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Lab Invest. 2019 Jun 11. doi: 10.1038/s41374-019-0271-4. [Epub ahead of print]

Hepatic pathology and altered gene transcription in a murine model of acid ceramidase deficiency.

Author information

1
Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI, USA.
2
Institute of Medical Science, University of Toronto, Toronto, ON, Canada.
3
Rare Diseases Research Unit, Department of Pediatrics and Adolescent Medicine, Charles University, 1st Faculty of Medicine and General University Hospital, Prague, Czech Republic.
4
Institute of Pathology, Charles University, 1st Faculty of Medicine and General University Hospital, Prague, Czech Republic.
5
Department of Physiology, Medical College of Wisconsin, Milwaukee, WI, USA.
6
Department of Pathobiology, University of Guelph, Guelph, ON, Canada.
7
Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI, USA. monty.mckillop@mcw.edu.
8
Department of Biochemistry, Medical College of Wisconsin, Milwaukee, WI, USA.
9
University Health Network, Toronto, ON, Canada.
10
Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada.

Abstract

Farber disease (FD) is a rare lysosomal storage disorder (LSD) characterized by systemic ceramide accumulation caused by a deficiency in acid ceramidase (ACDase). In its classic form, FD manifests with painful lipogranulomatous nodules in extremities and joints, respiratory complications, and neurological involvement. Hepatosplenomegaly is commonly reported, and severe cases of FD cite liver failure as a cause of early death. Mice homozygous for an orthologous patient mutation in the ACDase gene (Asah1P361R/P361R) recapitulate the classical form of human FD. In this study, we demonstrate impaired liver function and elevation of various liver injury markers in Asah1P361R/P361R mice as early as 5 weeks of age. Histopathology analyses demonstrated significant formation and recruitment of foamy macrophages, invasion of neutrophils, progressive tissue fibrosis, increased cell proliferation and death, and significant storage pathology within various liver cell types. Lipidomic analyses revealed alterations to various lipid concentrations in both serum and liver tissue. A significant accumulation of ceramide and other sphingolipids in both liver and hepatocytes was noted. Sphingolipid acyl chains were also altered, with an increase in long acyl chain sphingolipids coinciding with a decrease in ultra-long acyl chains. Hepatocyte transcriptome analyses revealed significantly altered gene transcription. Molecular pathways related to inflammation were found activated, and molecular pathways involved in lipid metabolism were found deactivated. Altered gene transcription within the sphingolipid pathway itself was also observed. The data presented herein demonstrates that deficiency in ACDase results in liver pathology as well as sphingolipid and gene transcription profile changes that lead to impaired liver function.

PMID:
31186526
DOI:
10.1038/s41374-019-0271-4

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