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 pleiotro pic effects of fatty acids in the pancreatic beta-cell, we investigated whe ther fatty acids regulate immediate-early response genes (IEGs) coding for transcription factors implicated in cell proliferation, differentiation, an d 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 kina se C (PKC) activator phorbol myristate acetate (PMA). The effect was dose d ependent and occurred at concentrations between 0.1 and 0.5 mmol/l in the p resence of 0.5% albumin. The action of the fatty acid occurred at the trans criptional level, and the mRNA accumulation displayed a bell-shaped kinetic s with a maximal effect at 1 h. 2-Bromopalmitate was ineffective, indicatin g 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 cel ls incubated in the presence of the Ca2+ channel blocker nifedipine or the Ca2+ chelator EGTA, suggesting involvement of the PKC and Ca2+ signaling pa thways. Palmitate and oleate also increased c-fos protein expression and DN A binding activity of the transcription factor AP-1. Oleate, but not palmit ate, increased [H-3]thymidine incorporation in INS cells. Finally, both pal mitate and oleate caused c-fos and nur-77 mRNA accumulation in isolated rat islets. It is suggested that IEG induction by the most abundant circulatin g fatty acids plays a role in the adaptive process of the beta-cell to hype rlipidemia. These results have implications for our understanding of obesit y-associated diabetes and the link between fatty acids and tumorigenesis.