PUBLICATION

Increase of hepatic fat accumulation by liver specific expression of Hepatitis B virus X protein in zebrafish

Authors
Shieh, Y.S., Chang, Y.S., Hong, J.R., Chen, L.J., Jou, L.K., Hsu, C.C., and Her, G.M.
ID
ZDB-PUB-100427-20
Date
2010
Source
Biochimica et biophysica acta. Molecular and cell biology of lipids   1801(7): 721-730 (Journal)
Registered Authors
Her, Guor Muor, Hong, Jiann-Ruey
Keywords
Hepatitis B virus X protein, Fatty liver disease, Non-alcoholic steatohepatitis, Liver degeneration, Transgenic zebrafish, GFP
MeSH Terms
  • Animals
  • Animals, Genetically Modified
  • Apoptosis/genetics
  • Disease Models, Animal
  • Fatty Acids/biosynthesis*
  • Fatty Acids/genetics
  • Fatty Liver/genetics
  • Fatty Liver/metabolism*
  • Fatty Liver/pathology
  • Hepatitis B virus*
  • Liver/metabolism*
  • Liver/pathology
  • Trans-Activators/biosynthesis*
  • Trans-Activators/genetics
  • Transcription Factors/genetics
  • Transcription Factors/metabolism
  • Zebrafish/genetics
  • Zebrafish/metabolism*
(all 18)
PubMed
20416398 Full text @ BBA Molecular and Cell Biology of Lipids
Abstract
The pathogenesis of fatty liver disease remains largely unknown. Here, we assessed the importance of hepatic fat accumulation on the progression of hepatitis in zebrafish by liver specific expression of Hepatitis B virus X protein (HBx). Transgenic zebrafish lines, GBXs, which selectively express the GBx transgene (GFP-fused HBx gene) in liver, were established. GBX Liver phenotypes were evaluated by histopathology and molecular analysis of fatty acid (FA) metabolism-related genes expression. Most GBXs (66 approximately 81%) displayed obvious emaciation starting at 4 months old. Over 99% of the emaciated GBXs developed hepatic steatosis or steatohepatitis, which in turn led to liver hypoplasia. The liver histology of GBXs displayed steatosis, lobular inflammation, and balloon degeneration, similar to non-alcoholic steatohepatitis (NASH). Oil red O stain detected the accumulation of fatty droplets in GBXs. RT-PCR and Q-rt-PCR analysis revealed that GBx induced hepatic steatosis had significant increases in the expression of lipogenic genes, C/EBP-alpha, SREBP1, ChREBP and PPAR-gamma, which then activate key enzymes of the de novo FA synthesis, ACC1, FAS, SCD1, AGAPT, PAP and DGAT2. In addition, the steatohepatitic GBX liver progressed to liver degeneration and exhibited significant differential gene expression in apoptosis and stress. The GBX models exhibited both the genetic and functional factors involved in lipid accumulation and steatosis-associated liver injury. In addition, GBXs with transmissible NASH-like phenotypes provide a promising model for studying liver disease.
Genes / Markers
Marker Marker Type Name
acacbGENEacetyl-CoA carboxylase beta
acox3GENEacyl-CoA oxidase 3, pristanoyl
adipoqaGENEadiponectin, C1Q and collagen domain containing, a
agpat4GENE1-acylglycerol-3-phosphate O-acyltransferase 4 (lysophosphatidic acid acyltransferase, delta)
cav1GENEcaveolin 1
cd36GENECD36 molecule (CD36 blood group)
cebpaGENECCAAT enhancer binding protein alpha
cpt1aaGENEcarnitine palmitoyltransferase 1Aa (liver)
cyp4t8GENEcytochrome P450, family 4, subfamily T, polypeptide 8
dgat2GENEdiacylglycerol O-acyltransferase 2
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Expression
Phenotype
Mutations / Transgenics
Allele Construct Type Affected Genomic Region
two9TgTransgenic Insertion
    two10TgTransgenic Insertion
      two11TgTransgenic Insertion
        two12TgTransgenic Insertion
          1 - 4 of 4
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          Human Disease / Model
          Sequence Targeting Reagents
          No data available
          Fish
          1 - 4 of 4
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          Antibodies
          No data available
          Orthology
          No data available
          Engineered Foreign Genes
          Marker Marker Type Name
          GFPEFGGFP
          1 - 1 of 1
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          Mapping