title: A mouse model for alpha-methylacyl-CoA racemase deficiency: adjustment of bile acid synthesis and intolerance to dietary methyl-branched lipids.
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.
authors.affiliation: Department of Biochemistry, Biocenter Oulu, University of Oulu, FIN-90014, Finland.
authors.forename: Kalle
authors.initials: K
authors.lastname: Savolainen
authors.forename: Tiina J
authors.initials: TJ
authors.lastname: Kotti
authors.forename: Werner
authors.initials: W
authors.lastname: Schmitz
authors.forename: Teuvo I
authors.initials: TI
authors.lastname: Savolainen
authors.forename: Raija T
authors.initials: RT
authors.lastname: Sormunen
authors.forename: Mika
authors.initials: M
authors.lastname: Ilves
authors.forename: Seppo J
authors.initials: SJ
authors.lastname: Vainio
authors.forename: Ernst
authors.initials: E
authors.lastname: Conzelmann
authors.forename: J Kalervo
authors.initials: JK
authors.lastname: Hiltunen
mesh_terms: D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics / Q000378:metabolism; D001647:Bile Acids and Salts / Q000096:biosynthesis* / Q000378:metabolism; D001835:Body Weight / Q000235:genetics; D002784:Cholesterol / Q000097:blood / Q000378:metabolism; D000072556:Cholesterol 24-Hydroxylase; D002994:Clofibrate / Q000494:pharmacology; D051544:Cytochrome P-450 CYP3A; D003677:Deficiency Diseases / Q000188:drug therapy / Q000209:etiology*; D015252:Deoxyribonucleases, Type II Site-Specific / Q000235:genetics; D004041:Dietary Fats / Q000494:pharmacology; D004195:Disease Models, Animal; D005260:Female; D005786:Gene Expression Regulation; D000960:Hypolipidemic Agents / Q000494:pharmacology; D007668:Kidney / Q000201:enzymology; D008055:Lipids / Q000097:blood / Q000737:chemistry / Q000494:pharmacology*; D008099:Liver / Q000201:enzymology / Q000473:pathology; D008297:Male; D008565:Membrane Proteins; D051379:Mice; D008817:Mice, Mutant Strains; D010089:Oxidoreductases, N-Demethylating / Q000235:genetics / Q000378:metabolism; D010836:Phytol / Q000494:pharmacology; D019998:Racemases and Epimerases / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D013250:Steroid Hydroxylases / Q000235:genetics / Q000378:metabolism; D014812:Vitamin K / Q000378:metabolism
chemical_list: D001647:Bile Acids and Salts; D004041:Dietary Fats; D000960:Hypolipidemic Agents; D008055:Lipids; D008565:Membrane Proteins; D014812:Vitamin K; D010836:Phytol; D002784:Cholesterol; D013250:Steroid Hydroxylases; D001189:Aryl Hydrocarbon Hydroxylases; C496508:Cyp3a11 protein, mouse; D051544:Cytochrome P-450 CYP3A; D000072556:Cholesterol 24-Hydroxylase; D010089:Oxidoreductases, N-Demethylating; C059776:endodeoxyribonuclease MfeI; D015252:Deoxyribonucleases, Type II Site-Specific; D019998:Racemases and Epimerases; C108352:alpha-methylacyl-CoA racemase; D002994:Clofibrate