Protective role of autophagy in palmitate-induced INS-1 beta-cell death.
Autophagy, a vacuolar degradative pathway, constitutes a stress adaptation that avoids cell death or elicits the alternative cell-death pathway. This study was undertaken to determine whether autophagy is activated in palmitate (PA)-treated beta-cells and, if activated, what the role of autophagy is in the PA-induced beta-cell death. The enhanced formation of autophagosomes and autolysosomes was observed by exposure of INS-1 beta-cells to 400 microm PA in the presence of 25 mm glucose for 12 h. The formation of green fluorescent protein-LC3-labeled structures (green fluorescent protein-LC3 dots), with the conversion from LC3-I to LC3-II, was also distinct in the PA-treated cells. The phospho-mammalian target of rapamycin level, a typical signal pathway that inhibits activation of autophagy, was gradually decreased by PA treatment. Blockage of the mammalian target of rapamycin signaling pathway by treatment with rapamycin augmented the formation of autophagosomes but reduced PA-induced INS-1 cell death. In contrast, reduction of autophagosome formation by knocking down the ATG5, inhibition of fusion between autophagosome and lysosome by treatment with bafilomycin A1, or inhibition of proteolytic degradation by treatment with E64d/pepstatin A, significantly augmented PA-induced INS-1 cell death. These findings showed that the autophagy system could be activated in PA-treated INS-1 beta-cells, and suggested that the induction of autophagy might play an adaptive and protective role in PA-induced cell death.
Choi
Sung-E
SE
Institute for Medical Science, Ajou University School of Medicine, Wonchon-dong san5, Yongtong-gu, Suwon, Gyeonggi-do 442-749, Republic of Korea.
Lee
Sung-Mi
SM
Lee
Youn-Jung
YJ
Li
Ling-Ji
LJ
Lee
Soo-Jin
SJ
Lee
Ji-Hyun
JH
Kim
Youngsoo
Y
Jun
Hee-Sook
HS
Lee
Kwan-Woo
KW
Kang
Yup
Y
D000818:Animals; D001343:Autophagy / Q000187:drug effects; D053148:Caspase 3 / Q000187:drug effects / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects*; D002467:Cell Nucleus / Q000187:drug effects / Q000473:pathology; D002470:Cell Survival / Q000187:drug effects; D005947:Glucose / Q000494:pharmacology; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000473:pathology*; D007340:Insulinoma / Q000473:pathology; D019308:Palmitic Acid / Q000494:pharmacology*; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000473:pathology; D034622:RNA Interference; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects
D019308:Palmitic Acid; D053148:Caspase 3; D005947:Glucose