Premium
Differential Changes in MAP Kinases, Histone Modifications, and Liver Injury in Rats Acutely Treated With Ethanol
Author(s) -
Aroor Annayya R.,
James Taryn T.,
Jackson Daniel E.,
Shukla Shivendra D.
Publication year - 2010
Publication title -
alcoholism: clinical and experimental research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.267
H-Index - 153
eISSN - 1530-0277
pISSN - 0145-6008
DOI - 10.1111/j.1530-0277.2010.01239.x
Subject(s) - p38 mitogen activated protein kinases , phosphorylation , kinase , histone , acetylation , histone h3 , mapk/erk pathway , western blot , liver injury , ethanol , chemistry , biology , medicine , endocrinology , biochemistry , gene
Background: Acute ethanol is known to affect cells and organs but the underlying molecular mechanisms are poorly explored. Recent developments highlight the potential importance of mitogen‐activated protein kinases, MAPKs (i.e., ERK1/2, p38, and JNK1/2) signaling, and histone modifications (i.e., acetylation, methylation, and phosphorylation) in the actions of ethanol in hepatocytes. We have therefore investigated significance of these molecular steps in vivo using a model in which rats were acutely administered ethanol intraperitoneally (IP). Methods: Ethanol was administered IP (3.5 gm/kg body weight) to 12‐week‐old male Sprague–Dawley rats. Liver was subsequently removed at 1 and 4 hours. Serum was used for alcohol and ALT assays. At the time of the removal of liver, small portions of each liver were formalin‐fixed and stained with hematoxylin and eosin (H&E) and used for light microscopy. Western blot analysis was carried out with specific primary antibodies for various parameters. Results: There were clear differences at 1 and 4 hours in blood ethanol, ALT, steatosis, and cleaved caspase 3. Apoptosis at 1 hour was followed by necrosis at 4 hours. Acute alcohol elicited a marked increase in the phosphorylation of ERK1/2 and moderate increases in the phosphorylation of p38 MAPK and JNK. Temporally different phosphorylation of histone H3 at ser‐10 and ser‐28 occurred and acetylation of histone H3 at lys 9 increased progressively. Conclusions: There were distinct differences in the behavior of the activation of the 3 MAP kinases and histone modifications after acute short exposure of liver to ethanol in vivo. Although all 3 MAPKs were rapidly activated at 1 hour, the necrosis, occurring at 4 hours, correlated to sustained activation of ERK1/2. Transient activation of p38 is associated with rapid phosphorylation of histone H3, whereas prolonged activation of ERK1/2 is correlated to persistent histone H3 acetylation.