Palmitate induces autophagy in pancreatic β-cells via endoplasmic reticulum stress and its downstream JNK pathway

Ying-Ying Chen, Lian-Qing Sun, Bao-An Wang, Xiao-Man Zou, Yi-Ming Mu, Ju-Ming Lu
International Journal of Molecular Medicine 2013, 32 (6): 1401-6
Endoplasmic reticulum (ER) stress and autophagy have both been reported to be associated with lipotoxicity in β-cells, yet the relationship between them has not been fully clarified. In the present study, we tested the hypothesis that the ER stress-autophagic pathway in β-cells is a downstream pathway activated following saturated fatty acid treatment. Mouse insulinoma (MIN6) β-cells were treated with either palmitate or thapsigargin (TG) with or without various inhibitors. The results indicated that palmitate strongly enhanced the protein expression of microtubule-associated protein 1 light chain 3 (LC3)-II. Furthermore, the expression levels of ER stress markers, BiP and CHOP, and phosphorylation levels of JNK were increased after palmitate treatment. In addition, palmitate-induced autophagy was blocked by 500 µM of the ER stress inhibitor tauroursodeoxycholic acid (TUDCA) or 20 µM JNK inhibitor SP600125. In turn, the phosphorylation of Akt (Ser473) was also downregulated by palmitate, while the levels of insulin receptor β (IRβ) were not reduced. A further increase in LC3-II levels was observed in cells treated with both palmitate and 50 µM PI3K/Akt inhibitor LY294002 compared with cells treated with palmitate alone. Palmitate-induced phospho-Akt (Ser473) downregulation was also inhibited by TUDCA or SP600125. Pretreatment with the autophagy inhibitor 3-methyladenine (3-MA, 5 mM) for 1 h increased the expression of ER stress markers, and enhanced cell injuries caused by 0.1 µM TG, including decreased cell viability and insulin secretion. Palmitate induces autophagy in pancreatic β-cells possibly through activation of ER stress and its downstream JNK pathway. Palmitate-induced autophagy may protect β-cells against cell injuries caused by ER stress.

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