Insulin-degrading enzyme is responsible for initiating insulin degradation in cells, but little is known about the factors controlling its activity. Because obesity and high levels of free fatty acids decrease insulin clearance, we examined the effect of some common free fatty acids and their acyl-coenzyme A thioesters on insulin-degrading enzyme partially purified from the livers of male Sprague Dawley rats. Octanoic acid (C8:0) had no effect on activity. Long-chain free fatty acids (C16-C20) inhibited between 50% and 90% of the insulin degradation with ICso values in the range of 10-50 μM. In general, the corresponding acyl-coenzyme A thioesters had lower IC50 values and were slightly more efficacious. 125I-insulin cross-linking studies showed free fatty acids did not inhibit hormone binding to insulin-degrading enzyme. Kinetic analysis showed a noncompetitive type of inhibition. Furthermore, fatty acids eliminated the ability of insulin to inhibit the proteasome. These results suggest that when intracellular long-chain fatty acid concentrations are elevated, they may act directly on insulin-degrading enzyme to decrease insulin metabolism and alter insulin action in intact cells. This mechanism may contribute to the hyperinsulinemia and insulin resistance seen with elevated fatty acids and obesity.
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