title: Phytol is lethal for Amacr-deficient mice.
abstract: 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.
authors.affiliation: Faculty of Biochemistry and Molecular Medicine, University of Oulu, P.O. Box 5400, FI-90014, Finland; Biocenter Oulu, University of Oulu, Finland.
authors.forename: Eija M
authors.initials: EM
authors.lastname: Selkälä
authors.affiliation: Faculty of Biochemistry and Molecular Medicine, University of Oulu, P.O. Box 5400, FI-90014, Finland; Biocenter Oulu, University of Oulu, Finland.
authors.forename: Remya R
authors.initials: RR
authors.lastname: Nair
authors.affiliation: Theodor-Boveri-Institut für Biowissenschaften, Lehrstuhl für Biochemie und Molekularbiologie der Universität Würzburg, Am Hubland, 97974 Würzburg, Germany.
authors.forename: Werner
authors.initials: W
authors.lastname: Schmitz
authors.affiliation: Faculty of Biochemistry and Molecular Medicine, University of Oulu, P.O. Box 5400, FI-90014, Finland; Biocenter Oulu, University of Oulu, Finland.
authors.forename: Ari-Pekka
authors.initials: AP
authors.lastname: Kvist
authors.affiliation: Laboratory of Cell Metabolism, Department of Pharmaceutical and Pharmacological Sciences, University of Leuven, Herestraat 49 O&N 2, 3000 Leuven, Belgium.
authors.forename: Myriam
authors.initials: M
authors.lastname: Baes
authors.affiliation: Faculty of Biochemistry and Molecular Medicine, University of Oulu, P.O. Box 5400, FI-90014, Finland; Biocenter Oulu, University of Oulu, Finland.
authors.forename: J Kalervo
authors.initials: JK
authors.lastname: Hiltunen
authors.affiliation: Faculty of Biochemistry and Molecular Medicine, University of Oulu, P.O. Box 5400, FI-90014, Finland; Biocenter Oulu, University of Oulu, Finland. Electronic address: kaija.autio@oulu.fi.
authors.forename: Kaija J
authors.initials: KJ
authors.lastname: Autio
mesh_terms: D000818:Animals; D001647:Bile Acids and Salts / Q000235:genetics / Q000378:metabolism; D001921:Brain / Q000378:metabolism / Q000473:pathology; D056486:Chemical and Drug Induced Liver Injury / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D005786:Gene Expression Regulation / Q000187:drug effects; D007668:Kidney / Q000378:metabolism / Q000473:pathology; D007728:Kupffer Cells / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D010836:Phytol / Q000633:toxicity*; D019998:Racemases and Epimerases / Q000172:deficiency*
chemical_list: D001647:Bile Acids and Salts; D010836:Phytol; D019998:Racemases and Epimerases; C108352:alpha-methylacyl-CoA racemase
keywords: Alpha-methylacyl-CoA racemase; Knock-out mouse model; Peroxisome; Phytol; Refsum disease