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Updated: May 11, 2026
08:26
Saturated Fatty Acids Induce Ceramide-associated Macrophage Cell Death
Published on: October 31, 2017
Systemic ceramide accumulation leads to severe and varied pathological consequences
Abdulfatah M Alayoubi1, James C M Wang, Bryan C Y Au
1Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada.
EMBO Molecular Medicine
|May 18, 2013
Summary
Farber disease, a lipid metabolism disorder, was modeled in mice with acid ceramidase (ACDase) deficiency. Gene therapy showed promise in treating this ceramide accumulation disorder.
Area of Science:
- Biochemistry
- Genetics
- Cell Biology
Background:
- Farber disease (FD) is a severe inherited lipid metabolism disorder caused by deficient lysosomal acid ceramidase (ACDase) activity.
- This deficiency leads to ceramide accumulation, impacting cell apoptosis and proliferation.
Purpose of the Study:
- To create the first animal model of systemic acid ceramidase deficiency.
- To investigate the pathophysiology of Farber disease and the role of ACDase and ceramide.
Main Methods:
- A single-nucleotide mutation from human FD patients was introduced into the murine Asah1 gene.
- Homozygous Asah1(P361R/P361R) mice were generated to model systemic ACDase deficiency.
- Neonatal mice received a lentiviral vector encoding human ACDase for therapeutic assessment.
Main Results:
- The Asah1(P361R/P361R) mice exhibited ACDase defects, ceramide accumulation, FD manifestations, and premature death.
- Increased MCP-1 levels and lipid-laden macrophages were observed in affected tissues.
- Lentivector treatment improved growth, reduced ceramide levels, lessened cellular infiltrations, and extended lifespan.
Conclusions:
- The novel murine model provides insights into Farber disease pathophysiology.
- ACDase, ceramide, and sphingolipids play crucial roles in cell signaling and growth.
- Gene therapy using a lentivector shows therapeutic potential for Farber disease.
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