A mouse model for alpha-methylacyl-CoA racemase deficiency: adjustment of bile acid synthesis and intolerance to dietary methyl-branched lipids.
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.
Savolainen
Kalle
K
Department of Biochemistry, Biocenter Oulu, University of Oulu, FIN-90014, Finland.
Kotti
Tiina J
TJ
Schmitz
Werner
W
Savolainen
Teuvo I
TI
Sormunen
Raija T
RT
Ilves
Mika
M
Vainio
Seppo J
SJ
Conzelmann
Ernst
E
Hiltunen
J Kalervo
JK
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
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