Fatty acid oxidation uptake activity

Palmitic acid serves as the major metabolic fuel, particularly in the brain, which utilizes fatty acids as a major fuel source during fatty acid oxidation and active transport into cerebral microvessels (Williams et al., 1997). Up on transport across the palmitic is incorporated into brain phospholipids, contributing to 29% of phospholipids (pmol/g) in rat brain (Rapoport, 2001). The uptake of palmitic acid is enhanced with the expression of the fatty acid transport protein, which facilitates the transcellular transversion of fatty acids across the blood-brain... 

FIGURE 25.16 Regulation of fatty acid synthesis and fatty acid oxidation are conpled as shown. Malonyl-CoA, produced during fatty acid synthesis, inhibits the uptake of fatty acylcarnitine (and thus fatty acid oxidation) by mitochondria. When fatty acyl CoA levels rise, fatty acid synthesis is inhibited and fatty acid oxidation activity increases. Rising citrate levels (which reflect an abundance of acetyl-CoA) similarly signal the initiation of fatty acid synthesis. 

The rate of mitochondrial oxidations and ATP synthesis is continually adjusted to the needs of the cell (see reviews by Brand and Murphy 1987 Brown, 1992). Physical activity and the nutritional and endocrine states determine which substrates are oxidized by skeletal muscle. Insulin increases the utilization of glucose by promoting its uptake by muscle and by decreasing the availability of free long-chain fatty acids, and of acetoacetate and 3-hydroxybutyrate formed by fatty acid oxidation in the liver, secondary to decreased lipolysis in adipose tissue. Product inhibition of pyruvate dehydrogenase by NADH and acetyl-CoA formed by fatty acid oxidation decreases glucose oxidation in muscle. 

Figure 7.14 Regulation of rate of fatty acid oxidation in tissues. Arrows indicate direction of change (i) Changes in the concentrations of various hormones control the activity of hormone-sensitive lipase in adipose tissue (see Figure 7.10). (ii) Changes in the blood level of fatty acid govern the uptake and oxidation of fatty acid, (iii) The activity of the enzyme CPT-I is controlled by changes in the intracellular level of malonyl-CoA, the formation of which is controlled by the hormones insulin and glucagon. Insulin increases malonyl-CoA concentration, glucagon decrease it. Three factors are important TAG-lipase, plasma fatty acid concentration and the intracellular malonyl-CoA concentration.

Merrill, G. F., Kurth, E. J., Hardie, D. G., and Winder, W. W. 1997. AICA riboside increases AMP-activated protein kinase, fatty acid oxidation, and glucose uptake in rat muscle. Am J Physiol 273(6 Ptl) El 107-El 112. 

ATP hydrolysis and this could be seen as beneficial competes with calcium and decreases contractility, inhibits nucleotidases and prevents further breakdown of AMP. AMP activates AMP kinase with subsequent increase in the rate of glycolysis and fatty acid oxidation. Figure 2. AMPK is responsible for the activation of glucose uptake and glycolysis during low-flow ischemia and seems to play an important protective role in limiting damage and apoptotic activity associated with ischemia and reperfusion in the heart.44... 

As Otto Shape runs, his skeletal muscles increase their use of ATP and their rate of fuel oxidation. Fatty acid oxidation is accelerated by the increased rate of the electron transport chain. As ATP is used and AMP increases, an AMP-dependent protein kinase acts to facilitate fuel utilization and maintain ATP homeostasis. Phosphorylation of acetyl CoA carboxylase results in a decreased level of malonyl CoA and increased activity of carnitine palmitoyl CoA transferase I. At the same time, AMP-dependent protein kinase facilitates the recruitment of glucose transporters into the plasma membrane of skeletal muscle, thereby increasing the rate of glucose uptake. AMP and hormonal signals also increase the supply of glucose 6-P from glycogenoly-sis. Thus, his muscles are supplied with more fuel, and all the oxidative pathways are accelerated. 

Fatty acid uptake by muscle requires the participation of fatty acid-binding proteins and the usual enzymes of fatty acid oxidation. Fatty acyl-CoA uptake into the mitochondria is controlled by malonyl-CoA, which is produced by an isozyme of acetyl-coA carboxylase (ACC-2 the ACC-1 isozyme is found in liver and adipose tissue and is used for fatty acid biosynthesis). ACC-2 is inhibited by phosphorylation by the AMP-activated protein kinase (AMP-PK) such that when energy levels are low the levels of malonyl CoA will drop, allowing fatty acid oxidation by the mitochondria. In addition, muscle cells also contain the enzyme malonyl CoA decarboxylase, which is activated by phosphorylation by the AMP-PK. Malonyl CoA decarboxylase converts malonyl CoA to acetyl CoA, thereby relieving the inhibition of carnitine palmitoyl transferase I (CPT-I) and stimulating fatty acid oxidation (Fig. 47.5). Muscle cells do not synthesize fatty acids the presence of acetyl CoA carboxylase in muscle is exclusively for regulatory purposes. 

Fatty acid uptake into cardiac muscle is similar to that for other muscle cell types and requires fatty acid-binding proteins and carnitine palmitoyl transferase I for transfer into the mitochondria. Fatty acid oxidation in cardiac muscle cells is regulated by altering the activities of ACC-2 and malonyl CoA decarboxylase. 

Although the balance between glucose and fatty acid oxidation is described in Chap. 13, it is relevant to note here that malonyl-CoA inhibits carnitine acyl transferase I (CAT-1), the enzyme that catalyzes the exchange of fatty acids for carnitine as part of the cytosol-to-matrix fatty acid transport system. Inhibition of CAT-I occurs when acetyl-CoA carboxylase is activated by insulin. By inhibiting the uptake of fatty acids into mitochondria, malonyl CoA favors the oxidation of glucose and prevents fatty acids from being oxidized at the same time as they are being synthesized. 

It may seem logical that a rise in fatty acid availability will cause an increase in the rate of fatty acid oxidation. However, the rate of oxidation of fuel is matched purely to the demand for ATP and if glucose oxidation provides sufficient ATP, the extra supply of fatty acids is not metabolized. Fatty acid oxidation can be regulated by controlling the rate at which the fatty acids enter the mitochondria, and this, in turn, is dependent on the activity of carnitine acyl transferase I. This transferase is inhibited by malonyl CoA, the production of which (by acetyl-CoA carboxylase) is stimulated by insulin. So, under conditions of hypo-insulinemia, malonyl-CoA concentrations fall and carnitine acyl transferase I is activated. This stimulates the uptake of fatty acids into the mitochondrial matrix and promotes P-oxidation. It is not so much the rise in fatty acids in the blood that stimulates P-oxidation, but the fall in insulin concentration. 

The increase in cGMP activates the cyclic-dependent protein kinase (PKG), which reduces the intracellular concentration of calcium and activates the myosin light chain phosphatase (MLCP), leading to relaxation of the vascular smooth muscle. In addition, NO can also exert a large number of effects such as inhibition of platelet adhesion and aggregation, smooth muscle prohferation, monocyte adhesion, as well as activation of glucose uptake, glycolysis, and fatty acid oxidation (for reviews, see [23, 37]). 

After uptake by the liver, free fatty acids are either P Oxidized to COj or ketone bodies or esterified to triacylglycerol and phospholipid. There is regulation of entry of fatty acids into the oxidative pathway by carnitine palmitojdtransferase-I (CPT-I), and the remainder of the fatty acid uptake is esterified. CPT-I activity is... 

When the diet contains more fatty acids than are needed immediately as fuel, they are converted to triacylglycerols in the liver and packaged with specific apolipoproteins into very-low-density lipoprotein (VLDL). Excess carbohydrate in the diet can also be converted to triacylglycerols in the liver and exported as VLDLs (Fig. 21-40a). In addition to triacylglycerols, VLDLs contain some cholesterol and cholesteryl esters, as well as apoB-100, apoC-I, apoC-II, apoC-III, and apo-E (Table 21-3). These lipoproteins are transported in the blood from the liver to muscle and adipose tissue, where activation of lipoprotein lipase by apoC-II causes the release of free fatty acids from the VLDL triacylglycerols. Adipocytes take up these fatty acids, reconvert them to triacylglycerols, and store the products in intracellular lipid droplets myocytes, in contrast, primarily oxidize the fatty acids to supply energy. Most VLDL remnants are removed from the circulation by hepatocytes. The uptake, like that for chylomicrons, is... 

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