Hepatic pathology and altered gene transcription in a murine model of acid ceramidase deficiency
The result's identifiers
Result code in IS VaVaI
<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00064165%3A_____%2F19%3A10400998" target="_blank" >RIV/00064165:_____/19:10400998 - isvavai.cz</a>
Alternative codes found
RIV/00216208:11110/19:10400998
Result on the web
<a href="https://verso.is.cuni.cz/pub/verso.fpl?fname=obd_publikace_handle&handle=guS8EEa1KE" target="_blank" >https://verso.is.cuni.cz/pub/verso.fpl?fname=obd_publikace_handle&handle=guS8EEa1KE</a>
DOI - Digital Object Identifier
<a href="http://dx.doi.org/10.1038/s41374-019-0271-4" target="_blank" >10.1038/s41374-019-0271-4</a>
Alternative languages
Result language
angličtina
Original language name
Hepatic pathology and altered gene transcription in a murine model of acid ceramidase deficiency
Original language description
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 (Asah1(P361R/P361R)) recapitulate the classical form of human FD. In this study, we demonstrate impaired liver function and elevation of various liver injury markers in Asah1(P361R/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.
Czech name
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Czech description
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Classification
Type
J<sub>imp</sub> - Article in a specialist periodical, which is included in the Web of Science database
CEP classification
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OECD FORD branch
10600 - Biological sciences
Result continuities
Project
<a href="/en/project/LM2015091" target="_blank" >LM2015091: National Center for Medical Genomic</a><br>
Continuities
O - Projekt operacniho programu
Others
Publication year
2019
Confidentiality
S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů
Data specific for result type
Name of the periodical
Laboratory Investigation
ISSN
0023-6837
e-ISSN
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Volume of the periodical
99
Issue of the periodical within the volume
10
Country of publishing house
US - UNITED STATES
Number of pages
21
Pages from-to
1572-1592
UT code for WoS article
000493299100013
EID of the result in the Scopus database
2-s2.0-85067402206