title: Metabolic adaptation allows Amacr-deficient mice to remain symptom-free despite low levels of mature bile acids.
abstract: Bile acids play multiple roles in the physiology of vertebrates; they facilitate lipid absorption, serve as signaling molecules to control carbohydrate and lipid metabolism, and provide a disposal route for cholesterol. Unexpectedly, the α-methylacyl-CoA racemase (Amacr) deficient mice, which are unable to complete the peroxisomal cleavage of C27-precursors to the mature C24-bile acids, are physiologically asymptomatic when maintained on a standard laboratory diet. The aim of this study was to uncover the underlying adaptive mechanism with special reference to cholesterol and bile acid metabolism that allows these mice to have a normal life span. Intestinal cholesterol absorption in Amacr-/- mice is decreased resulting in a 2-fold increase in daily cholesterol excretion. Also fecal excretion of bile acids (mainly C27-sterols) is enhanced 3-fold. However, the body cholesterol pool remains unchanged, although Amacr-deficiency accelerates hepatic sterol synthesis 5-fold. Changes in lipoprotein profiles are mainly due to decreased phospholipid transfer protein activity. Thus Amacr-deficient mice provide a unique example of metabolic regulation, which allows them to have a normal lifespan in spite of the disruption of a major metabolic pathway. This metabolic adjustment can be mainly explained by setting cholesterol and bile acid metabolism to a new balanced level in the Amacr-deficient mouse.
authors.affiliation: Department of Biochemistry and Biocenter Oulu, University of Oulu, Oulu, Finland.
authors.forename: Eija M
authors.initials: EM
authors.lastname: Selkälä
authors.forename: Sanna M
authors.initials: SM
authors.lastname: Kuusisto
authors.forename: Tuire
authors.initials: T
authors.lastname: Salonurmi
authors.forename: Markku J
authors.initials: MJ
authors.lastname: Savolainen
authors.forename: Matti
authors.initials: M
authors.lastname: Jauhiainen
authors.forename: Päivi L
authors.initials: PL
authors.lastname: Pirilä
authors.forename: Ari-Pekka
authors.initials: AP
authors.lastname: Kvist
authors.forename: Ernst
authors.initials: E
authors.lastname: Conzelmann
authors.forename: Werner
authors.initials: W
authors.lastname: Schmitz
authors.forename: Stefan E
authors.initials: SE
authors.lastname: Alexson
authors.forename: Tiina J
authors.initials: TJ
authors.lastname: Kotti
authors.forename: J Kalervo
authors.initials: JK
authors.lastname: Hiltunen
authors.forename: Kaija J
authors.initials: KJ
authors.lastname: Autio
mesh_terms: D000818:Animals; D001647:Bile Acids and Salts / Q000235:genetics / Q000378:metabolism*; D002784:Cholesterol / Q000235:genetics / Q000378:metabolism*; D050356:Lipid Metabolism / Q000502:physiology*; D008099:Liver / Q000378:metabolism*; D008136:Longevity / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D019998:Racemases and Epimerases / Q000235:genetics / Q000378:metabolism*
chemical_list: D001647:Bile Acids and Salts; D002784:Cholesterol; D019998:Racemases and Epimerases; C108352:alpha-methylacyl-CoA racemase