Oxidative stress and oval cell accumulation in mice and humans with alcoholic and nonalcoholic fatty liver disease

Tania Roskams, Shi Qi Yang, Aymen Koteish, Anne Durnez, Rita DeVos, Xiawen Huang, Ruth Achten, Chris Verslype, Anna Mae Diehl

Research output: Contribution to journalArticle

Abstract

In animals, the combination of oxidative liver damage and inhibited hepatocyte proliferation increases the numbers of hepatic progenitors (oval cells). We studied different murine models of fatty liver disease and patients with nonalcoholic fatty liver disease or alcoholic liver disease to determine whether oval cells increase in fatty livers and to clarify the mechanisms for this response. To varying degrees, all mouse models exhibit excessive hepatic mitochondrial production of H2O2, a known inducer of cell-cycle inhibitors. In mice with the greatest H2O2 production, mature hepatocyte proliferation is inhibited most, and the greatest number of oval cells accumulates. These cells differentiate into intermediate hepatocyte-like cells after a regenerative challenge. Hepatic oval cells are also increased significantly in patients with nonalcoholic fatty liver disease and alcoholic liver disease. In humans, fibrosis stage and oval cell numbers, as well as the number of intermediate hepatocyte-like cells, are strongly correlated. However, cirrhosis is not required for oval cell accumulation in either species. Rather, as in mice, progenitor cell activation in human fatty liver diseases is associated with inhibited replication of mature hepatocytes. The activation of progenitor cells during fatty liver disease may increase the risk for hepatocellular cancer, similar to that observed in the Soft-Farber model of hepatocarcinogenesis in rats.

Original languageEnglish (US)
Pages (from-to)1301-1311
Number of pages11
JournalAmerican Journal of Pathology
Volume163
Issue number4
DOIs
StatePublished - Oct 1 2003

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

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    Roskams, T., Yang, S. Q., Koteish, A., Durnez, A., DeVos, R., Huang, X., Achten, R., Verslype, C., & Diehl, A. M. (2003). Oxidative stress and oval cell accumulation in mice and humans with alcoholic and nonalcoholic fatty liver disease. American Journal of Pathology, 163(4), 1301-1311. https://doi.org/10.1016/S0002-9440(10)63489-X