title: Reduced cholesterol accumulation and improved deficient peroxisomal functions in a murine model of Niemann-Pick type C disease upon treatment with peroxisomal proliferators.
abstract: Niemann-Pick type C disease is an inherited disorder characterized by lysosomal accumulation of cholesterol and the mutant gene has recently been identified. The predicted gene product is a transmembrane protein showing homology to proteins involved in the regulation of cholesterol homeostasis, such as 3-hydroxy-3-methylglutaryl-coenzyme A and the sterol regulatory element binding protein cleavage-activating protein. Recent investigations have established a peroxisomal deficiency, which raised the question of whether peroxisomal proliferation could affect this cholesterol-processing error. Mutant mice with Niemann-Pick type C disease were treated with the peroxisomal inducer perfluorooctanoic acid, which increased peroxisomal beta-oxidation and catalase activity to the same level as in control mice. Not only the peroxisomal, but also the lysosomal malfunctions were corrected and the cholesterol content was decreased. Clofibrate, another peroxisomal inducer, restored both peroxisomal enzyme activities and ubiquinone content. It appears that in Niemann-Pick type C disease treatment with appropriate peroxisomal inducers restores basic cellular functions, indicating a relationship between peroxisomes and cholesterol homeostasis, and thereby may effectively interfere with the development of the disease.
authors.affiliation: Department of Biochemistry, Stockholm University, Sweden. fia@biokemi.su.se
authors.forename: S
authors.initials: S
authors.lastname: Schedin
authors.forename: P
authors.initials: P
authors.lastname: Pentchev
authors.forename: G
authors.initials: G
authors.lastname: Dallner
mesh_terms: D000818:Animals; D002210:Caprylates / Q000494:pharmacology; D002784:Cholesterol / Q000378:metabolism*; D005466:Fluorocarbons / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D008830:Microbodies / Q000502:physiology*; D009542:Niemann-Pick Diseases / Q000188:drug therapy* / Q000378:metabolism; D020025:Peroxisome Proliferators / Q000494:pharmacology*
chemical_list: D002210:Caprylates; D005466:Fluorocarbons; D020025:Peroxisome Proliferators; C023036:perfluorooctanoic acid; D002784:Cholesterol