Cholesterol biosynthesis is not defective in peroxisome biogenesis defective fibroblasts.
Abstract
To evaluate the presumed peroxisomal involvement in cholesterol/isoprenoid biosynthesis, we determined the protein levels and activities of five different enzymes of the presqualene segment of the cholesterol/isoprenoid biosynthetic pathway in primary skin fibroblasts of selected patients with a peroxisomal biogenesis disorder (PBD). These five enzymes all have been reported to be partly or exclusively peroxisomal and include HMG-CoA reductase, mevalonate kinase, phosphomevalonate kinase, mevalonate pyrophosphate decarboxylase, and isopentenyl pyrophosphate isomerase. To exclude that genetic differences, resulting in different defects in peroxisomal biogenesis, have differential effects on the activity of the cholesterol biosynthetic enzymes and on de novo cholesterol biosynthesis, we chose fibroblasts of patients with defined defects in one of four different PEX genes leading to Zellweger syndrome (PEX1, PEX5, PEX16 or PEX19). We found that all enzymes measured are at least as active in the peroxisome-deficient cells cultured in cholesterol-depleted medium as in identically cultured control cells. This indicates that if these presumed peroxisomal proteins are mislocalized to the cytosol they do not loose their activity, nor get degraded unlike most other authentic peroxisomal proteins. We also measured de novo cholesterol synthesis from radio-labeled acetate in all cell lines and found similar or even elevated rates for the PBD cells when compared to controls. Our results imply that functional peroxisomes are not a prerequisite for the functioning of enzymes involved in cholesterol/isoprenoid biosynthesis and as such raise doubts about the true involvement of peroxisomes therein.
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The involvement of peroxisomes in mammalian cholesterol synthesis remains controversial.
“However, the involvement of peroxisomes in mammalian cholesterol synthesis remains controversial (Hogenboom et al., 2003).”
From The neurological pathology of peroxisomal ACBD5 deficiency – lessons from patients and mouse models (2025) · cites this paper as Hogenboom et al., 2003
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- Authors
- Hogenboom, S.
- Affiliations
- Amsterdam UMC Location University of Amsterdam (NL)
- Corresponding author
- Hogenboom, S
- Venue
- Molecular Genetics and Metabolism
- Publisher
- Elsevier BV
- Published
- 2003-11
- Volume
- 80
- Issue
- 3
- Pages
- 290-295
- ISSN
- 1096-7192 (ISSN-L)
- OpenAlex
- W2128697397
- Cited by
- 22
- References
- 36
- Citations by year
- 2025: 1 · 2024: 1 · 2022: 1 · 2021: 3 · 2013: 2 · 2012: 1
- FWCI
- 2.24
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Molecular Genetics and Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Pure Amsterdam UMC (submittedVersion)
- Funders
- Koninklijke Nederlandse Akademie van Wetenschappen
- Topics
- Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Metabolism and Genetic Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Lipids, and Metabolism
- Keywords
- cholesterol biosynthesis, peroxisome biogenesis disorders, peroxisomes, isoprenoid biosynthesis, Zellweger syndrome, PEX genes, PEX1, PEX5, PEX16, PEX19, HMG-CoA reductase, mevalonate kinase, phosphomevalonate kinase, isopentenyl pyrophosphate isomerase, enzyme localization, de novo cholesterol synthesis, fibroblasts
- MeSH terms
- Carboxy-Lyases, Cholesterol, Fibroblasts, Humans, Hydroxymethylglutaryl CoA Reductases, Proteins, Radiochemistry, Immunoblotting, Phosphotransferases (Alcohol Group Acceptor), Phosphotransferases (Phosphate Group Acceptor), Peroxisomal Disorders, Carbon-Carbon Double Bond Isomerases, Hemiterpenes, PHEX Phosphate Regulating Neutral Endopeptidase
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