Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.24.56 (insulin-degrading enzyme)
 737 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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 IC(50) values in the range of 10-50 micro M. In general, the corresponding acyl-coenzyme A thioesters had lower IC(50) values and were slightly more efficacious. (125)I-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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PMID:In vitro inhibition of insulin-degrading enzyme by long-chain fatty acids and their coenzyme A thioesters. 1274 1

There is evidence in animal studies that free fatty acids (FFA) can decrease protein degradation, but the exact mechanism is not known. We have shown that FFA can inhibit proteasome activity in vitro by interacting with insulin-degrading enzyme. Here we show that FFA can also inhibit the proteasome in whole cells. HepG2 cells were treated with various FFA, and proteasome activity was measured using a cell-permeable substrate for the chymotrypsin-like activity. Octanoic acid, a medium-chain fatty acid, did not affect proteasome activity. However, oleic and linoleic acids inhibited the chymotrypsin-like activity up to 80%, with approximate IC50s of 80 and 40 micromol/L, respectively. Insulin also inhibited but was not additive with the FFA, suggesting that they work through the same mechanism. These results show that the proteasome can be inhibited by FFA in whole cells and suggest that insulin-degrading enzyme may mediate this effect. This mechanism may be applicable to whole animals and represents a means to integrate hormonal and nutrient signals on the control of protein degradation.
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PMID:Preliminary report: inhibition of cellular proteasome activity by free fatty acids. 1942 42