title: Induction of autophagy by palmitic acid via protein kinase C-mediated signaling pathway independent of mTOR (mammalian target of rapamycin).
abstract: 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 pro-survival 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.
authors.affiliation: Saw Swee Hock School of Public Health, National University of Singapore, Singapore 117597.
authors.forename: Shi Hao
authors.initials: SH
authors.lastname: Tan
authors.forename: Guanghou
authors.initials: G
authors.lastname: Shui
authors.forename: Jing
authors.initials: J
authors.lastname: Zhou
authors.forename: Jasmine Jia'En
authors.initials: JJ
authors.lastname: Li
authors.forename: Boon-Huat
authors.initials: BH
authors.lastname: Bay
authors.forename: Markus R
authors.initials: MR
authors.lastname: Wenk
authors.forename: Han-Ming
authors.initials: HM
authors.lastname: Shen
mesh_terms: D000818:Animals; D001343:Autophagy / Q000187:drug effects* / Q000235:genetics; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D004789:Enzyme Activation / Q000187:drug effects / Q000235:genetics; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D056945:Hep G2 Cells; D006801:Humans; D051379:Mice; D019308:Palmitic Acid / Q000494:pharmacology*; D051571:Protein Kinase C-alpha / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects* / Q000235:genetics; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*
chemical_list: D004791:Enzyme Inhibitors; D019308:Palmitic Acid; C546842:MTOR protein, human; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases; C496628:PRKCA protein, human; C496630:Prkca protein, mouse; D051571:Protein Kinase C-alpha