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 beta-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 beta-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.

New strategies in sport nutrition to increase exercise performance

“…The inhibition of ACC by AMPK leads to a reduction in the levels of manonyl CoA, which allows for the activation of the mitochondrial fatty acid transporter Carnitine palmitoyltransferase I (CPT1) allowing for a greater flux of fatty acids into the mitochondria for oxidation [15]. In addition to this event exercise induced AMPK is also thought to phosphorylate and inhibit the Rab-GAP proteins TBC1D1/TBC1D4 [16][17][18].…”

Substrate cycling between de novo lipogenesis and lipid oxidation: a thermogenic mechanism against skeletal muscle lipotoxicity and glucolipotoxicity

“…Indeed, whenever the expression or activity of a key rate-limiting enzyme for de novo lipogenesis (eg, fatty acid synthase which catalyzes the conversion of malonyl-CoA to fatty acids) was reported in skeletal muscle, this was attributed to artifactual contamination from adipocyte infiltration rather than to de novo lipogenesis occurring in myocytes. 39,40 Consequently, the importance of skeletal muscle substrate metabolism in the homeostatic control of blood glucose has been viewed entirely from the reciprocal nature of interactions between glucose and lipid metabolism. Recent evidence, however, suggests otherwise.…”

Mutant mice lacking acetyl-CoA carboxylase 1 are embryonically lethal

“…In addition, malonylCoA, as a precursor of the synthesis of long-chain fatty acids, has been implicated as a signal molecule for insulin secretion from the pancreatic ␤-islets (1,2). The role that ACC plays in energy metabolism in lipogenic tissues (liver and adipose) and in oxidative tissues (liver, heart, and skeletal muscle) have become the focus of many studies (3)(4)(5)(6)(7)(8). In lipogenic tissues, malonylCoA is the C 2 -unit donor for de novo synthesis of long-chain fatty acids catalyzed by fatty acid synthase (FAS) and for the chain elongation of fatty acid to very long-chain fatty acids.…”

“…The livers of both wild-type and Acc1 ϩ/Ϫ mice (matched by age and sex) were isolated, and their malonyl-CoA contents were determined and compared. Protein-free extracts of these tissues were prepared by using 5% HClO 4 (wt͞vol) and were neutralized and analyzed for their malonyl-CoA contents, as measured by the incorporation of 14 C-acetyl-CoA into palmitate in the presence of NADPH and highly purified fatty acid synthase (7,31).…”