Role of endoplasmic reticulum stress in alcoholic liver disease-related hepatocyte apoptosis / 中华肝脏病杂志

ABSTRACT

<p><b>OBJECTIVE</b>To investigate the role of endoplasmic reticulum stress (ERS) in alcoholic liver disease (ALD)-related hepatocyte apoptosis.</p><p><b>METHODS</b>A rat model of ALD was established by continuous intragastric administration of ethanol. At 4, 8, 12, and 16 weeks later, randomly selected rats were sacrificed for serum and liver sample collection. Serum levels of total homocysteine (tHcy) were examined by chemiluminescence analysis. Cystathionine beta-synthase (CBS) activity in liver tissue was measured by chromatometry. The mRNA and protein expressions of ERS-related factors, glucose-regulated protein (GRP)-78, calpain 2 and caspase-12, were analyzed by reverse transcription-polymerase chain reaction and immunohistochemistry, respectively. Hepatocyte apoptosis was detected by the TdT-mediated dUTP nick end labeling assay.</p><p><b>RESULTS</b>At 16 weeks, the ALD rats' livers exhibited diffuse microvesicular adipose degeneration and fibrosis in the liver sinus and portal septa. As the duration of ethanol administration extended, the tHcy levels gradually increased (P less than 0.01), CBS activity decreased (P less than 0.01), gene expression levels of GRP-78, calpain 2, and caspase-12 were up-regulated (P less than 0.01), and protein expression levels of GRP-78 and calpain 2 were gradually increased. However, the protein level of procaspase-12 was found to decrease with increased duration of ethanol administration. Finally, the hepatocyte apoptosis index showed an increasing trend over time (P less than 0.01).</p><p><b>CONCLUSION</b>In our experimental ALD rat model, hepatic apoptosis was detected with increasing frequency over the duration of ALD. Increased apoptosis was likely due to decreased CBS activity causing hyperhomocysteinemia, which further induced ERS and activated the calpain 2 and caspase-12 signaling pathway. These ethanol-induced molecular changes may provoke hepatic apoptosis and subsequently promote the pathogenic processes of alcoholic liver disease.</p>