| First Author | Hong IH | Year | 2014 |
| Journal | J Biol Chem | Volume | 289 |
| Issue | 2 | Pages | 1106-18 |
| PubMed ID | 24273171 | Mgi Jnum | J:207179 |
| Mgi Id | MGI:5554632 | Doi | 10.1074/jbc.M113.526780 |
| Citation | Hong IH, et al. (2014) Age-associated change of C/EBP family proteins causes severe liver injury and acceleration of liver proliferation after CCl4 treatments. J Biol Chem 289(2):1106-18 |
| abstractText | The aged liver is more sensitive to the drug treatments and has a high probability of developing liver disorders such as fibrosis, cirrhosis, and cancer. Here we present mechanisms underlying age-associated severe liver injury and acceleration of liver proliferation after CCl4 treatments. We have examined liver response to CCl4 treatments using old WT mice and young C/EBPalpha-S193D knockin mice, which express an aged-like isoform of C/EBPalpha. Both animal models have altered chromatin structure as well as increased liver injury and proliferation after acute CCl4 treatments. We found that these age-related changes are associated with the repression of key regulators of liver biology: C/EBPalpha, Farnesoid X Receptor (FXR) and telomere reverse transcriptase (TERT). In quiescent livers of old WT and young S193D mice, the inhibition of TERT is mediated by HDAC1-C/EBPalpha complexes. After CCl4 treatments, TERT, C/EBPalpha and FXR are repressed by different mechanisms. These mechanisms include the increase of a dominant negative isoform, C/EBPbeta-LIP, and subsequent repression of C/EBPalpha, FXR, and TERT promoters. C/EBPbeta-LIP also disrupts Rb-E2F1 complexes in C/EBPalpha-S193D mice after CCl4 treatments. To examine if these alterations are involved in drug-mediated liver diseases, we performed chronic treatments of mice with CCl4. We found that C/EBPalpha-S193D mice developed fibrosis much more rapidly than WT mice. Thus, our data show that the age-associated alterations of C/EBP proteins create favorable conditions for the increased liver proliferation after CCl4 treatments and for development of drug-mediated liver diseases. |
