Long-chain fatty acids inhibit acetyl-CoA carboxylase gene expression in the pancreatic beta-cell line INS-1. 
The mechanism whereby long-term exposure of the beta-cell to fatty acids alters the beta-cell response to glucose is not known.  We hypothesized that fatty acids may alter beta-cell function by changing the expression level of metabolic enzymes implicated in the regulation of insulin 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 show that the polyunsaturated fatty acid linoleate (C18:2) inhibited both basal and glucose-stimulated ACC mRNA induction.  The inhibition was detected 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 glucose.  The saturated fatty acids myristate (C14:0), palmitate (C16:0), and stearate (C18:0) were also effective as well as the monounsaturated oleate (C18:1) and the short-chain fatty acids butyrate (C4:0) and caproate (C6:0); long-chain omega3 fatty acids were ineffective.  The threshold concentration for long-chain fatty acids was 0.05 mmol/l, and maximal inhibition occurred at 0.3 mmol/l. 2-bromopalmitate, a nonmetabolizable 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 glucose-induced insulin response, resulting in high basal insulin release and a suppression of glucose-induced insulin secretion.  This was associated with an exaggerated (twofold to threefold) rate of fatty acid oxidation at all tested glucose concentrations.  The data provide a possible mechanism to at least partially explain how fatty acids cause beta-cell insensitivity to glucose, i.e., by downregulating ACC with a resulting exaggerated fatty acid oxidation.