Article first published online: 26 JAN 2007
Copyright © 2007 American Association for the Study of Liver Diseases
Volume 45, Issue 2, pages 391–403, February 2007
How to Cite
Donthamsetty, S., Bhave, V. S., Mitra, M. S., Latendresse, J. R. and Mehendale, H. M. (2007), Nonalcoholic fatty liver sensitizes rats to carbon tetrachloride hepatotoxicity. Hepatology, 45: 391–403. doi: 10.1002/hep.21530
Presented in part at the 2005 Annual Meeting of the American Association for the Study of Liver Disease.
Potential conflict of interest: Nothing to report.
- Issue published online: 26 JAN 2007
- Article first published online: 26 JAN 2007
- Manuscript Accepted: 25 OCT 2006
- Manuscript Received: 25 JUL 2006
- Louisiana Board of Regents Support Funds
- Kitty DeGree Endowed Chair in Toxicology
This study tested whether hepatic steatosis sensitizes liver to toxicant-induced injury and investigated the potential mechanisms of hepatotoxic sensitivity. Male Sprague-Dawley rats were fed a methionine- and choline-deficient diet for 31 days to induce steatosis. On the 32nd day, administration of a nonlethal dose of CCl4 (2 mL/kg, intraperitoneally) yielded 70% mortality in steatotic rats 12-72 hours after CCl4administration, whereas all nonsteatotic rats survived. Neither CYP2E1 levels nor covalent binding of [14C]CCl4-derived radiolabel differed between the groups, suggesting that increased bioactivation is not the mechanism for this amplified toxicity. Cell division and tissue repair, assessed by [3H]thymidine incorporation and proliferative cell nuclear antigen assay, were inhibited in the steatotic livers after CCl4administration and led to progressive expansion of liver injury culminating in mortality. The hypothesis that fatty hepatocytes undergo cell cycle arrest due to (1) an inability to replenish ATP due to overexpressed uncoupling protein-2 (UCP-2) or (2) induction of growth inhibitor p21 leading to G1/S phase arrest was tested. Steatotic livers showed 10-fold lower ATP levels due to upregulated UCP-2 throughout the time course after CCl4 administration, leading to sustained inhibition of cell division. Western blot analysis revealed an up-regulation of p21 due to overexpression of TGF β1 and p53 and down-regulation of transcription factor Foxm1b in steatotic livers leading to lower phosphorylated retinoblastoma protein. Thus, fatty hepatocytes fail to undergo compensatory cell division, rendering the liver susceptible to progression of liver injury. Conclusion: Impaired tissue repair sensitizes the steatotic livers to hepatotoxicity. (HEPATOLOGY 2007;45:391–403.)