Ronald J.A. Wanders and Sacha Ferdinandusse Pages 1401 - 1411 ( 11 )
The group of peroxisomal disorders represents a growing number of genetically determined diseases in humans in which there is an impairment in one or more peroxisomal functions. The peroxisomal disorders are usually subdivided in two major subgroups including (1) the peroxisome biogenesis disorders (PBDs) and (2) the single peroxisomal enzyme deficiencies. Liver pathology is a frequent finding in patients affected by a peroxisomal disorder. This is not only true for patients affected by a PBD, but also for patients with a single enzyme defect in one of the metabolic pathways in which peroxisomes are involved. By comparing the different peroxisomal disorders, we provide evidence suggesting that the main hepatotoxic metabolites responsible for the liver pathology found in patients, are the bile acid synthesis intermediates di- and trihydroxycholestanoic acid (DHCA and THCA). Studies in different experimental systems have shown that DHCA and THCA, especially in the unconjugated form, interfere with different physiological processes including mitochondrial oxidative phosphorylation. The implications of these findings will be discussed with special emphasis on patients with di- and trihydroxycholestanoic acidaemia.
Peroxisomes, hepatoxicity, fatty acids, fatty acid metabolism
Laboratory Genetic Metabolic Diseases, Room F0-226, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands.