Cited by 84Metabolism and Genetic DisordersCholesterol and Lipid MetabolismDrug Transport and Resistance Mechanisms

A mouse model for α-methylacyl-CoA racemase deficiency: adjustment of bile acid synthesis and intolerance to dietary methyl-branched lipids

Savolainen, Kalle, Kotti, Tiina J., Schmitz, Werner, Savolainen, Teuvo I., Sormunen, Raija T., Ilves, Mika, Vainio, Seppo J., Conzelmann, Ernst +1 more·2004·Human Molecular Genetics

Abstract

alpha-Methylacyl-CoA racemase (Amacr) deficiency in humans leads to sensory motor neuronal and liver abnormalities. The disorder is recessively inherited and caused by mutations in the AMACR gene, which encodes Amacr, an enzyme presumed to be essential for bile acid synthesis and to participate in the degradation of methyl-branched fatty acids. To generate a model to study the pathophysiology in Amacr deficiency we inactivated the mouse Amacr gene. As per human Amacr deficiency, the Amacr(-/-) mice showed accumulation (44-fold) of C27 bile acid precursors and decreased (over 50%) primary (C24) bile acids in bile, serum and liver, however the Amacr(-/-) mice were clinically symptomless. Real-time quantitative PCR analysis showed that, among other responses, the level of mRNA for peroxisomal multifunctional enzyme type 1 (pMFE-1) was increased 3-fold in Amacr(-/-) mice. This enzyme can be placed, together with CYP3A11 and CYP46A1, to make an Amacr-independent pathway for the generation of C24 bile acids. Exposure of Amacr(-/-) mice to a diet supplemented with phytol, a source for branched-chain fatty acids, triggered the development of a disease state with liver manifestations, redefining the physiological significance of Amacr. Amacr is indispensable for the detoxification of dietary methyl-branched lipids and, although it contributes normally to bile acid synthesis from cholesterol, the putative pMFE-1-mediated cholesterol degradation can provide for generation of bile acids, allowing survival without Amacr. Based upon our mouse model, we propose elimination of phytol from the diet of patients suffering from Amacr deficiency.

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Crossref · 10.1093/hmg/ddh107

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  • The absence of developmental problems in the CNS of racemase-deficient mice, in which bile acid precursors accumulate, renders an exclusive effect of bile acid precursors quite unlikely.

    “However, the absence of developmental problems in the CNS of racemase-deficient mice, in which bile acid precursors accumulate as well [78], renders an exclusive effect of bile acid precursors quite unlikely.”

    From Peroxisomes in brain development and function (2016) · cites this paper as [78]

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Authors
Savolainen, K., Kotti, T. J., Schmitz, W., Savolainen, T. I., Sormunen, R. T., Ilves, M., Vainio, S. J., Conzelmann, E., & Hiltunen, J. K.
Affiliations
  • University of Oulu (FI)
  • University of Würzburg (DE)
  • Päijät-Hämeen Keskussairaala (FI)
Corresponding author
Savolainen, Kalle
Venue
Human Molecular Genetics
Published
2004-03-11
Volume
13
Issue
9
Pages
955-965
ISSN
  • 0964-6906 (ISSN-L)
  • 1460-2083
OpenAlex
W2027614771
Cited by
83
References
53
Citations by year
2026: 1 · 2025: 3 · 2023: 3 · 2022: 3 · 2021: 3 · 2020: 3 · 2019: 4 · 2018: 3 · 2017: 3 · 2015: 6 · 2014: 8 · 2013: 5 · 2012: 3
FWCI
5.39
Type
journal article
Language
en
Open access
closed
Locations
  • Human Molecular Genetics (publishedVersion)
  • PubMed (publishedVersion)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Metabolism and Genetic Disorders
  • Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
  • Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
Keywords
bile acid synthesis, methyl-branched fatty acids, phytol, cholesterol degradation, food intolerance, mouse model, liver abnormalities
MeSH terms
Cholesterol 24-Hydroxylase, Animals, Hypolipidemic Agents, Aryl Hydrocarbon Hydroxylases, Bile Acids and Salts, Body Weight, Cholesterol, Clofibrate, Deficiency Diseases, Dietary Fats, Disease Models, Animal, Female, Gene Expression Regulation, Kidney, Lipids, Liver, Male, Membrane Proteins, Mice, Mutant Strains, Oxidoreductases, N-Demethylating, Phytol, Steroid Hydroxylases, Vitamin K, Deoxyribonucleases, Type II Site-Specific, Racemases and Epimerases, Mice, Cytochrome P-450 CYP3A

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