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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. Copyright © 2013 Elsevier B.V. All rights reserved.

Citation

Eija M Selkälä, Sanna M Kuusisto, Tuire Salonurmi, Markku J Savolainen, Matti Jauhiainen, Päivi L Pirilä, Ari-Pekka Kvist, Ernst Conzelmann, Werner Schmitz, Stefan E Alexson, Tiina J Kotti, J Kalervo Hiltunen, Kaija J Autio. Metabolic adaptation allows Amacr-deficient mice to remain symptom-free despite low levels of mature bile acids. Biochimica et biophysica acta. 2013 Aug;1831(8):1335-43

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PMID: 23680781

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