Increase of hepatic fat accumulation by liver specific expression of Hepatitis B virus X protein in zebrafish |
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Authors: | Yun-Sheng Shieh Yin-Shan Chang Jiann-Ruey Hong Li-Je Chen Luen-Kuang Jou Chia-Chun Hsu Guor Mour Her |
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Institution: | 1. Institute of Bioscience and Biotechnology, National Taiwan Ocean University, Keelung, Taiwan;2. Institute of Biotechnology, National Cheng-Kung University, Tainan, Taiwan;3. Department of Radiology, Tri-Service General Hospital, Taipei, Taiwan;4. Present address: Department of Radiology, Buddhist Tzu Chi General Hospital, Taichung Branch, Taichung, Taiwan |
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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 (66–81%) 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-α, SREBP1, ChREBP and PPAR-γ, 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. |
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Keywords: | HBV Hepatitis B virus HBx HBV X protein HCC hepatocellular carcinoma GBXs zebrafish transgenic GBX lines GBx GFP-fused HBx C/EBP-α CCAAT enhancer binding protein-alpha PPAR-γ peroxisome proliferator-activated receptor gamma SREBP1 sterol regulatory element binding protein1 ChREBP carbohydrate-response element-binding protein ACC Acetyl-CoA carboxylase 1 FAS Fatty acid synthase SCD stearoyl-CoA desaturase 1 AGAPT acyl-CoA: 1-acylglycerol-sn-3-phosphate acyltransferase PAP phosphatidic acid phosphatase DGAT2 diacylglycerol O-acyltransferase 2 |
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