期刊
JOURNAL OF HEPATOLOGY
卷 62, 期 6, 页码 1367-1374出版社
ELSEVIER SCIENCE BV
DOI: 10.1016/j.jhep.2015.01.032
关键词
Palmitic acid; Reactive oxygen species; Apoptosis; Mitochondria; Hepatocytes
资金
- NIH [RO1-DK067215, RO1-AA014428]
- USC Research Center for Liver Disease Cellular and Tissue Imaging, Cell Separation and Culture [P30-DK48522]
- Analytical/Metabolic/Instrumentation Cores
- Southern California Research Center for Alcoholic Liver and Pancreatic Disease [P30-AA11999]
Background & 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 b-oxidation. At >= 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-1 alpha 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. (C) 2015 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
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