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Bax‐mediated apoptosis in the livers of rats after partial hepatectomy in the retrorsine model of hepatocellular injury
Author(s) -
Gordon Gavin J.,
Coleman William B.,
Grisham Joe W.
Publication year - 2000
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1053/jhep.2000.9144
Subject(s) - hepatocyte , apoptosis , chemistry , tunel assay , endocrinology , population , medicine , liver injury , andrology , biology , biochemistry , in vitro , environmental health
Abstract Retrorsine is a member of the pyrrolizidine alkaloid family of compounds whose toxic effects on the liver include a long‐lasting inhibition of the proliferative capacity of hepatocytes. Despite the retrorsine‐induced blockade of hepatocyte proliferation, retrorsine‐exposed rats are able to reconstitute completely their liver mass after surgical partial hepatectomy (PH) via the sustained proliferation of a population of small, incompletely differentiated hepatocyte‐like progenitor cells (SHPCs). The extensive proliferation of SHPCs in retrorsine‐injured livers is accompanied by the progressive loss of irreversibly injured megalocytes. To study the mechanism by which retrorsine‐damaged hepatocytes are removed after PH, we performed TUNEL analysis to establish apoptotic indices for hepatocytes in the livers of retrorsine‐exposed and control rats up to 14 days post‐PH. Apoptotic indices are highest (approximately 6.0%) in the livers of retrorsine‐exposed rats at 1 day post‐PH, gradually declining thereafter, yet remaining significantly elevated (approximately 1%) over control rats (<0.1%) at 14 days post‐PH ( P < .05). After PH, levels of the proapoptotic protein Bax are increased in livers from retrorsine‐exposed rats relative to the levels observed in control livers. Similarly, levels of the antiapoptotic protein Bcl‐x L are significantly decreased ( P < .05) compared with controls at t = 0 resulting in an increased (approximately 3.5‐fold) Bax/Bcl‐x protein ratio that is significantly elevated ( P < .05) compared with controls. Finally, increased levels of Bax protein are localized to the mitochondria of retrorsine‐exposed rat livers after PH during the same time that cytochrome c is released. These observations combine to suggest that retrorsine‐injured hepatocytes are removed after PH via apoptotic pathways dependent on relative levels and localization of Bax and Bcl‐x L protein.