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Impaired Skin Barrier Function Due to Reduced omega-O-Acylceramide Levels in a Mouse Model of Sjogren-Larsson Syndrome
- Source :
- Mol Cell Biol
- Publication Year :
- 2021
- Publisher :
- American Society for Microbiology, 2021.
-
Abstract
- Sjögren-Larsson syndrome (SLS) is an inherited neurocutaneous disorder whose causative gene encodes the fatty aldehyde dehydrogenase ALDH3A2. To date, the detailed molecular mechanism of the skin pathology of SLS has remained largely unclear. We generated double-knockout (DKO) mice for Aldh3a2 and its homolog Aldh3b2 (a pseudogene in humans). These mice showed hyperkeratosis and reduced fatty aldehyde dehydrogenase activity and skin barrier function. The levels of ω-O-acylceramides (acylceramides), which are specialized ceramides essential for skin barrier function, in the epidermis of DKO mice were about 60% of those in wild-type mice. In the DKO mice, levels of acylceramide precursors (ω-hydroxy ceramides and triglycerides) were increased, suggesting that the final step of acylceramide production was inhibited. A decrease in acylceramide levels was also observed in human immortalized keratinocytes lacking ALDH3A2. Differentiated keratinocytes prepared from the DKO mice exhibited impaired long-chain base metabolism. Based on these results, we propose that the long-chain-base-derived fatty aldehydes that accumulate in DKO mice and SLS patients attack and inhibit the enzyme involved in the final step of acylceramide production. Our findings provide insight into the pathogenesis of the skin symptoms of SLS, i.e., decreased acylceramide production, and its molecular mechanism.
- Subjects :
- Keratinocytes
Male
Ceramide
skin
Aldehyde dehydrogenase
Ceramides
Pathogenesis
Mice
chemistry.chemical_compound
Fatty aldehyde
aldehyde dehydrogenase
lipid
medicine
Animals
ceramide
Molecular Biology
Mice, Knockout
Aldehydes
Sjögren–Larsson syndrome
integumentary system
biology
Epidermis (botany)
Fatty Acids
long-chain base
Cell Differentiation
Cell Biology
medicine.disease
Sjogren-Larsson syndrome
Aldehyde Oxidoreductases
Molecular biology
Sphingolipid
Mice, Inbred C57BL
Disease Models, Animal
chemistry
Fatty aldehyde dehydrogenase activity
biology.protein
Female
ichthyosis
sphingolipid
Epidermis
Research Article
Subjects
Details
- Language :
- English
- ISSN :
- 02707306
- Volume :
- 41
- Issue :
- 10
- Database :
- OpenAIRE
- Journal :
- Molecular and cellular biology
- Accession number :
- edsair.doi.dedup.....7076e3ee864d84f0797e31ae786c23d1