning

confidence: 99%

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: Peroxisomal β-Oxidation Deficiencies and Impairment Of Dca Mmentioning

confidence: 99%

Hepatic dysfunction in peroxisomal disorders

Baes

Veldhoven

2016

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

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“…The deletion stains used were fox1⌬ (or pox1⌬, peroxisomal acyl-CoA oxidase) and double mutant pxa1⌬ and pxa2⌬ (peroxisomal ABC transporters 1 and 2). The mutants were constructed from BJ1991 as described previously (7)(8)(9). Yeast transformants containing the expression plasmids with the different chimeric constructs of ABCD1 and ABCD2 were selected and grown in minimal medium containing 6.…”

Section: Methodsmentioning

confidence: 99%

“…Sucrose density gradient and coimmunoprecipitation experiments have shown that ABCD1 and ABCD3 occur predominantly as homodimers (6). Functional complementation assays in yeast pxa1/pxa2⌬ double mutants also suggested the functionality of ABCD1, ABCD2, and ABCD3 as homodimers (7)(8)(9). However, yeast two-hybrid, co-immunoprecipitation, FRET, and proximity ligation assays have provided evidence for the existence of heterodimers formed between ABCD1 and one of the two other peroxisomal ABC transporters (10 -14).…”

mentioning

confidence: 99%

“…ABCD2 would be involved in the transport of the same VLCFA but also in the transport of C20:0, C22:0, C22:1, and polyunsaturated fatty acids such as DHA (C22:6 n-3) and its immediate precursor C24:6 n-3 (8 -10, 21-23). Finally, ABCD3 would preferentially transport branched-chain fatty acids, bile acid precursors, and dicarboxylic acids (9,24,25). The relationships between the substrate specificity of the peroxisomal ABC transporters and their state of dimerization (homo-or heterodimerization) have remained unexplored.…”

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confidence: 99%

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Structure-Function Analysis of Peroxisomal ATP-binding Cassette Transporters Using Chimeric Dimers

Geillon

Gondcaille

Charbonnier

et al. 2014

Journal of Biological Chemistry

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Background: Peroxisomal ABC transporters are predicted to function as homodimers in mammals. Results: ABCD1 interacts with ABCD2. Chimeric proteins mimicking full-length dimers represent novel tools for functional study. Artificial homodimers and heterodimers are functional. Conclusion: Interchangeability between ABCD1 and ABCD2 is confirmed, but PUFA transport depends on ABCD2. Significance: For the first time, heterodimers in mammals are proven to be functional.

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“…We identified several CYP4A orthologs induced by SQ1, which we propose catalyzes the v-hydroxylation of farnesoic acid followed by sequential oxidation at the v-carbon, possibly by the same enzymes involved in farnesol oxidation. The C 15 -DCA could then be activated by ACSL1 to its CoA derivative for transport into the peroxisome via the dicarboxylic acid transporter ABCD3 (van Roermund et al, 2014), and then undergo one or two rounds of b-oxidation, producing C 10 and C 12 DCAs as well as propionyl-CoA and acetyl-CoA. The chain-shortened DCAs could either be conjugated with carnitine and exported to the mitochondria for further oxidation or processed by ACOT enzymes, producing free acids that are then eliminated from the cell.…”

Section: Regulation Of Hepatocellular Gene Expression By Isoprenoidsmentioning

confidence: 99%

Differential Regulation of Gene Expression by Cholesterol Biosynthesis Inhibitors That Reduce (Pravastatin) or Enhance (Squalestatin 1) Nonsterol Isoprenoid Levels in Primary Cultured Mouse and Rat Hepatocytes

Rondini

Duniec-Dmuchowski

Cukovic

et al. 2016

Journal of Pharmacology and Experimental Therapeutics

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Squalene synthase inhibitors (SSIs), such as squalestatin 1 (SQ1), reduce cholesterol biosynthesis but cause the accumulation of isoprenoids derived from farnesyl pyrophosphate (FPP), which can modulate the activity of nuclear receptors, including the constitutive androstane receptor (CAR), farnesoid X receptor, and peroxisome proliferator-activated receptors (PPARs). In comparison, 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors (e.g., pravastatin) inhibit production of both cholesterol and nonsterol isoprenoids. To characterize the effects of isoprenoids on hepatocellular physiology, microarrays were used to compare orthologous gene expression from primary cultured mouse and rat hepatocytes that were treated with either SQ1 or pravastatin. Compared with controls, 47 orthologs were affected by both inhibitors, 90 were affected only by SQ1, and 51 were unique to pravastatin treatment (P , 0.05, $1.5-fold change). When the effects of SQ1 and pravastatin were compared directly, 162 orthologs were found to be differentially coregulated between the two treatments. Genes involved in cholesterol and unsaturated fatty acid biosynthesis were up-regulated by both inhibitors, consistent with cholesterol depletion; however, the extent of induction was greater in rat than in mouse hepatocytes. SQ1 induced several orthologs associated with microsomal, peroxisomal, and mitochondrial fatty acid oxidation and repressed orthologs involved in cell cycle regulation. By comparison, pravastatin repressed the expression of orthologs involved in retinol and xenobiotic metabolism. Several of the metabolic genes altered by isoprenoids were inducible by a PPARa agonist, whereas cytochrome P450 isoform 2B was inducible by activators of CAR. Our findings indicate that SSIs uniquely influence cellular lipid metabolism and cell cycle regulation, probably due to FPP catabolism through the farnesol pathway.

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A role for the human peroxisomal half-transporter ABCD3 in the oxidation of dicarboxylic acids

Cited by 85 publications

References 35 publications

Hepatic dysfunction in peroxisomal disorders

Hepatic dysfunction in peroxisomal disorders

Structure-Function Analysis of Peroxisomal ATP-binding Cassette Transporters Using Chimeric Dimers

Differential Regulation of Gene Expression by Cholesterol Biosynthesis Inhibitors That Reduce (Pravastatin) or Enhance (Squalestatin 1) Nonsterol Isoprenoid Levels in Primary Cultured Mouse and Rat Hepatocytes

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