Malonyl-CoA levels

ACC2 selective inhibitors exemplified by 16 (ACC1 IC50 > 30 gM, ACC2 IC50 38 nM) have also been reported and were shown to reduce malonyl CoA levels in muscle tissues of Sprague-Dawley rats [51]. Although ACC inhibitors have... 

Kudo, N., Barr, A. J., Barr, R. L., Desai, S., and Lopaschuk, G. D. 1995. High rates of fatty acid oxidation during reperfusion of ischemic hearts are associated with a decrease in malonyl-CoA levels due to an increase in 5 -AMP-activated protein kinase inhibition of acetyl-CoA carboxylase. J Biol Chem 270 17513-17520. 

In the physiological context, the malonyl-CoA level is controlled by the activity of ACC, which is phosphorylated/inactivated by AMPK. Changes in hypothalamic AMPK activity are consistent with the predicted changes in the malonyl-CoA level and food intake. Furthermore, central administration of the AMP analog, AICAR (5 -aminoimidazole-... 

In the liver, the oxidation of newly synthesized fatty acids back to acetyl CoA via the mitochondrial (3-oxidation pathway is prevented by malonyl CoA. Carnitine palmitoyltransferase I, the enzyme involved in the transport of long-chain fatty acids into mitochondria (see Chapter 23), is inhibited by malonyl CoA (Fig. 33.16). Malonyl CoA levels are elevated when acetyl CoA carboxylase is activated, and, thus, fatty acid oxidation is inhibited while fatty acid synthesis is proceeding. This inhibition prevents the occurrence of a futile cycle. 

Fig. 33.16. Inhibition of carnitine palmitoyltransferase (CPTI, also called carnitine acyl-transferase I) by malonyl CoA. During fatty acid synthesis, malonyl CoA levels are high. This compound inhibits CPTI, which is involved in the transport of long-chain fatty acids into mitochondria for p-oxidation. This mechanism prevents newly synthesized fatty acids from undergoing immediate oxidation.

Malonyl CoA, the product of the acetyl CoA carboxylase reaction, provides the carbons for the synthesis of palmitate on the fatty acid synthase complex. Malonyl CoA also inhibits carnitine palmitoyltransferase I (CPTI, also known as carnitine acyltransferase 1), the enzyme that prepares long-chain fatty acyl CoA for transport into mitochondria (Fig. 36.6). In the fed state, when acetyl CoA carboxylase is active and malonyl CoA levels are elevated, newly synthesized fatty acids are converted to triacylglycerols for storage, rather than being transported into mitochondria for oxidation and ketone body formation. 

S ATP -I- acetyl-CoA carboxylase <2, 4> (<4> substrate Rattus norvegicus hepatic acetyl-CoA carboxylase, enzyme phosphorylates Ser-residues 79, 1200 and 1215 [10] <2> AMPK plays an important role in regulating malonyl-CoA levels through the phosphorylation of acetyl-CoA carboxylase [18]) (Reversibility <2,4> [10,14,16,18]) [10, 14, 16, 18]... 

Leptin stimulates the oxidation of fatty acids and the uptake of glucose by muscle cells. It does so by stimulating AMP-activated protein kinase, which phosphorylates an isoform of acetyl-GoA carboxylase (ACC) in muscle cells, rendering it less active (Figure 24.4). Recall from Section 21.6 that ACC plays a pivotal role in fat metabolism. When ACC activity is decreased, malonyl-CoA levels decrease and the mitochondria can take up and oxidize fatty acids. 

Table 1. EtVect of disruptors of the cytoskeleton on CPT 1 activity and malonyl-CoA levels Hepatocytes were preincubated for 45 min in the absence or in the presence of the modulators of the integrity of the cytoskeleton as indicated. Incubations were continued for 15 additional min with or without 0.5pM OA, and then aliquots were taken to determine the level of malonyl-CoA as well as the activity of CPT 1 by the one-step assay." Results correspond to the number of experiments indicated in parentheses for CPT I activity and to 3 different experiments for malonyl-CoA concentration.

Figure 11.10 Interactions between fatty acid synthesis and oxidation in liver. In the fed state malonyl-CoA levels are high. This allows rapid fatty acid synthesis and inhibits jS-oxidation by lowering carnitine acyltransferase I activity. If triacylglycerol synthesis is impaired then acyl-CoAs will feedback to inhibit acetyl-CoA carboxylase. In the fed state this does not normally happen and tri-acylglycerols are incorporated into very-low-density lipoprotein for export to extrahepatic tissues. Glucagon excess in fasting leads to a suppression of glycolysis, cessation of lipogenesis and activation of -oxidation and ketogenesis. Reproduced with permission from Annual Review of Biochemistry, 49, 1980 by Annual Reviews Inc.

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