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Tumor necrosis factor–alpha modulates CCAAT/enhancer binding proteins–DNA binding activities and promotes hepatocyte‐specific gene expression during liver regeneration
Author(s) -
Diehl Anna Mae,
Yang Shi Qi,
Yin Ming,
Lin Hui Zhi,
Nelson Steve,
Bagby Greg
Publication year - 1995
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.1840220136
Subject(s) - ccaat enhancer binding proteins , microbiology and biotechnology , gene expression , biology , liver regeneration , hepatocyte , messenger rna , phosphoenolpyruvate carboxykinase , enhancer , transcription factor , gene , nuclear protein , biochemistry , regeneration (biology) , in vitro
Injury‐related cytokines, such as tumor necrosis factor–alpha (TNF), may preserve liver‐specific gene expression during the subsequent regenerative response by modulating the activity of transcription factors, including CCAAT/enhancer binding proteins (C/EBPs), which regulate differentiated gene expression in hepato‐cytes. To test this theory, rats were treated with neutralizing antibody to TNF or nonimmune immunoglobulin before partial hepatectomy (PH) and regenerative changes in the messenger RNAs (mRNAs), proteins, and DNA‐binding activities of C/EBP isoforms and the expression of a C/EBP‐regulated gene, phosphoenol pyruvate carboxykinase (PEPCK), were compared. Before PH, the expressions of C/EBP‐α, C/EBP‐β, and C/EBP‐γ were similar in the two treatment groups. Dimers containing C/EBP‐α and C/EBP‐β accounted for virtually all of the C/EBP DNA binding activity and mRNA for PEPCK, the rate limiting hepatocyte enzyme for gluconeogenesis, was barely detected. After PH, in control rats, mRNA and nuclear protein concentrations of C/EBP‐β and C/EBP‐γ increased approximately fivefold by 3 hours after PH. This was accompanied by increased DNA binding activity of these C/EBP isoforms and decreased DNA binding activity of C/EBP‐α. mRNA levels of PEPCK, a gene that is strongly transactivated by non‐α C/EBP isoforms, increased fivefold. Pretreatment with anti‐TNF antibodies prevented regenerative induction of C/EBP β and γ expression and DNA‐binding activity. The nature of dimers binding to C/EBP cis‐acting elements remained similar to that observed in liver before PH and increases in PEPCK mRNA were blunted. These results support the theory that TNF helps maintain liver‐specific gene expression during liver regeneration by altering transcription factor complexes that regulate differentiated gene expression in hepatocytes. (H EPATOLOGY 1995; 22:252–261.)