title: Role of AMACR (α-methylacyl-CoA racemase) and MFE-1 (peroxisomal multifunctional enzyme-1) in bile acid synthesis in mice.
abstract: Cholesterol is catabolized to bile acids by peroxisomal β-oxidation in which the side chain of C27-bile acid intermediates is shortened by three carbon atoms to form mature C24-bile acids. Knockout mouse models deficient in AMACR (α-methylacyl-CoA racemase) or MFE-2 (peroxisomal multifunctional enzyme type 2), in which this β-oxidation pathway is prevented, display a residual C24-bile acid pool which, although greatly reduced, implies the existence of alternative pathways of bile acid synthesis. One alternative pathway could involve Mfe-1 (peroxisomal multifunctional enzyme type 1) either with or without Amacr. To test this hypothesis, we generated a double knockout mouse model lacking both Amacr and Mfe-1 activities and studied the bile acid profiles in wild-type, Mfe-1 and Amacr single knockout mouse line and Mfe-1 and Amacr double knockout mouse lines. The total bile acid pool was decreased in Mfe-1-/- mice compared with wild-type and the levels of mature C24-bile acids were reduced in the double knockout mice when compared with Amacr-deficient mice. These results indicate that Mfe-1 can contribute to the synthesis of mature bile acids in both Amacr-dependent and Amacr-independent pathways.
authors.forename: Kaija J
authors.initials: KJ
authors.lastname: Autio
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.forename: Remya R
authors.initials: RR
authors.lastname: Nair
authors.forename: Eija M
authors.initials: EM
authors.lastname: Selkälä
authors.forename: Raija T
authors.initials: RT
authors.lastname: Sormunen
authors.affiliation: †Biocenter Oulu, University of Oulu, P.O. Box 5000, FI-90014, Finland.
authors.forename: Ilkka J
authors.initials: IJ
authors.lastname: Miinalainen
authors.affiliation: ∥Institute of Mass Spectrometry, College of Medicine, Swansea University, Singleton Park, Swansea SA2 8PP, U.K.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Crick
authors.affiliation: ∥Institute of Mass Spectrometry, College of Medicine, Swansea University, Singleton Park, Swansea SA2 8PP, U.K.
authors.forename: Yuqin
authors.initials: Y
authors.lastname: Wang
authors.affiliation: ∥Institute of Mass Spectrometry, College of Medicine, Swansea University, Singleton Park, Swansea SA2 8PP, U.K.
authors.forename: William J
authors.initials: WJ
authors.lastname: Griffiths
authors.affiliation: ¶Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, U.S.A.
authors.forename: Janardan K
authors.initials: JK
authors.lastname: Reddy
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.forename: J Kalervo
authors.initials: JK
authors.lastname: Hiltunen
mesh_terms: D000818:Animals; D001647:Bile Acids and Salts / Q000096:biosynthesis*; D005260:Female; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D023421:Models, Animal; D009097:Multienzyme Complexes / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D019998:Racemases and Epimerases / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology
chemical_list: D001647:Bile Acids and Salts; C508129:Ehhadh protein, rat; D009097:Multienzyme Complexes; D019998:Racemases and Epimerases; C108352:alpha-methylacyl-CoA racemase