Palmitoyl-carnitine activity

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... 

Figure 6. Effect of glycerol-3-phosphate (G3P) addition on carnitine palmitoyltransferase I specific activity in highly purified mitochondrial fractions (HPMF) as the palmitoyl-CoA/albumin ratios assayed. Values are expressed as nmol of palmitoyl-carnitine (palm-carnitine) synthesized / min per mg of protein, (open circles) HPMF, (open squares) addition of 0.5 mM G3P. Results are representative of four independent experiments.

The steps in the subsequent utilization of muscle LCFAs may be summarized as follows. The free fatty acids, liberated from triglycerides by a neutral triglyceride lipase, are activated to form acyl CoAs by the mediation of LCFAcyl-CoA synthetase which is situated on the outer mitochondrial membrane. The next step involves carnitine palmitoyl transferase I (CPT I, see Figure 9) which is also located on the outer mitochondrial membrane and catalyzes the transfer of LCFAcyl residues from CoA to carnitine (y-trimethyl-amino-P-hydroxybutyrate). LCFAcyl... 

Hepatocytes isolated from male Wistar rats (180-250 g) were treated with 0.2 mM mono(2-ethylhexyl) phthalate or 1 mM 2-ethylhexanol for 48 h (Gray et al., 1982). Both di(2-ethylhexyl) phthalate metabolites increased carnitine acetyltransferase activity about nine-fold. In studies with hepatocytes from male Sprague-Dawley rats (180-220 g), treatment with 0.2 mM mono(2-ethylhexyl) phthalate and 1.0 mM 2-ethylhexanol for 48 h resulted in induction of carnitine acetyltransferase activity about 15-fold and six-fold, respectively (Gray et al., 1983). Mono(2-ethylhexyl) phthalate was also shown to induce cyanide-insensitive palmitoyl-CoA oxidation and, by ultra-structural examination, to increase numbers of peroxisomes. Hepatocytes were isolated from Wistar-derived rats (180-220 g) and treated for 72 h with 0-0.5 mM mono(2-ethylhexyl) phthalate and some mono(2-ethylhexyl) phthalate metabolites (Mitchell etal., 1985). Treatment with mono(2-ethylhexyl) phthalate and metabolites VI and IX (see Figure 1) resulted in a concentration-dependent induction of cyanide-insensitive palmitoyl-CoA oxidation. In addition, 0-0.5 mM mono(2-ethylhexyl) phthalate and 0-1.0 mM metabolite VI produced concentration-dependent increases in lauric acid hydroxylation. Treatment with metabolites I and V resulted in only small effects on the enzymatic markers of peroxisome proliferation. In another study with hepatocytes from Wistar-derived rats (180-220 g), metabolite VI was shown by subjective ultrastructural examination to cause proliferation of peroxisomes (Elcombe Mitchell, 1986). 

Sutton, S.C., E.L. LeCluyse, L. Cammack, and J.A. Fix. 1992. Enhanced bioavailability of cefoxitin using palmitoyl L-carnitine. I. Enhancer activity in different intestinal regions. Pharm Res 9 191. 

Rat (Sprague- Dawley) 5 d 1x/d (GO) Hepatic 10 100 (increased liver weight and activity of palmitoyl CoA oxidase and carnitine acetyl transferase) Dostal et al. 1987a ... 

Hepatic Effects. No studies were located regarding hepatic effects in humans after oral exposure to DEHP. Limited information on hepatic effects in humans exposed to DEHP is available from studies of dialysis patients and cultured human hepatocytes. In one individual there was an increased number of liver peroxisomes after 1 year, but not after 1 month of treatment (Ganning et al. 1984, 1987). A serious limitation of this observation is that repeat biopsies were not obtained from the same patient, so that an appropriately controlled analysis is not possible. Additionally, analysis of liver biopsies from patients receiving other kinds of hypolipidemic drugs has not yielded any evidence for peroxisomal proliferation (Doull et al. 1999). Recognizing some limitations of using primary hepatocytes in vitro because of their tendency to lose some metabolic capabilities (Reid 1990), in cultured human hepatocytes there were no changes in the activities of peroxisomal palmitoyl-CoA oxidase and/or carnitine acetyltransferase when... 

This reaction is catalyzed by palmitoyl-CoA-camitine acyltransferase and does not require ATP. The acyl-CoA is sufficiently "activated" to be able to react with carnitine. 

In animals, the production of CO2 from [ Cjpalmitate or octanoate is not consistendy affected by riboflavin deficiency, possibly as a result of increased activity of carnitine palmitoyl transferase, which is more a response to food deprivation than to riboflavin deficiency. However, the production of C02 from [ C] adipic acid is significandy reduced, and responds rapidly (with some overshoot) to repletion with the vitamin. It has been suggested that the abiUty to metabolize a test dose of [ Cjadipic acid may provide a sensitive means of investigating ribodavin nutritional status in human beings (Bates, 1989, 1990). 

Fatty acids are activated on the outer mitochondrial membrane, whereas they are oxidized in the mitochondrial matrix. A special transport mechanism is needed to carry long-chain acyl CoA molecules across the inner mitochondrial membrane. Activated long-chain fatty acids are transported across the membrane by conjugating them to carnitine, a zwitterionic alcohol. The acyl group is transferred from the sulfur atom of CoA to the hydroxyl group of carnitine to form acyl carnitine. This reaction is catalyzed by carnitine acyltransferase I (also called carnitine palmitoyl transferase I), which is bound to the outer mitochondrial membrane. 

This hepatomegaly is correlated to PPARa activation of acyl-CoA oxidase (AOX), the first enzyme of peroxisomal /3-oxidation of fatty acids and a gene with a PPRE in its promoter region14. In addition, hepatic mitochondrial /3-oxidation and microsomal w-oxidation of fatty acids are increased, as a direct result of PPARa activation of mRNA of specific enzymes associated with these pathways (carnitine palmitoyl transferase I and cytochrome P4504A, respectively). Activation of fatty acid oxidation by these three pathways would lead to enhanced fatty acid oxidation, given the appropriate substrate. PPARa has also been shown to enhance delivery of fatty acids to the oxidizing systems (Fig. 3). 

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