TY - JOUR
T1 - Induction of autophagy by palmitic acid via protein kinase C-mediated signaling pathway independent of mTOR (mammalian target of rapamycin)
AU - Tan, Shi Hao
AU - Shui, Guanghou
AU - Zhou, Jing
AU - Li, Jasmine Jia En
AU - Bay, Boon Huat
AU - Wenk, Markus R.
AU - Shen, Han Ming
PY - 2012/4/27
Y1 - 2012/4/27
N2 - Lipotoxicity refers to the cytotoxic effects of excess fat accumulation in cells and has been implicated as one of the contributing factors to diseases like obesity, diabetes, and non-alcoholic fatty liver. In this study we sought to examine effects of palmitic acid (PA) and oleic acid, two of the common dietary fatty acids on the autophagic process. We found that PA, but not oleic acid, was able to cause an increase in autophagic flux, evidenced by LC3-II accumulation and formation of GFP-LC3 puncta. Notably, PA-induced autophagy was found to be independent of mTOR regulation. Next, in search of the mechanism mediating PA-induced autophagy, we found increased levels of diacylglycerol species and protein kinase C (PKC) activation in PA-treated cells. More importantly, inhibition of classical PKC isoforms (PKC-α) was able to effectively suppress PA-induced autophagy. Finally, we showed that inhibition of autophagy sensitized the cells to PA-induced apoptosis, suggesting the prosurvival function of autophagy induced by PA. Taken together, results from this study reveal a novel mechanism underlying free fatty acid-mediated autophagy. Furthermore, the pro-survival function of autophagy suggests modulation of autophagy as a potential therapeutic strategy in protection of cells against lipotoxicity and lipid-related metabolic diseases.
AB - Lipotoxicity refers to the cytotoxic effects of excess fat accumulation in cells and has been implicated as one of the contributing factors to diseases like obesity, diabetes, and non-alcoholic fatty liver. In this study we sought to examine effects of palmitic acid (PA) and oleic acid, two of the common dietary fatty acids on the autophagic process. We found that PA, but not oleic acid, was able to cause an increase in autophagic flux, evidenced by LC3-II accumulation and formation of GFP-LC3 puncta. Notably, PA-induced autophagy was found to be independent of mTOR regulation. Next, in search of the mechanism mediating PA-induced autophagy, we found increased levels of diacylglycerol species and protein kinase C (PKC) activation in PA-treated cells. More importantly, inhibition of classical PKC isoforms (PKC-α) was able to effectively suppress PA-induced autophagy. Finally, we showed that inhibition of autophagy sensitized the cells to PA-induced apoptosis, suggesting the prosurvival function of autophagy induced by PA. Taken together, results from this study reveal a novel mechanism underlying free fatty acid-mediated autophagy. Furthermore, the pro-survival function of autophagy suggests modulation of autophagy as a potential therapeutic strategy in protection of cells against lipotoxicity and lipid-related metabolic diseases.
UR - http://www.scopus.com/inward/record.url?scp=84860372433&partnerID=8YFLogxK
U2 - 10.1074/jbc.M111.294157
DO - 10.1074/jbc.M111.294157
M3 - Article
C2 - 22408252
AN - SCOPUS:84860372433
SN - 0021-9258
VL - 287
SP - 14364
EP - 14376
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 18
ER -