Persistent activation of Akt or ERK prevents the toxicity induced by saturated and polyunsaturated fatty acids in RINm5F β-cells.
The aim of this study was to investigate whether the toxicity of saturated and polyunsaturated fatty acids (PUFA) on RINm5F cells is related to the phosphorylation state of Akt, ERK and PKC delta. The regulation of these kinases was compared in three experimental designs: (a) 4h-exposure, (b) 4h-exposure and a subsequent withdrawn of the FA for a 20 h period and (c) 24h-exposure. Saturated and PUFA were toxic to RINm5F cells even at low concentrations. Also, evidence is provided for a late (i.e. the effect only appeared hours after the treatment) and a persistent regulation (i.e. maintenance of the effect for several hours) of Akt, ERK and PKC delta phosphorylation by the FA. Late activation of PKC delta seems important for palmitate cytotoxicity. Persistent activation of the survival proteins Akt and ERK by stearate, oleate and arachidonate might play an important role to prevent the toxic effect of posterior PKC delta activation. The results shown may explain why a short-period exposure to FA is not enough to induce cytotoxicity in pancreatic beta-cells, since survival pathways are activated. Besides, when this activation is persistent, it may overcome a posterior induction of death pathways.
Simon
Monique Nouailhetas
MN
Department of Physiology and Biophysics, Institute of Biomedical Sciences, Brazil.
Azevedo-Martins
Anna Karenina
AK
Amanso
Angélica M
AM
Carvalho
Carla R O
CR
Curi
Rui
R
D000818:Animals; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000187:drug effects / Q000378:metabolism*; D005227:Fatty Acids / Q000008:administration & dosage / Q000633:toxicity*; D005231:Fatty Acids, Unsaturated / Q000008:administration & dosage / Q000633:toxicity*; D050417:Insulin-Secreting Cells / Q000187:drug effects* / Q000201:enzymology; D007340:Insulinoma / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D051745:Protein Kinase C-delta / Q000187:drug effects / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D013997:Time Factors
D005227:Fatty Acids; D005231:Fatty Acids, Unsaturated; D051057:Proto-Oncogene Proteins c-akt; D051745:Protein Kinase C-delta; D048049:Extracellular Signal-Regulated MAP Kinases