Hepatic toxicity in twitcher mice: effect on peroxisomes

Abstract

Krabbe disease and twitcher mice are characterized by accumulation of psychosine, induction of neuroinflammatory disease, degeneration/dysfunction of myelin producing oligodendrocytes, and demyelination, inducing physical impairment and death. Effects of psychosine on peripheral tissues/metabolic functions are unknown. We investigated its toxic effect in liver, and on peroxisomal metabolism in twitcher mice. Ratio of liver:body weight of adult twitcher mice indicates a marked slow growth/development of this organ as compared to wild type mice. Hematoxylin and eosin staining of fixed hepatic tissue showed increased number of cells, and hepatocytes of smaller size, less intense stained in twitcher liver as compared with wild type. Immunoblot and mRNA analyses for peroxisomal proteins indicate reduced levels of catalase, 3-ketoacyl-CoA thiolase, PMP-70 and ALDP in twitcher liver. Electron microscopy analysis of DAB-stained tissue showed no significant changes in the peroxisomal population in twitcher liver; however, their matrix was less stained, indicating reduced matrix enzyme activities. In addition, immunohistochemistry analysis showed induction of TNF-α and IL-6 in twitcher liver. Our data indicate that psychosine toxicity by itself or in combination with cytokines induces peroxisomes and hepatocytes impairment. (NIH grants NS-40810, NS-22576, NS-34741, C06 RR018823 and C06 RR015455).