Functional characterisation of peroxisomal β‐oxidation disorders in fibroblasts using lipidomics
Open accessAbstract
Peroxisomes play an important role in a variety of metabolic pathways, including the α‐ and β‐oxidation of fatty acids, and the biosynthesis of ether phospholipids. Single peroxisomal enzyme deficiencies (PEDs) are a group of peroxisomal disorders in which either a peroxisomal matrix enzyme or a peroxisomal membrane transporter protein is deficient. To investigate the functional consequences of specific enzyme deficiencies on the lipidome, we performed lipidomics using cultured skin fibroblasts with different defects in the β‐oxidation of very long‐chain fatty acids, including ABCD1‐ (ALD), acyl‐CoA oxidase 1 (ACOX1)‐, D‐bifunctional protein (DBP)‐, and acyl‐CoA binding domain containing protein 5 (ACBD5)‐deficient cell lines. Ultra‐high performance liquid chromatography coupled with high‐resolution mass spectrometry revealed characteristic changes in the phospholipid composition in fibroblasts with different fatty acid β‐oxidation defects. Remarkably, we found that ether phospholipids, including plasmalogens, were decreased. We defined specific phospholipid ratios reflecting the different enzyme defects, which can be used to discriminate the PED fibroblasts from healthy control cells.
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Data from patient fibroblasts do not indicate a significant reduction of DHA in phospholipids.
“Data from patient fibroblasts do not indicate a significant reduction of DHA in phospholipids (Herzog et al., 2018; Yagita et al., 2017).”
From The neurological pathology of peroxisomal ACBD5 deficiency – lessons from patients and mouse models (2025) · cites this paper as Herzog et al., 2018
The Results section, “Decrease of phospholipid species containing docosahexaenoic acid” (page unavailable), reports decreased DHA-containing phospholipid species in ACOX1- and DBP-deficient patient fibroblasts compared with controls. It says this decrease was not observed in ALD cells. Although the passage does not state a statistical significance test for DHA specifically, it contradicts the claim’s broad assertion that patient-fibroblast data do not indicate a reduction. (LLM, conf=0.88)
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Experimental — accuracy not yet measuredAltered plasmalogen metabolism may also contribute to the tissue-specific manifestations of RDLKD.
“In addition, altered plasmalogen metabolism may also contribute to the tissue-specific manifestations of RDLKD.”
From The neurological pathology of peroxisomal ACBD5 deficiency – lessons from patients and mouse models (2025) · cites this paper as Herzog et al., 2018
The Discussion reports decreased ether phospholipids, including plasmalogens, in fibroblasts from several peroxisomal disorders. It does not address RDLKD or whether altered plasmalogen metabolism contributes to its tissue-specific manifestations. (LLM, conf=0.84)
Experimental — accuracy not yet measuredThe consistent VLCFA accumulation in ACBD5-deficient cells may be a consequence of impaired palmitoyl-CoA synthesis, which is primarily performed in peroxisomes from C26:0-CoA β-oxidation.
“The consistent VLCFA accumulation may be a consequence of impaired palmitoyl-CoA synthesis, which is primarily performed in peroxisomes from C26:0-CoA β-oxidation (Herzog et al., 2018) but could further be related to reduced membrane contacts between peroxisomes and the ER, both of which cooperate in ether lipid synthesis.”
From The neurological pathology of peroxisomal ACBD5 deficiency – lessons from patients and mouse models (2025) · cites this paper as Herzog et al., 2018
The Results and Discussion report VLCFA accumulation in ACBD5-deficient fibroblasts. But the Discussion proposes reduced palmitoyl-CoA generation from C26:0-CoA as one possible explanation for decreased ether phospholipids, not for VLCFA accumulation; it also calls limited hexadecanol supply a more probable explanation. (LLM, conf=0.86)
Experimental — accuracy not yet measuredThe phospholipid deficiency in ACBD5-deficient cells extends to phosphatidylethanolamine-ether and phosphatidylcholine-ether phospholipids, pointing to a general phospholipid biosynthesis defect including a general decrease in phosphatidylethanolamine-plasmalogens.
“This phospholipid deficiency extends to phosphatidylethanolamine-ether and phosphatidylcholine-ether phospholipids, and therefore pointing to a general phospholipid biosynthesis defect, including a general decrease in phosphatidylethanolamine-plasmalogens (Hua et al., 2017; Herzog et al., 2018).”
From The neurological pathology of peroxisomal ACBD5 deficiency – lessons from patients and mouse models (2025) · cites this paper as Herzog et al., 2018
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Experimental — accuracy not yet measuredFibroblasts from ACBD5-deficient patients showed in part reduced levels of ether phospholipids, indicating that efficient ether lipid synthesis depends on the physical interaction between peroxisomes and the ER.
“Fibroblasts from ACBD5-deficient patients showed in part reduced levels of ether phospholipids, indicating that efficient ether lipid synthesis depends on the physical interaction between these two organelles (Herzog et al., 2018; Figure 3).”
From The neurological pathology of peroxisomal ACBD5 deficiency – lessons from patients and mouse models (2025) · cites this paper as Herzog et al., 2018
The Results (Fig. 2D) report decreased ether phospholipids in ACBD5-deficient fibroblasts. The Discussion describes a proposed peroxisome–ER tether mechanism for ether phospholipid biosynthesis, but also says the mechanism behind the decreased levels is not yet known. The claim presents dependence on physical interaction more firmly than this paper establishes. (LLM, conf=0.86)
Experimental — accuracy not yet measured
Lipidomic analysis of ACBD5 patient cells revealed an increase in VLCFA accumulation within phospholipids, along with a decrease in ether-phospholipids.
“Lipidomic analysis of ACBD5 patient cells revealed an increase in VLCFA accumulation within phospholipids, reflecting similar results from ACOX1-, DBP-, and X-ALD-deficient fibroblasts (Herzog et al., 2018), along with a decrease in ether-phospholipids.”
From The neurological pathology of peroxisomal ACBD5 deficiency – lessons from patients and mouse models (2025) · cites this paper as Herzog et al., 2018
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- Authors
- Herzog, K., Pras‐Raves, M. L., Ferdinandusse, S., Vervaart, M. A. T., Luyf, A. C. M., van Kampen, A. H. C., Wanders, R. J. A., Waterham, H. R., & Vaz, F. M.
- Affiliations
- University of Amsterdam (NL)
- Amsterdam UMC Location University of Amsterdam (NL)
- Department of Clinical Epidemiology, Biostatistics, and Bioinformatics, Academic Medical Center University of Amsterdam Meibergdreef 9 Amsterdam 1105 AZ The Netherlands
- Corresponding author
- Waterham, Hans R.
- Vaz, Frédéric M.
- ORCID
- Venue
- Journal of Inherited Metabolic Disease
- Publisher
- Wiley
- Published
- 2017-08-28
- Volume
- 41
- Issue
- 3
- Pages
- 479-487
- ISSN
- 0141-8955 (ISSN-L)
- 1573-2665
- PMC
- PMC5959964
- OpenAlex
- W2746883268
- Cited by
- 57
- References
- 6
- Citations by year
- 2026: 6 · 2025: 3 · 2024: 3 · 2023: 6 · 2022: 11 · 2021: 10 · 2020: 8 · 2019: 4 · 2018: 5 · 2017: 1
- FWCI
- 4.09
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Inherited Metabolic Disease (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, other-oa)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Pure Amsterdam UMC (publishedVersion, cc-by)
- UvA-DARE (University of Amsterdam) (submittedVersion, cc-by)
- Data Archiving and Networked Services (DANS) (submittedVersion, other-oa)
- Funders
- FP-7-PEOPLE-2012-Marie Curie (ITN316723 PERFUME)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Metabolism and Genetic Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Lipid metabolism and biosynthesis
- Health Sciences › Medicine › Physiology › Lysosomal Storage Disorders Research
- Keywords
- peroxisomal disorders, peroxisomal beta-oxidation, very long chain fatty acids, ACOX1, dermal fibroblasts, lipidomics, phospholipid composition, ether phospholipids, plasmalogens, diagnostic biomarkers, peroxisomal enzyme deficiency
- MeSH terms
- Cells, Cultured, Chromatography, High Pressure Liquid, Fatty Acids, Fibroblasts, Humans, Lipids, Oxidation-Reduction, Skin, Mass Spectrometry, Case-Control Studies, Peroxisomal Disorders, Peroxisomes, Lipid Metabolism, Metabolomics
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