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Delayed fas‐mediated hepatocyte apoptosis during liver regeneration in mice: hepatoprotective role of TNFα
Author(s) -
Takehara Tetsuo,
Hayashi Norio,
Mita Eiji,
Kanto Tatsuya,
Tatsumi Tomohide,
Sasaki Yutaka,
Kasahara Akinori,
Hori Masatsugu
Publication year - 1998
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.510270625
Subject(s) - apoptosis , hepatocyte , liver regeneration , tumor necrosis factor alpha , fas ligand , medicine , endocrinology , stimulation , necrosis , biology , caspase , caspase 3 , liver injury , programmed cell death , regeneration (biology) , microbiology and biotechnology , biochemistry , in vitro
Fas‐mediated apoptosis is one of the major death processes of hepatocytes in liver diseases. Although compensatory regeneration occurs during liver injury, it has not been determined whether regenerating hepatocytes die by the same apoptotic process as quiescent hepatocytes. To clarify this issue, the hepatocyte apoptotic process, after injection of agonistic anti‐mouse Fas, was compared between sham‐operated mice and two‐thirds partially hepatectomized mice. The onset of hepatocyte apoptosis was retarded in hepatectomized mice, as evidenced by both morphological and biochemical observations, resulting in significantly prolonged animal survival. Flow cytometric analysis revealed similar levels of Fas expression on hepatocytes between hepatectomized mice and sham‐operated mice; however, the activation of liver caspase‐3‐like protease after Fas stimulation was suppressed in hepatectomized mice, whereas pro‐caspase‐3 expression did not change with or without hepatectomy. Anti‐tumor necrosis factor alfa (TNFα), when administered before hepatectomy, partially reversed suppression of caspase‐3‐like activity after Fas stimulation. Furthermore, the injection of TNFα into untreated mice suppressed caspase‐3‐like activity and prolonged animal survival after Fas stimulation. These results indicate that Fas‐signaling events at the level or upstream of caspase‐3‐like protease are suppressed during liver regeneration, resulting in delayed hepatocyte apoptosis, and also that TNFα acts as one of the protective factors against Fas‐mediated hepatocyte apoptosis.