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Independent phenotype of binuclear hepatocytes and cellular localization of UbD
Joan Oliva1, Fawzia Bardag-Gorce, Barbara A French
1Department of Pathology, LABioMed, Torrance, CA 90502, USA. joliva@labiomed.org
Abstract:
Mice fed DDC (0.1%) for 10 weeks, and then withdrawn from the drug for 1 month, retain the ability to form Mallory-Denk bodies (MDBs) when the drug is refed for 7 days. The number of liver cells that form MDBs increased and partially replaced normal liver cells, at the end of 7 days of refeeding DDC. The MDBs that formed were associated with increased expression of UbD (also called FAT10) in the Mallory-Denk body forming cells. UbD is over expressed in 70% of human HCCs, but its cellular localization is not well established. UbD belongs to the UbL family (ubiquitin-like), and can be linked to others proteins with their 2 C-terminal glycine to lysine. By Western Blot, UbD was found to be covalently linked with proteins. We performed immunohistochemistry on tissue from mouse liver and found that UbD was located in the cytoplasm and in one or two nuclei of the same hepatocyte. However, in primary cell culture, UbD formed speckles within the cytoplasm of the liver cell. A similar pattern of cytoplasmic localization was observed in the Hepa 1-6 cell lines, which over expressed UbD fused with GFP at the C-Terminal. The localization and the control of UbD localization remain unclear. The identification of proteins that interact with UbD and the post translational modification of UbD would help to determine the regulation of this localization and function.
Insights
Mice can form Mallory-Denk bodies (MDBs) after DDC drug withdrawal and refeeding. This process is linked to increased UbD (FAT10) expression in liver cells, a protein implicated in human liver cancer.
Area of Science:
- Hepatology
- Molecular Biology
- Cancer Research
Background:
- Mallory-Denk bodies (MDBs) are cytoplasmic inclusions in hepatocytes.
- Ubiquitin-like protein D (UbD), also known as FAT10, is overexpressed in human hepatocellular carcinoma (HCC).
- The cellular localization and function of UbD are not fully understood.
Purpose of the Study:
- To investigate the formation of MDBs in a mouse model.
- To examine the association between MDB formation and UbD expression.
- To determine the cellular localization of UbD in hepatocytes.
Main Methods:
- Mice were administered DDC (0.1%) for 10 weeks, followed by a 1-month withdrawal and 7-day refeeding period.
- Immunohistochemistry was used to detect MDBs and UbD expression in mouse liver tissue.
- Western Blot analysis was performed to assess UbD protein linkage.
- Primary liver cell cultures and Hepa 1-6 cell lines were used to study UbD localization.
Main Results:
- DDC refeeding induced MDB formation in mice, with increased numbers of MDB-containing hepatocytes.
- MDB formation was associated with increased UbD expression within these cells.
- Western Blot confirmed UbD covalently linked to other proteins.
- Immunohistochemistry revealed UbD in the cytoplasm and nuclei of hepatocytes, with distinct speckle patterns in cell cultures.
Conclusions:
- DDC refeeding can induce MDB formation and increase UbD expression in hepatocytes.
- UbD exhibits varied cellular localization (cytoplasm, nuclei, cytoplasmic speckles) depending on the cellular context.
- Further research into UbD-interacting proteins and post-translational modifications is needed to clarify its localization and function in liver cells and HCC.
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