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In recent years, the association between saturated fatty acids (FA) and bone cells has received a high level of attention. Previous studies have shown that palmitate (PA), a common saturated FA, can cause apoptosis in bone marrow mesenchymal stem cells (BMSCs). However, whether PA can induce autophagy, an important intracellular protection mechanism that is closely associated with apoptosis, in BMSCs is still unknown; the association between autophagy and apoptosis is also unclear. The aim of the present study was to determine whether PA can induce autophagy in BMSCs. When BMSCs were treated with PA for >18 h, p62 began to accumulate, indicating that autophagic flux was impaired by prolonged exposure to PA. In addition, the proportion of apoptotic cells was increased when autophagy was inhibited by the autophagy inhibitor 3-methyladenine. Furthermore, inducing autophagy by pretreating cells with rapamycin, a known inducer of autophagy, markedly reduced PA-induced apoptosis, suggesting that autophagy may serve a protective role in PA-induced apoptosis in BMSCs. PA also increased intracellular reactive oxygen species (ROS) production, which was decreased by the antioxidant N-Acetyl-cysteine, and promoted the activation of c-Jun N-terminal kinases (JNKs) and p38 mitogen-activated protein kinase (MAPK). The addition of JNK and p38 MAPK inhibitors substantially reduced autophagy. Therefore, the results indicated that PA can induce autophagy in BMSCs and protect cells from PA-induced apoptosis through the ROS-JNK/p38 MAPK signaling pathways. These results may improve the general understanding of the mechanisms through which BMSCs adapt to PA-induced apoptosis. The present study also provides a novel approach for the prevention and treatment of PA-induced lipotoxicity.

Background Non-alcoholic fatty liver disease, one of the most common liver diseases, has obtained increasing attention. Palmitate (PA)-induced liver injury is considered a risk factor for the development of non-alcoholic fatty liver disease. Autophagy, a cellular degradative pathway, is an important self-defense mechanism in response to various stresses. In this study, we investigated whether autophagy plays a protective role in the progression of PA-induced hepatocytes injury. Results Annexin V-FITC/PI staining by FCM analysis, TUNEL assay and the detection of PARP and cleaved caspase3 expression levels demonstrated that PA treatment prominently induced the apoptosis of hepatocytes. Meanwhile, treatment of PA strongly induced the formation of GFP-LC3 dots, the conversion from LC3I to LC3II, the decrease of p62 protein levels and the increase of autophagosomes. These results indicated that PA also induced autophagy activation. Autophagy inhibition through chloroquine pretreatment or Atg5shRNA infection led to the increase of cell apoptosis after PA treatment. Moreover, induction of autophagy by pretreatment with rapamycin resulted in distinct decrease of PA-induced apoptosis. Therefore, autophagy can prevent hepatocytes from PA-induced apoptosis. In the further study, we explored pathway of autophagy activation in PA-treated hepatocytes. We found that PA activated PKCα in hepatocytes, and had no influence on mammalian target of rapamycin and endoplasmic reticulum stress pathways. Conclusions These results demonstrated that autophagy plays a protective role in PA-induced hepatocytes apoptosis. And PA might induce autophagy through activating PKCα pathway in hepatocytes.

Autophagy serves as a dynamic degradation and recycling system that provides biological materials and energy in response to stress. The role of autophagy in tumor development is complex. Various studies suggest that autophagy mainly contributes to tumor suppression during the early stage of tumorigenesis and tumor promotion during the late stage of tumorigenesis. During the tumorization of normal cells, autophagy protects genomic stability by retarding stem cells-involved damage/repair cycle, and inhibits the formation of chronic inflammatory microenvironment, thus protecting normal cell homeostasis and preventing tumor generation. On the other hand, autophagy also protects tumor cells survival during malignant progression by supporting cellular metabolic demands, decreasing metabolic damage and supporting anoikis resistance and dormancy. Taken together, autophagy appears to play a role as a protector for either normal or tumor cells during the early or late stage of tumorigenesis, respectively. The process of tumorigenesis perhaps needs to undergo twice autophagy-associated screening. The normal cells that have lower autophagy capacity are prone to tumorization, and the incipient tumor cells that have higher autophagy capacity possibly are easier to survival in the hash microenvironment and accumulate more mutations to promote malignant progression.