Institution: | 1. Department of Biochemistry and Biocenter Oulu, University of Oulu, Oulu, Finland;2. Institute of Clinical Medicine, Department of Internal Medicine, Biocenter Oulu and Clinical Research Center, University of Oulu, Oulu, Finland;3. Public Health Genomics Unit, National Institute for Health and Welfare, Helsinki, Finland;4. Theodor-Boveri-Institut für Biowissenschaften, Lehrstuhl für Biochemie und Molecularbiologie, der Universität Würzburg, Würzburg, Germany;5. Division of Clinical Chemistry, Department of Laboratory Medicine, Karolinska Institutet, Karolinska University Hospital at Huddinge, Stockholm, Sweden;6. Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, TX, USA |
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. |