Palmitate and oleate induce the immediate-early response genes c-fos and nur-77 in the pancreatic beta-cell line INS-1.
To better understand the link between fatty acid signaling and the pleiotropic effects of fatty acids in the pancreatic beta-cell, we investigated whether fatty acids regulate immediate-early response genes (IEGs) coding for transcription factors implicated in cell proliferation, differentiation, and apoptosis. Palmitate and oleate, but not long-chain polyunsaturated fatty acids, caused a pronounced accumulation of c-fos and nur-77 mRNAs in beta-cells (INS cells) to an extent similar to that produced by the protein kinase C (PKC) activator phorbol myristate acetate (PMA). The effect was dose dependent and occurred at concentrations between 0.1 and 0.5 mmol/l in the presence of 0.5% albumin. The action of the fatty acid occurred at the transcriptional level, and the mRNA accumulation displayed a bell-shaped kinetics with a maximal effect at 1 h. 2-Bromopalmitate was ineffective, indicating that fatty acids must be metabolized to cause their effect. Neither fatty acid was able to induce c-fos and nur-77 in PKC-downregulated cells or cells incubated in the presence of the Ca2+ channel blocker nifedipine or the Ca2+ chelator EGTA, suggesting involvement of the PKC and Ca2+ signaling pathways. Palmitate and oleate also increased c-fos protein expression and DNA binding activity of the transcription factor AP-1. Oleate, but not palmitate, increased [3H]thymidine incorporation in INS cells. Finally, both palmitate and oleate caused c-fos and nur-77 mRNA accumulation in isolated rat islets. It is suggested that IEG induction by the most abundant circulating fatty acids plays a role in the adaptive process of the beta-cell to hyperlipidemia. These results have implications for our understanding of obesity-associated diabetes and the link between fatty acids and tumorigenesis.
Roche
E
E
Instituto de Bioingeniería/Division of Nutrition, University Miguel Hernández, Alicante, Spain.
Buteau
J
J
Aniento
I
I
Reig
J A
JA
Soria
B
B
Prentki
M
M
D000818:Animals; D002118:Calcium / Q000378:metabolism; D004247:DNA / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics*; D005947:Glucose / Q000494:pharmacology; D007515:Islets of Langerhans / Q000187:drug effects* / Q000378:metabolism; D007527:Isoenzymes / Q000378:metabolism; D007700:Kinetics; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D019301:Oleic Acid / Q000494:pharmacology*; D010168:Palmitates / Q000494:pharmacology*; D011493:Protein Kinase C / Q000378:metabolism; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics*; D011987:Receptors, Steroid / Q000235:genetics*; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics*; D014158:Transcription, Genetic
D004268:DNA-Binding Proteins; D007527:Isoenzymes; C539820:Nr4a1 protein, rat; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D010168:Palmitates; D016760:Proto-Oncogene Proteins c-fos; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D011987:Receptors, Steroid; D018808:Transcription Factor AP-1; D014157:Transcription Factors; D019301:Oleic Acid; D004247:DNA; D011493:Protein Kinase C; D005947:Glucose; D002118:Calcium