title: Activation of autophagy by globular adiponectin attenuates ethanol-induced apoptosis in HepG2 cells: involvement of AMPK/FoxO3A axis.
abstract: Hepatocellular apoptosis is an important pathological entity of alcoholic liver disease. Previously, we have shown that globular adiponectin (gAcrp) protects liver cells from ethanol-induced apoptosis by modulating an array of signaling pathways. In the present study, we investigated the role of autophagy induction by gAcrp in the suppression of ethanol-induced apoptosis and its potential mechanism(s) in liver cells. Here, we demonstrated that gAcrp significantly restores ethanol-induced suppression of autophagy-related genes, including Beclin-1 and microtubule-associated protein light chain (LC3B) both in primary rat hepatocytes and human hepatoma cell line (HepG2). Globular adiponectin also restored autophagosome formation suppressed by ethanol treatment in HepG2. Furthermore, inhibition of gAcrp-induced autophagic process by knock-down of LC3B prevented protection from ethanol-induced apoptosis. In particular, the autophagic process induced by gAcrp was involved in the suppression of ethanol-induced activation of caspase-8 and expression of Bax. Moreover, knock-down of AMPK by small interfering RNA (siRNA) blocked gAcrp-induced expression of genes related to autophagy, which in turn prevented protection from ethanol-induced apoptosis, suggesting that AMPK plays an important role in the induction of autophagy and protection of liver cells by gAcrp. Finally, we also showed that gAcrp treatment induces translocation of the forkhead box O member protein, FoxO3A, into the nucleus, which may play a role in the induction of autophagy-related genes. Taken together, our data demonstrated that gAcrp protects liver cells from ethanol-induced apoptosis via induction of autophagy. Further, the AMPK-FoxO3A axis plays a cardinal role in gAcrp-induced autophagy and subsequent inhibition of ethanol-induced apoptosis.
authors.affiliation: College of Pharmacy, Yeungnam University, Gyeongsangbuk-do, Republic of Korea.
authors.forename: Saroj
authors.initials: S
authors.lastname: Nepal
authors.forename: Pil-Hoon
authors.initials: PH
authors.lastname: Park
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D052242:Adiponectin / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001343:Autophagy / Q000187:drug effects*; D015153:Blotting, Western; D053148:Caspase 3 / Q000378:metabolism; D053181:Caspase 8 / Q000378:metabolism; D002478:Cells, Cultured; D002492:Central Nervous System Depressants / Q000633:toxicity*; D000431:Ethanol / Q000633:toxicity*; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008297:Male; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D052242:Adiponectin; D002492:Central Nervous System Depressants; C499515:FOXO3 protein, rat; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D000431:Ethanol; D055372:AMP-Activated Protein Kinases; D053148:Caspase 3; D053181:Caspase 8
keywords: AMPK; Adiponectin; Apoptosis; Autophagy; Ethanol; FoxO3