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Sab (Sh3bp5) dependence of JNK mediated inhibition of mitochondrial respiration in palmitic acid induced hepatocyte lipotoxicity.

AutorWin, Sanda; Than, Tinaung; Le, Bao Han; García-Ruiz, Carmen ; Fernández-Checa, José C. ; Kaplowitz, Neil
Palabras claveApoptosis
Palmitic acid
Reactive oxygen species
Fecha de publicación1-jun-2015
EditorEuropean Association for the Study of the Liver
CitaciónJournal of Hepatology 62(6): 1367-1374 (2015)
ResumenBackground & Aims Sustained c-Jun N-terminal kinase (JNK) activation by saturated fatty acids plays a role in lipotoxicity and the pathogenesis of non-alcoholic steatohepatitis (NASH). We have reported that the interaction of JNK with mitochondrial Sab leads to inhibition of respiration, increased reactive oxygen species (ROS), cell death and hepatotoxicity. We tested whether this pathway underlies palmitic acid (PA)-induced lipotoxicity in hepatocytes. Methods Primary mouse hepatocytes (PMH) from adeno-shlacZ or adeno-shSab treated mice and HuH7 cells were used. Results In PMH, PA dose-dependently up to 1 mM stimulated oxygen consumption rate (OCR) due to mitochondrial β-oxidation. At â>4;1.5 mM, PA gradually reduced OCR, followed by cell death. Inhibition of JNK, caspases or treatment with antioxidant butylated hydroxyanisole (BHA) protected PMH against cell death. Sab knockdown or a membrane permeable Sab blocking peptide prevented PA-induced mitochondrial impairment, but inhibited only the late phase of both JNK activation (beyond 4 h) and cell death. In PMH, PA increased p-PERK and its downstream target CHOP, but failed to activate the IRE-1α arm of the UPR. However, Sab silencing did not affect PA-induced PERK activation. Conversely, specific inhibition of PERK prevented JNK activation and cell death, indicating a major role upstream of JNK activation. Conclusions The effect of p-JNK on mitochondria plays a key role in PA-mediated lipotoxicity. The interplay of p-JNK with mitochondrial Sab leads to impaired respiration, ROS production, sustained JNK activation, and apoptosis. © 2015 European Association for the Study of the Liver
Versión del editorhttp://dx.doi.org/10.1016/j.jhep.2015.01.032
Identificadoresdoi: 10.1016/j.jhep.2015.01.032
issn: 0168-8278
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