LONG-CHAIN FATTY-ACIDS INHIBIT ACETYL-COA CARBOXYLASE GENE-EXPRESSIONIN THE PANCREATIC BETA-CELL LINE INS-1

The mechanism whereby long-term exposure of the beta-cell to fatty aci ds alters the beta-cell response to glucose is not known. We hypothesi zed that fatty acids may alter beta-cell function by changing the expr ession level of metabolic enzymes implicated in the regulation of insu lin secretion, in particular acetyl-CoA carboxylase (ACC). This enzyme catalyzes the formation of malonyl-CoA, a key regulator of fatty acid oxidation. Using the beta-cell line INS-1 as a model, the results sho w that the polyunsaturated fatty acid linoleate (C18:2) inhibited both basal and glucose-stimulated ACC mRNA induction. The inhibition was d etected by 4-6 h, and a maximal 60% effect occurred at 12 h after cell exposure to the fatty acid. Linoleate, as glucose, did not modify the half-life of the ACC transcript. Prolonged exposure of INS-1 cells to linoleate also inhibited ACC protein accumulation at low and high glu cose. The saturated fatty acids myristate (C14:0), palmitate (C16:0), and stearate (C18:0) were also effective as well as the monounsaturate d oleate (C18:1) and the short-chain fatty acids butyrate (C4:0) and c aproate (C6:0); long-chain omega 3 fatty acids were ineffective. The t hreshold concentration for long-chain fatty acids was 0.05 mmol/l, and maximal inhibition occurred at 0.3 mmol/l. 2-bromopalmitate, a nonmet abolizable analog, had no effect, suggesting that fatty acids must be metabolized to change ACC gene expression. Prolonged exposure of INS-1 cells to palmitate, oleate, and Linoleate markedly altered the glucos e-induced insulin response, resulting in high basal insulin release an d a suppression of glucose-induced insulin secretion. This was associa ted with an exaggerated (twofold to threefold) rate of fatty acid oxid ation at all tested glucose concentrations. The data provide a possibl e mechanism to at least partially explain how fatty acids cause beta-c ell insensitivity to glucose, i.e., by downregulating ACC with a resul ting exaggerated fatty acid oxidation.