TY - JOUR
T1 - Oxidative stress and oval cell accumulation in mice and humans with alcoholic and nonalcoholic fatty liver disease
AU - Roskams, Tania
AU - Yang, Shi Qi
AU - Koteish, Aymen
AU - Durnez, Anne
AU - DeVos, Rita
AU - Huang, Xiawen
AU - Achten, Ruth
AU - Verslype, Chris
AU - Diehl, Anna Mae
N1 - Funding Information:
Supported by research grants from the National Institutes of Health ( RO1 AA010154 and RO1 DK3579 to A. M. D.) and F. W. O. Vlaanderen ( G.0139.00N to T. R.).
PY - 2003/10/1
Y1 - 2003/10/1
N2 - 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.
AB - 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.
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U2 - 10.1016/S0002-9440(10)63489-X
DO - 10.1016/S0002-9440(10)63489-X
M3 - Article
C2 - 14507639
AN - SCOPUS:0042033294
SN - 0002-9440
VL - 163
SP - 1301
EP - 1311
JO - American Journal of Pathology
JF - American Journal of Pathology
IS - 4
ER -