Phytol is lethal for Amacr-deficient mice
Open accessAbstract
α-Methylacyl-CoA racemase (Amacr) catalyzes the racemization of the 25-methyl group in C27-intermediates in bile acid synthesis and in methyl-branched fatty acids such as pristanic acid, a metabolite derived from phytol. Consequently, patients with Amacr deficiency accumulate C27-bile acid intermediates, pristanic and phytanic acid and display sensorimotor neuropathy, seizures and relapsing encephalopathy. In contrast to humans, Amacr-deficient mice are clinically symptomless on a standard laboratory diet, but failed to thrive when fed phytol-enriched chow. In this study, the effect and the mechanisms behind the development of the phytol-feeding associated disease state in Amacr-deficient mice were investigated. All Amacr-/- mice died within 36weeks on a phytol diet, while wild-type mice survived. Liver failure was the main cause of death accompanied by kidney and brain abnormalities. Histological analysis of liver showed inflammation, fibrotic and necrotic changes, Kupffer cell proliferation and fatty changes in hepatocytes, and serum analysis confirmed the hepatic disease. Pristanic and phytanic acids accumulated in livers of Amacr-/- mice after a phytol diet. Microarray analysis also revealed changes in the expression levels of numerous genes in wild-type mouse livers after two weeks of the phytol diet compared to a control diet. This indicates that detoxification of phytol metabolites in liver is accompanied by activation of multiple pathways at the molecular level and Amacr-/- mice are not able to respond adequately. Phytol causes primary failure in liver leading to death of Amacr-/- mice thus emphasizing the indispensable role of Amacr in detoxification of α-methyl-branched fatty acids.
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Upon phytol supplementation of the diet, racemase-deficient mice develop severe brain pathology after 40 days, including demyelination and activation of astroglial cells.
“However, upon phytol supplementation of the diet, the mice developed severe pathology in the brain after 40 days, including demyelination and activation of astroglial cells [101].”
From Peroxisomes in brain development and function (2016) · cites this paper as [101]
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- Authors
- Selkälä, E. M., Nair, R. R., Schmitz, W., Kvist, A.-P., Baes, M., Hiltunen, J. K., & Autio, K. J.
- Affiliations
- University of Oulu (FI)
- University of Würzburg (DE)
- KU Leuven (BE)
- Corresponding author
- Autio, Kaija J.
- Venue
- Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids
- Publisher
- Elsevier BV
- Published
- 2015-10
- Volume
- 1851
- Issue
- 10
- Pages
- 1394-1405
- ISSN
- 1388-1981 (ISSN-L)
- OpenAlex
- W1652963135
- Cited by
- 11
- References
- 16
- Citations by year
- 2023: 2 · 2022: 2 · 2020: 1 · 2019: 2 · 2017: 1 · 2016: 1 · 2015: 2
- FWCI
- 1.10
- Type
- journal article
- Language
- en
- Open access
- Licence
- cc-by-nc-nd
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- Locations
- Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids (publishedVersion)
- PubMed (publishedVersion)
- Lirias (submittedVersion, cc-by-nc-nd)
- Funders
- NordForsk (070010)
- Sigrid Juséliuksen Säätiö
- European Commission (LSHG-CT-2004-512018)
- Academy of Finland (138690)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Metabolism and Genetic Disorders
- Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
- Life Sciences › Neuroscience › Neurology › Neurological diseases and metabolism
- Keywords
- AMACR, phytol, pristanic acid, phytanic acid, methyl-branched fatty acids, bile acid synthesis, liver failure, hepatotoxicity, hepatic gene expression, Kupffer cells, mouse model
- MeSH terms
- Animals, Bile Acids and Salts, Brain, Gene Expression Regulation, Kidney, Kupffer Cells, Phytol, Mice, Knockout, Racemases and Epimerases, Mice, Chemical and Drug Induced Liver Injury
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