Liver carnitine synthesis

Ascorbic acid or vitamin C is found in fruits, especially citrus fruits, and in fresh vegetables. Man is one of the few mammals unable to manufacture vitamin C in the liver. It is essential for the formation of collagen as it is a cofactor for the conversion of proline and lysine residues to hydroxyproline and hydroxylysine. It is also a cofactor for carnitine synthesis, for the conversion of folic acid to folinic acid and for the hydroxylation of dopamine to form norepinephrine. Being a lactone with two hydroxyl groups which can be oxidized to two keto groups forming dehydroascorbic acid, ascorbic acid is also an anti-oxidant. By reducing ferric iron to the ferrous state in the stomach, ascorbic acid promotes iron absorption. 

Participation as a cofactor in an number of enzymatic reactions, including the synthesis of collagen, carnitine, and norepinephrine the metabolism of tryptophan, tyrosine, histamine, and cholesterol the amidation of neuropeptides and detoxification reactions in the liver... 

A specific transport protein, the carnitine-acylcarnitine translocase, moves the fatty acylcarnitine into the mitochondrial matrix while returning carnitine from the matrix to the cytoplasm. Once inside the mitochondria, another enzyme, carnitine palmitoyltransferase II (CPT II), located on the matrix side of the mitochondrial inner membrane, catalyzes the reconversion of fatty acylcarnitine to fatty acyl-CoA. Intramitochondrial fatty acyl-CoA then undergoes (3-oxidation to generate acetyl-CoA.Acetyl-CoA can enter the Kreb s cycle for complete oxidation or, in the liver, be used for the synthesis of acetoacetate and P-hydroxybutyrate (ketone bodies). 

Not all the transporters discussed above are present in aU types of mitochondria the set of activities present in mitochondria depends on the functional needs of the cells from which the mitochondria are isolated. The adenine nucleotide and phosphate transporters are present in all mitochondria thus far studied. This reflects the fact that the major function of mitochondria is the synthesis of ATP. Even in the rare instances (e.g., brown fat mitochondria [55] and mitochondria in anaerobically growing yeast [56]) where the major function is not ATP synthesis, mitochondria normally have active adenine nucleotide transport. The pyruvate transporter also appears to be ubiquitous. The carnitine transporter has been studied in liver [57], heart [35] and sperm [58] and is probably present in all mitochondria which use long-chain fatty acids. 

B. After an overnight fast, fatty acids, released from adipose tissue, serve as fuel for other tissues. Carnitine is required to transport the fatty acids into mitochondria for P-oxidation. In the liver, P-oxidation supplies acetyl CoA for ketone body (acetoacetate and 3-hydroxybutyrate) synthesis. In a carnitine deficiency, blood levels of fatty acids will be elevated and ketone bodies will be low. Consequently, the body will use more glucose, so glucose levels will be decreased. 

In muscle, most of the fatty acids undergoing beta oxidation are completely oxidized to C02 and water. In liver, however, there is another major fate for fatty acids this is the formation of ketone bodies, namely acetoacetate and b-hydroxybutyrate. The fatty acids must be transported into the mitochondrion for normal beta oxidation. This may be a limiting factor for beta oxidation in many tissues and ketone-body formation in the liver. The extramitochondrial fatty-acyl portion of fatty-acyl CoA can be transferred across the outer mitochondrial membrane to carnitine by carnitine palmitoyltransferase I (CPTI). This enzyme is located on the inner side of the outer mitochondrial membrane. The acylcarnitine is now located in mitochondrial intermembrane space. The fatty-acid portion of acylcarnitine is then transported across the inner mitochondrial membrane to coenzyme A to form fatty-acyl CoA in the mitochondrial matrix. This translocation is catalyzed by carnitine palmitoyltransferase II (CPTII Fig. 14.1), located on the inner side of the inner membrane. This later translocation is also facilitated by camitine-acylcamitine translocase, located in the inner mitochondrial membrane. The CPTI is inhibited by malonyl CoA, an intermediate of fatty-acid synthesis (see Chapter 15). This inhibition occurs in all tissues that oxidize fatty acids. The level of malonyl CoA varies among tissues and with various nutritional and hormonal conditions. The sensitivity of CPTI to malonyl CoA also varies among tissues and with nutritional and hormonal conditions, even within a given tissue. Thus, fatty-acid oxidation may be controlled by the activity and relative inhibition of CPTI. 

The control of fatty-acid oxidation is related to the availability of circulating fatty acids and the activity of palmitoyl carnitine transferase 1. When circulating fatty acids are elevated, considerable fatty-acyl CoA is formed in a number of tissues, including the liver, which is sufficient to inhibit both acetyl CoA carboxylase in the cytosol and, indirectly, pyruvate dehydrogenase in the mitochondrion. Under this condition, neither malonyl CoA nor citrate would accumulate thus, there would be a diminution of fatty-acid synthesis. When large amounts of fatty... 

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. 

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.

There is abundant evidence indicating that a natural hydrophobic inhibitor of acetyl-CoA carboxylase is present in crude enzyme extracts of liver and adipose tissue [128,129,182,192,236-238]. The activating effect of (+)-palmityl carnitine on fatty acid synthesis in crude liver extracts and on impure acetyl-CoA carboxylase preparations has tentatively been ascribed to the displacement of hydrophobic inhibitors such as fatty acids or fatty acyl-CoA derivatives [129,182,192,236-238]. Inhibition of rat liver acetyl-CoA carboxylase by added palmityl-CoA can be reversed in part by (+)-palmityl carnitine [236], but not by citrate. This activating effect does not appear to be specific with respect to (+)-palmityl carnitine in that cetyl trimethylammonium ion is also effective [192]. Furthermore, impure preparations of acetyl-CoA carboxylase from adipose tissue or rat liver are markedly activated by serum albumin [123,129,238] or extensive dilution of the enzyme preparation prior to assay [129,182]. On the other hand, none of these agents [(+)-palmityl carnitine, serum albumin, or dilution], which activate the impure carboxylase, have an activating effect on the homogeneous acetyl-CoA carboxylases from adipose tissue or liver [129,182, 239]. It is evident that an inhibitory substance, apparently hydrophobic in nature, is removed either by purification of the enzyme or by the agents or treatments mentioned above. 

L-ascorbic acid is essential for the synthesis of liver (Sayed-Ahmed carnitine (P-hydroxy-epsilon-iV-trimethyl-L- et al. 2001, Hulse... 

Lysine, like most other AAs, is a building block of body protdns. Among the indispensable AAs, lysine is present in the greatest amounts, at 93.0 and 38 mmol/dl in tissues and serum, respectively (see Table 15.3). Carnitine, a compound responsible for transport of long-chain fatty adds into the mitochondria for oxidation, is synthesized in the liver and kidneys from lysine and methionine. Lysine is also required for collagen synthesis and may be central to bone health. - Lysine s effects... 

In the second trial conducted by Murata et al. (1997), varying amounts of dietary TAG were replaced by DAG while the dietary fatty acid content was maintained at 9.39 g/100 g diet. After 21 days on the new diets, significant reductions in serum and liver TAG levels were found in the groups of rats fed diets in which DAG supplied more than 6.58 gfatty acids/100 g diet. Reductions in the activities of enzymes involved in fatty acid synthesis and increases in palmitoyl-CoA oxidation rates by both mitochondrial and peroxisomal pathways were also apparent when DAG replaced TAG in diets to supply more than 6.58 g fatty acid/100 g diet. Increasing dietary levels of DAG progressively increased the activities of enzymes involved in the P-oxidation pathway in the liver, including carnitine palmitoyltransferase (EC 2.3.1.21), acyl-CoA... 

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