Altered hepatic fatty acid metabolism in endotoxicosis: effect of L-carnitine on survival
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Abstract:
The activities of palmitoyl-coenzyme A (CoA) synthetase, carnitine acetyltransferase (CAT), and carnitine palmitoyltransferase (CPT) and the levels of ketone bodies, reduced coenzyme A (CoASH), carnitine, and their esters, which are involved in fatty acid metabolism, in rat liver and plasma were measured after the administration of Escherichia coli lipopolysaccharide (LPS). We also studied the effect of L-carnitine treatment before LPS administration on survival and on hepatic fatty acid metabolism. The activities of CAT and CPT and the concentrations of ketone bodies, CoA, and carnitine derivatives (except for malonyl-CoA) declined in the liver after LPS administration. The activity of palmitoyl-CoA synthetase was changed little after LPS administration, and the level of hepatic malonyl-CoA increased significantly, suggesting that LPS causes activated fatty acids to undergo esterification and lipogenesis rather than oxidation. Treatment of rats with L-carnitine before LPS greatly increased the survival rate, but did not affect enzymes that metabolize fatty acids, CoA, or carnitine derivatives in the liver. Further studies are necessary to elucidate the mechanism of the effect of carnitine on post-LPS survival.Keywords:
Coenzyme A
Lipogenesis
Fatty Acid Metabolism
Malonyl-CoA
Carnitine O-palmitoyltransferase
Acyl-CoA
A soluble extract was obtained on treatment of rat liver mitochondrial outer membranes with cholate which bound ( 14 C]malonyl‐CoA but was essentially free of carnitine palmitoyltransferase (CPT) activity. Extraction of mitochondrial inner membranes with cholate readily solubilized a CPT activity which was insensitive to malonyl‐CoA. Combination of these two extracts caused the CPT derived from inner membranes to become inhibitable by malonyl‐CoA.
Malonyl-CoA
Carnitine palmitoyltransferase I
Carnitine O-palmitoyltransferase
Inner membrane
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Carnitine O-palmitoyltransferase
Carnitine palmitoyltransferase I
Palmitoylcarnitine
Bovine serum albumin
Malonyl-CoA
Acyl-CoA
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Malonyl-CoA
Carnitine O-palmitoyltransferase
Carnitine palmitoyltransferase I
Proteolysis
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Abstract Malonyl‐CoA binding and malonyl‐CoA inhibition of carnitine palmitoyltransferase‐1 (CPT‐I) were measured in hepatic mitochondria from normal and diabetic rats and in protease‐treated mitochondria from fed rats to test the hypothesis that proteolysis represents a mechanism by which diabetes produces changes in the sensitivity of CPT‐I to inhibition by malonyl‐CoA. As in diabetes, protease treatment increased the apparent K i values for malonyl‐CoA. Palmitoyl‐CoA greatly diminished malonyl‐CoA specific binding in the mitochondrial system being studied, suggesting strong competition at the malonyl‐CoA binding site. Proteolysis decreased capacity for specific binding of malonyl‐CoA by 60–80%, but it had no effect on binding affinity. In contrast, the decreased specific binding of malonyl‐CoA seen in the diabetic state is accompanied by increased binding affinity. Furthermore, observed K d values differed from K i values by a factor of 10 or more, suggesting that measured K d and K i may represent different ligand‐protein complexes. These data suggest that alterations in inhibition of CPT‐I by malonyl‐CoA occurring in the diabetic state may involve mechanisms other than simple proteolytic removal of malonyl‐CoA binding sites.
Lipidology
Malonyl-CoA
Carnitine O-palmitoyltransferase
Proteolysis
Carnitine palmitoyltransferase I
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Malonyl-CoA
Carnitine O-palmitoyltransferase
Acyl-CoA
Carnitine palmitoyltransferase I
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The kinetics of carnitine palmitoyltransferase I (CPT I; EC 2.3.1.21) were examined in mitochondria from rat liver, heart and skeletal muscle as a function of pH over the range 6.8-7.6. In all three tissues raising the pH resulted in a fall in the Km for carnitine, no change in the Km for palmitoyl-CoA or Octanoyl-CoA, and a marked decrease in the inhibitory potency of malonyl-CoA. Studies with skeletal-muscle mitochondria established that increasing pH was accompanied by an increase in the Kd of the malonyl-CoA binding site for this ligand, coupled with a decrease in the Kd for fatty acyl-CoA species to compete for malonyl-CoA binding. Three principal conclusions are drawn. (1) The pH-induced shift in malonyl-CoA sensitivity of CPT I is not a phenomenon restricted to liver mitochondria. (2) At any given pH within the range tested, the ability of malonyl-CoA (and closely related compounds) to inhibit enzyme activity is governed by the efficiency of their binding to the malonyl-CoA site. (3) The competitive interaction between fatty acyl-CoA substrates and malonyl-CoA as regards CPT I activity is exerted at the malonyl-CoA binding site. Finally, the possibility is strengthened that the malonyl-CoA binding site is distinct from the active site of CPT I.
Malonyl-CoA
Carnitine O-palmitoyltransferase
Carnitine palmitoyltransferase I
Acyl-CoA
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Although the malonyl-CoA sensitivity of peroxisomal carnitine octanoyltransferase (COT) is reportedly lost on solubilization, we show that malonyl-CoA does inhibit the purified enzyme. Assay conditions such as buffer composition, pH, acyl-CoA substrate and the presence or absence of BSA can affect the observed inhibition. When assayed in the absence of BSA, COT shows simple competitive inhibition by malonyl-CoA. The Ki value for inhibition of purified COT is high (106 microM) compared with physiological concentrations (1-6 microM) and other short-chain acyl-CoA esters inhibit COT to the same degree. However, when COT is assayed in intact peroxisomes, the Ki for malonyl-CoA is almost 20-fold lower than found with the purified enzyme, whereas inhibition by other short-chain acyl-CoA esters does not change significantly. Several features of the inhibition of peroxisomal COT, including the specificity of malonyl-CoA over other short-chain acyl-CoA esters, resemble those of carnitine palmitoyltransferase (CPT)-I, suggesting that the regulation of COT and CPT-I in parallel may be necessary for the control of cellular fatty acid metabolism.
Malonyl-CoA
Carnitine O-palmitoyltransferase
Acyl-CoA
Carnitine palmitoyltransferase I
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The activities of carnitine palmitoyltransferases (CPTs) of mitochondrial outer and inner membranes and of peroxisomes have been studied with carnitine analogues, namely DL-thiolcarnitine, DL-sulphocarnitine and L-aminocarnitine, using palmitoyl-CoA or octanoyl-CoA as co-substrate. With sulphocarnitine, both of the mitochondrial CPTs and the malonyl-CoA-sensitive CPT of peroxisomes showed appreciable activity with palmitoyl-CoA, but relatively lower activity when octanoyl-CoA was the co-substrate. The soluble CPT of peroxisomes did not show any activity with sulphocarnitine in the presence of either acyl-CoA. With thiolcarnitine, all of the CPTs showed more activity with palmitoyl-CoA than with octanoyl-CoA. None of the CPTs showed any activity with aminocarnitine and palmitoyl-CoA, but when the acyl donor was octanoyl-CoA, both of the malonyl-CoA-sensitive CPT enzymes showed considerable activity, unlike the malonyl-CoA-insensitive CPT isoenzymes. Aminocarnitine inhibited palmitoylcarnitine formation by both of the mitochondrial CPTs and by the CPT of gradient-purified peroxisomes, but the purified peroxisomal soluble CPT was not inhibited. These results show that the interaction of CPT enzymes with carnitine analogues, as substrates or inhibitors, is influenced by the chain length of the acyl-CoA substrate, and that the use of the appropriate carnitine analogue and acyl-CoA is likely to be useful for the discrimination of the various CPT activities in CPT deficiency disorders.
Palmitoylcarnitine
Carnitine O-palmitoyltransferase
Carnitine palmitoyltransferase I
Acyl-CoA
Malonyl-CoA
Coenzyme A
Acetyl-CoA
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Acyl-CoA
Transferase
Carnitine O-palmitoyltransferase
Malonyl-CoA
Fatty Acid Metabolism
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Citations (78)
Malonyl-CoA
Carnitine O-palmitoyltransferase
Carnitine palmitoyltransferase I
Acyl-CoA
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Citations (28)