Acyl-CoA inhibition of hexokinase in rat and human skeletal muscle is a potential mechanism of lipid-induced insulin resistance.
There are strong correlations between impaired insulin-stimulated glucose metabolism and increased intramuscular lipid pools; however, the mechanism by which lipids interact with glucose metabolism is not completely understood. Long-chain acyl CoAs have been reported to allosterically inhibit liver glucokinase (hexokinase IV). The aim of the present study was to determine whether long-chain acyl CoAs inhibit hexokinase in rat and human skeletal muscle. At subsaturating glucose concentrations, 10 micromol/l of the three major long-chain acyl-CoA species in skeletal muscle, palmitoyl CoA (16:0), oleoyl CoA (18:1, n = 9), and linoleoyl CoA (18:2, n = 6), reduced hexokinase activity of rat skeletal muscle to 61 +/- 3, 66 +/- 7, and 57 +/- 5% of control activity (P < 0.005), respectively. The inhibition was concentration-dependent (P < 0.005) with 5 pmol/l producing near maximal inhibition. Human skeletal muscle hexokinase was also inhibited by long-chain acyl CoAs (5 pmol/l palmitoyl CoA decreased activity to 75 +/- 6% of control activity, P < 0.005). Inhibition of hexokinase in rat and human muscle by long-chain acyl CoAs was additive to the inhibition of hexokinase by glucose-6-phosphate (an allosteric inhibitor of hexokinase). This inhibition of skeletal muscle hexokinase by long-chain acyl CoA suggests that increases in intramuscular lipid metabolites could interact directly with insulin-mediated glucose metabolism in vivo by decreasing the rate of glucose phosphorylation and decreasing glucose-6-phosphate concentrations.
Thompson
A L
AL
Garvan Institute of Medical Research, Darlinghurst, Australia.
Cooney
G J
GJ
D000214:Acyl Coenzyme A / Q000494:pharmacology*; D000818:Animals; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D019298:Glucose-6-Phosphate / Q000494:pharmacology; D006593:Hexokinase / Q000037:antagonists & inhibitors*; D006801:Humans; D007333:Insulin Resistance; D008055:Lipids / Q000494:pharmacology*; D008297:Male; D018482:Muscle, Skeletal / Q000201:enzymology*; D010171:Palmitoyl Coenzyme A / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar
D000214:Acyl Coenzyme A; D004791:Enzyme Inhibitors; D008055:Lipids; C017585:oleoyl-coenzyme A; D010171:Palmitoyl Coenzyme A; C026562:linoleoyl-coenzyme A; D019298:Glucose-6-Phosphate; D006593:Hexokinase