Malonyl-CoA and the regulation of fatty acid oxidation in soleus muscle

Abstract

1. Rat soleus strips were incubated with 5 mM glucose, after which tissue metabolites were measured. Alternatively, muscle strips were incubated with 5 mM glucose and 0.2 mM palmitate, and the formation of ¹⁴CO₂ from exogenous palmitate or from fatty acids released from prelabelled glycerolipids was measured. 2. Etomoxir, which inhibits the mitochondrial overt form of carnitine palmitoyltransferase (CPT₁), increased the tissue content of long-chain fatty acyl-CoA esters and decreased the ratio of fatty acylcarnitine to fatty acyl-CoA, suggesting that such changes could be a diagnostic for the inhibition of CPT₁. 3. Over a range of incubation conditions there was a positive correlation between the tissue contents of malonyl-CoA and long-chain fatty acyl-CoA esters. Under conditions in which these two metabolites increased in content (i.e. with insulin or with 3 mM dichloroacetate) there was a corresponding decrease in the ratio of fatty acylcarnitine to fatty acyl-CoA and a decrease in β-oxidation. Isoprenaline or palmitate (0.5 mM) opposed the effect of insulin, decreasing the contents of malonyl-CoA and long-chain fatty acyl-CoA, increasing the ratio of fatty acylcarnitine to fatty acyl-CoA and increasing β-oxidation. These findings are consistent with the notion that all of these agents can cause the acute regulation of CPT₁ in Type I skeletal muscle. 4. The addition of 5-amino-4-imidazolecarboxamide ribonucleoside (AICAriboside) to cause activation of the AMP-activated protein kinase decreased the tissue content of malonyl-CoA. AICAriboside also had an antilipolytic effect in the muscle strips. 5. Measurements were made of the activities of ATP-citrate lyase, acetyl-CoA carboxylase, fatty acid synthase and malonyl-CoA decarboxylase in soleus muscle and in representative Type IIa and Type IIb muscles. A cytosolic activity of malonyl-CoA decarboxylase would seem to offer a feasible route for the disposal of malonyl-CoA in skeletal muscle.