title: C16 ceramide is crucial for triacylglycerol-induced apoptosis in macrophages.
abstract: Triacylglycerol (TG) accumulation caused by adipose triglyceride lipase (ATGL) deficiency or very low-density lipoprotein (VLDL) loading of wild-type (Wt) macrophages results in mitochondrial-mediated apoptosis. This phenotype is correlated to depletion of Ca(2+) from the endoplasmic reticulum (ER), an event known to induce the unfolded protein response (UPR). Here, we show that ER stress in TG-rich macrophages activates the UPR, resulting in increased abundance of the chaperone GRP78/BiP, the induction of pancreatic ER kinase-like ER kinase, phosphorylation and activation of eukaryotic translation initiation factor 2A, the translocation of activating transcription factor (ATF)4 and ATF6 to the nucleus and the induction of the cell death executor CCAAT/enhancer-binding protein homologous protein. C16:0 ceramide concentrations were increased in Atgl-/- and VLDL-loaded Wt macrophages. Overexpression of ceramide synthases was sufficient to induce mitochondrial apoptosis in Wt macrophages. In accordance, inhibition of ceramide synthases in Atgl-/- macrophages by fumonisin B1 (FB1) resulted in specific inhibition of C16:0 ceramide, whereas intracellular TG concentrations remained high. Although the UPR was still activated in Atgl-/- macrophages, FB1 treatment rescued Atgl-/- macrophages from mitochondrial dysfunction and programmed cell death. We conclude that C16:0 ceramide elicits apoptosis in Atgl-/- macrophages by activation of the mitochondrial apoptosis pathway.
authors.affiliation: Institute of Molecular Biology and Biochemistry, Center of Molecular Medicine, Medical University of Graz, Graz, Austria.
authors.forename: E
authors.initials: E
authors.lastname: Aflaki
authors.forename: P
authors.initials: P
authors.lastname: Doddapattar
authors.forename: B
authors.initials: B
authors.lastname: Radović
authors.forename: S
authors.initials: S
authors.lastname: Povoden
authors.forename: D
authors.initials: D
authors.lastname: Kolb
authors.forename: N
authors.initials: N
authors.lastname: Vujić
authors.forename: M
authors.initials: M
authors.lastname: Wegscheider
authors.forename: H
authors.initials: H
authors.lastname: Koefeler
authors.forename: T
authors.initials: T
authors.lastname: Hornemann
authors.forename: W F
authors.initials: WF
authors.lastname: Graier
authors.forename: R
authors.initials: R
authors.lastname: Malli
authors.forename: F
authors.initials: F
authors.lastname: Madeo
authors.forename: D
authors.initials: D
authors.lastname: Kratky
mesh_terms: D051701:Activating Transcription Factor 4 / Q000378:metabolism; D051702:Activating Transcription Factor 6 / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D022762:CCAAT-Enhancer-Binding Proteins / Q000378:metabolism; D002118:Calcium / Q000172:deficiency; D002518:Ceramides / Q000378:metabolism*; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism; D000091342:Endoplasmic Reticulum Chaperone BiP; D004791:Enzyme Inhibitors / Q000494:pharmacology; D037341:Fumonisins / Q000494:pharmacology; D006360:Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D008049:Lipase / Q000037:antagonists & inhibitors / Q000172:deficiency; D008079:Lipoproteins, VLDL / Q000378:metabolism; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D014280:Triglycerides / Q000378:metabolism / Q000494:pharmacology*; D056811:Unfolded Protein Response / Q000187:drug effects; D000217:Acyltransferases
chemical_list: D051701:Activating Transcription Factor 4; D051702:Activating Transcription Factor 6; D022762:CCAAT-Enhancer-Binding Proteins; D002118:Calcium; D002518:Ceramides; D000091342:Endoplasmic Reticulum Chaperone BiP; D004791:Enzyme Inhibitors; D037341:Fumonisins; D006360:Heat-Shock Proteins; D008049:Lipase; D008079:Lipoproteins, VLDL; D014280:Triglycerides; C081452:Atf4 protein, mouse; C497112:Atf6 protein, mouse; C000717247:HSPA5 protein, human; C000717248:Hspa5 protein, mouse; C056933:fumonisin B1; C097760:N-palmitoylsphingosine; C494445:PNPLA2 protein, mouse; D000217:Acyltransferases