Upregulation of autophagy components in alcoholic hepatitis and nonalcoholic steatohepatitis

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• 作者：M. Masouminia^a ; S. Samadzadeh^b ; A.S. Mendoza^a ; B.A. French^b ; B. Tillman^b ; S.W. French^a ; ^{sfrench@labiomed.org" class="auth_mail" title="E-mail the corresponding author}
• 关键词：Mallory-Denk Bodies ; Autophagocytosis ; Protein quality control ; Alcoholic hepatitis
• 刊名：Experimental and Molecular Pathology
• 出版年：2016
• 出版时间：August 2016
• 年：2016
• 卷：101
• 期：1
• 页码：81-88
• 全文大小：2907 K

文摘

There are many homeostatic mechanisms for coping with stress conditions in cells, including autophagy. In many studies autophagy, as an intracellular pathway which degrades misfolded and damaged protein, and Mallory-Denk Body (MDB) formation have been shown to be protective mechanisms against stress such as alcoholic hepatitis. Alcohol has a significant role in alteration of lipid homeostasis, sterol regulatory element-binding proteins (SREBPs) and peroxidase proliferator-activated receptors through AMP-activated protein kinase (AMPK)-dependent mechanism. AMPK is one of the kinases that regulate autophagy through the dephosphorylation of ATG1. Activation of ATG1 (ULK kinases family) activates ATG6. These two activated proteins relocate to the site of initial autophagosome and activate the other downstream components of autophagocytosis. Many other proteins regulate autophagocytosis at the gene level. CHOP (C/EBP homologous protein) is one of the most important parts of stress-inducible transcription that encodes a ubiquitous transcription factor. In this report we measure the upregulation of the gene that are involved in autophagocytosis in liver biopsies of alcoholic hepatitis and NASH. Electron microscopy was used to document the presence of autophagosomes in the liver cells. Expression of AMPK1, ATG1, ATG6 and CHOP in ASH were significantly (p value < 0.05) upregulated in comparison to control. Electron microscopy findings of ASH confirmed the presence of autophagosomes, one of which contained a MDB, heretofore undescribed. Significant upregulations of AMPK-1, ATG-1, ATG-6, and CHOP, and uptrending of ATG-4, ATG-5, ATG-9, ATR, and ATM in ASH compared to normal control livers indicate active autophagocytosis in alcoholic hepatitis.