PUBLICATION

3-ketodihydrosphingosine reductase mutation induces steatosis and hepatic injury in zebrafish

Authors
Park, K.H., Ye, Z.W., Zhang, J., Hammad, S.M., Townsend, D.M., Rockey, D.C., Kim, S.H.
ID
ZDB-PUB-190206-8
Date
2019
Source
Scientific Reports   9: 1138 (Journal)
Registered Authors
Kim, Seok-Hyung, Park, Ki-Hoon
Keywords
none
MeSH Terms
  • Mitochondria/metabolism
  • Mitochondria/ultrastructure
  • Endoplasmic Reticulum Stress
  • Up-Regulation
  • Disease Models, Animal
  • Mutation, Missense*
  • Animals
  • Humans
  • Sphingolipids/metabolism
  • Zebrafish Proteins/genetics
  • Zebrafish Proteins/metabolism
  • Oxidative Stress
  • Phosphotransferases (Alcohol Group Acceptor)/genetics*
  • Phosphotransferases (Alcohol Group Acceptor)/metabolism
  • Lipidomics/methods
  • Alcohol Oxidoreductases/genetics*
  • Alcohol Oxidoreductases/metabolism
  • Fatty Liver/genetics*
  • Fatty Liver/metabolism
  • Zebrafish
(all 20)
PubMed
30718751 Full text @ Sci. Rep.
Abstract
3-ketodihydrosphingosine reductase (KDSR) is the key enzyme in the de novo sphingolipid synthesis. We identified a novel missense kdsrI105R mutation in zebrafish that led to a loss of function, and resulted in progression of hepatomegaly to steatosis, then hepatic injury phenotype. Lipidomics analysis of the kdsrI105R mutant revealed compensatory activation of the sphingolipid salvage pathway, resulting in significant accumulation of sphingolipids including ceramides, sphingosine and sphingosine 1-phosphate (S1P). Ultrastructural analysis revealed swollen mitochondria with cristae damage in the kdsrI105R mutant hepatocytes, which can be a cause of hepatic injury in the mutant. We found elevated sphingosine kinase 2 (sphk2) expression in the kdsrI105R mutant. Genetic interaction analysis with the kdsrI105R and the sphk2wc1 mutants showed that sphk2 depletion suppressed liver defects observed in the kdsrI105R mutant, suggesting that liver defects were mediated by S1P accumulation. Further, both oxidative stress and ER stress were completely suppressed by deletion of sphk2 in kdsrI105R mutants, linking these two processes mechanistically to hepatic injury in the kdsrI105R mutants. Importantly, we found that the heterozygous mutation in kdsr induced predisposed liver injury in adult zebrafish. These data point to kdsr as a novel genetic risk factor for hepatic injury.
Genes / Markers
Figures
Figure Gallery (6 images)
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Expression
Phenotype
Mutations / Transgenics
Allele Construct Type Affected Genomic Region
muz106
    		Point Mutation
    muz122
      		Indel
      wcm2
        		Indel
        1 - 3 of 3
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        Human Disease / Model
        Human Disease Fish Conditions Evidence
        liver diseasekdsrmuz106/muz106 (AB/TU)standard conditionsTAS
        metabolic dysfunction-associated steatohepatitissphk2wcm2/wcm2 (AB/TU)standard conditionsTAS
        1 - 2 of 2
        Show
        Sequence Targeting Reagents
        Target Reagent Reagent Type
        kdsrCRISPR1-kdsrCRISPR
        1 - 1 of 1
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        Fish
        Fish
        AB/TU
        kdsrmuz106/muz106 (AB/TU)
        kdsrmuz106/muz106; sphk2wcm2/wcm2 (AB/TU)
        kdsrmuz106/+ (AB/TU)
        sphk2wcm2/wcm2 (AB/TU)
        1 - 5 of 5
        Show
        Antibodies
        No data available
        Orthology
        No data available
        Engineered Foreign Genes
        No data available
        Mapping
        No data available
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        Citation
        Park, K.H., Ye, Z.W., Zhang, J., Hammad, S.M., Townsend, D.M., Rockey, D.C., Kim, S.H. (2019) 3-ketodihydrosphingosine reductase mutation induces steatosis and hepatic injury in zebrafish. Scientific Reports. 9:1138.