Journal
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
Volume 20, Issue 24, Pages -Publisher
MDPI
DOI: 10.3390/ijms20246268
Keywords
palmitic acid; p53; reactive oxygen species; cell apoptosis
Funding
- Youth National Natural Science Foundation of China [31501322]
- Postdoctoral Special Foundation of Sichuan Province [03130104]
- overseas project personnel in scientific and technological activities [03109138]
- NIH/NIGMS [R01GM112085]
- National Natural Science Foundation of China [31971960]
- National key research and development program [2016YFD0100503]
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Palmitic acid, the most common saturated free fatty acid, can lead to lipotoxicity and apoptosis when overloaded in non-fat cells. Palmitic acid accumulation can induce pancreatic beta-cell dysfunction and cardiac myocyte apoptosis. Under various cellular stresses, the activation of p53 signaling can lead to cell cycle arrest, DNA repair, senescence, or apoptosis, depending on the severity/type of stress. Nonetheless, the precise role of p53 in lipotoxicity induced by palmitic acid is not clear. Here, our results show that palmitic acid induces p53 activation in a dose- and time-dependent manner. Furthermore, loss of p53 makes cells sensitive to palmitic acid-induced apoptosis. These results were demonstrated in human colon carcinoma cells (HCT116) and primary mouse embryo fibroblasts (MEF) through analysis of DNA fragmentation, flow cytometry, colony formation, and Western blots. In the HCT116 p53(-/-) cell line, palmitic acid induced greater reactive oxygen species formation compared to the p53(+/+) cell line. The reactive oxygen species (ROS) scavengers N-acetyl cysteine (NAC) and reduced glutathione (GSH) partially attenuated apoptosis in the HCT116 p53(-/-) cell line but had no obvious effect on the p53(+/+) cell line. Furthermore, p53 induced the expression of its downstream target genes, p21 and Sesn2, in response to ROS induced by palmitic acid. Loss of p21 also leads to more palmitic acid-induced cell apoptosis in the HCT116 cell line compared with HCT116 p53(+/+) and HCT116 p53(-/-). In a mouse model of obesity, glucose tolerance test assays showed higher glucose levels in p53(-/-) mice that received a high fat diet compared to wild type mice that received the same diet. There were no obvious differences between p53(-/-) and p53(+/+) mice that received a regular diet. We conclude that p53 may provide some protection against palmitic acid- induced apoptosis in cells by targeting its downstream genes in response to this stress.
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