Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.3.1.21 (CPT)
4,580 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Ethanol decreased the activity of carnitine palmitoyltransferase I and the rate of fatty acid oxidation in rat hepatocytes in short-term incubations. These effects were mimicked by acetaldehyde, the product of hepatic ethanol metabolism, and were absent when ethanol oxidation was prevented by 4-methylpyrazole. Ethanol was also able to increase intracellular malonyl-CoA levels. The results suggest that inhibition of fatty acid translocation into mitochondria may play an important role in the ethanol-induced inhibition of hepatic fatty acid oxidation.
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PMID:Short-term inhibition of carnitine palmitoyltransferase I activity in rat hepatocytes incubated with ethanol. 340 Dec 27

Recent studies suggest that the induction of peroxisomal beta-oxidation in rodents may represent an adaptive response to disturbances in hepatic lipid metabolism. The following studies were done to determine the effects of 2-hydroxy-3-propyl-4-[6-(tetrazol-5-yl)hexyloxy]acetophenone (4-THA), a tetrazole-substituted acetophenone which induces peroxisomal beta-oxidation in rodent liver, on fatty acid oxidation in vitro. In isolated hepatocytes, 4-THA inhibited the oxidation of oleate (C18:1) and decreased the mitochondrial redox state. The inhibition was more pronounced in the presence of 0.2 mM-oleate than with 0.5 mM, indicating the inhibition may be competitive. 4-THA had no effect on the oxidation of octanoate (C8:0), suggesting that the site of inhibition of oleate oxidation was the carnitine-dependent transport across the mitochondrial inner membrane. In rat liver mitochondria, 4-THA inhibited carnitine palmitoyltransferase I (CPT-I) competitively with respect to the substrate palmitoyl-CoA, increasing the apparent Km from 19 microM to 86 microM. The inhibition of CPT-I by 4-THA was independent of the concentration of the co-substrate carnitine. Whereas fasting attenuated the inhibition of CPT-I by malonyl-CoA, it did not diminish the inhibition by 4-THA. Inhibition of transferase activity by 4-THA and malonyl-CoA was attenuated in mitochondria which had been solubilized with octyl glucoside to expose the latent form of carnitine palmitoyltransferase (CPT-II), suggesting that the inhibition was specific for CPT-I. The specificity was further demonstrated in studies of mitochondrial beta-oxidation in which 4-THA inhibited the oxidation of palmitoyl-CoA but not palmitoylcarnitine. The results demonstrate that 4-THA inhibits fatty acid oxidation in rat liver in vitro at the site of transport across the mitochondrial inner membrane, CPT-I. Whether this disruption in mitochondrial oxidation is causally related to the induction of peroxisomal beta-oxidation is yet to be determined.
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PMID:Inhibition of hepatic fatty acid oxidation at carnitine palmitoyltransferase I by the peroxisome proliferator 2-hydroxy-3-propyl-4-[6-(tetrazol-5-yl) hexyloxy]acetophenone. 341 64

Culture of rat hepatocytes with etomoxir, an inhibitor of carnitine palmitoyltransferase I (CPT I), for 48 h, resulted in increased carnitine acetyltransferase (CAT) activity (74%), a marked decrease in CPT activity (82%) measured in detergent extracts, and increased activities of glucose-6-phosphate dehydrogenase (227%) and fructose-1,6-bisphosphatase (65%). Changes in CAT and CPT activities were not observed after 4 h culture with etomoxir. When hepatocytes were cultured with etomoxir and benzafibrate (a hypolipidaemic analogue of clofibrate) for 48 h, etomoxir prevented the 5-fold increase in CAT activity caused by bezafibrate, whereas bezafibrate suppressed the increase in glucose-6-phosphate dehydrogenase and fructose-bisphosphatase caused by etomoxir. However, bezafibrate did not prevent the suppression of CPT activity by etomoxir. Etomoxir inhibited palmitate beta-oxidation and ketogenesis after short-term (0-4 h) and long-term (48 h) exposure, but it caused accumulation of triacylglycerol in hepatocytes only after short-term exposure (0-4 h). These effects of etomoxir on fatty acid metabolism and suppression of CPT (after 48 h) were similar in periportal and perivenous hepatocytes, but the increases in CAT and glucose-6-phosphate dehydrogenase activities were higher in periportal than in perivenous cells. The effects of CPT I inhibitors on CAT activity and long-term suppression of CPT activity are probably mediated by independent mechanisms.
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PMID:Interactions of inhibitors of carnitine palmitoyltransferase I and fibrates in cultured hepatocytes. 342 40

The effects of prolonged ethanol feeding on both carnitine palmitoyltransferase I activity and enzyme sensitivity to inhibition by malonyl-CoA were studied in rat liver, heart, skeletal muscle and kidney cortex mitochondria. Heart and skeletal muscle enzymes showed the highest specific activity and sensitivity to malonyl-CoA. Carnitine palmitoyltransferase I in extrahepatic tissues showed no changes on ethanol feeding. Only the liver enzyme activity was altered after long term ethanol administration, by suffering a progressive decrease in activity and a parallel increase in sensitivity to malonyl-CoA. These alterations reversed after 10 days of ethanol withdrawal. These results are discussed in relation to the control of carnitine palmitoyltransferase I and the effects of ethanol on fatty acid metabolism.
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PMID:Ethanol feeding to rats reversibly decreases hepatic carnitine palmitoyltransferase activity and increases enzyme sensitivity to malonyl-CoA. 342 84

This review discusses inhibitors of fatty acid oxidation for which sites and mechanisms of inhibition are reasonably well understood. Included in this review are hypoglycin, an inhibitor of butyryl-CoA dehydrogenase (EC 1.3.99.2), 4-pentenoic acid, 2-bromooctanoic acid, and 4-bromocrotonic acid all of which inhibit mitochondrial thiolases (EC 2.3.1.9 and 2.3.1.16) as well as several inhibitors of carnitine palmitoyltransferase I (EC 2.3.1.21) as for example 2-tetradecylglycidic acid, 2-bromopalmitic acid and aminocarnitine. Most of these inhibitors of fatty acid oxidation have been shown to cause hypoglycemia in animals and some also cause hypoketonemia. The advantages and limitations of using these inhibitors in metabolic studies are discussed.
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PMID:Inhibitors of fatty acid oxidation. 355 Mar 47

The changes in long-chain fatty acid oxidation during the first 24 h after birth were studied in isolated rabbit hepatocytes and liver mitochondria. The eightfold increase in this oxidation which occurs in hepatocytes between birth and 24 h was not triggered by a concomitant decrease in long-chain fatty acid esterification. Indeed, in isolated hepatocytes from 24-h-old rabbits, the 75% inhibition of the oxidation by 2-tetradecylglycidic acid, resulted in a total redirection of oleate metabolized towards triacylglycerol synthesis. Polarographic measurements of mitochondrial respiration showed that oxidative phosphorylation and respiratory chain capacity were fully functional at birth. By contrast, in liver mitochondria isolated from newborn rabbits, the rate of oxygen consumption from palmitoyl-L-carnitine was 60% higher than from palmitoyl-CoA. Similarly palmitoyl-CoA oxidation was increased 1.5-fold in isolated mitochondria from 24-h-old rabbits. These results were in agreement with the twofold increase in the activity of hepatic carnitine palmitoyltransferase I between birth and 24 h. However it is unlikely that the twofold increase in this enzyme activity totally explained the eightfold increase in long-chain fatty acid oxidation in isolated newborn rabbit hepatocytes. It was shown that the rate of the oxidation in isolated hepatocytes was inversely related to the rate of lipogenesis. Nevertheless, malonyl-CoA concentration per se is probably not the factor involved in the regulation of the oxidation between birth and 24 h, since a 90% decrease in hepatic malonyl-CoA concentration was not associated with a stimulation of long-chain fatty acid oxidation. The more likely mechanism was the 30-fold decrease in the sensitivity of carnitine palmitoyltransferase I to malonyl-CoA inhibition.
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PMID:Regulation of fatty acid oxidation in isolated hepatocytes and liver mitochondria from newborn rabbits. 356 93

Rats were subjected to laparotomy, or laparotomy and partial hepatectomy, at 0-48 h before administration of water or medium-chain-length triacylglycerol, having been starved post-operatively. Functional hepatectomies were performed at intervals after the intragastric load. Blood ketone-body concentrations after medium-chain triacylglycerol administration and/or functional hepatectomy of these rats were compared with values obtained in starved control rats. Decreased ketonaemia in response to medium-chain triacylglycerol was observed for up to 48 h after partial hepatectomy and at 1 and 2 h after laparotomy, but not at 24 or 48 h after laparotomy. Rates of ketone-body clearance after functional hepatectomy were unaffected by prior laparotomy or partial hepatectomy. Ketonaemia after medium-chain-triacylglycerol administration was only partially blocked by inhibition of CPT I (carnitine palmitoyltransferase I). The results demonstrate sustained effects of partial hepatectomy and short-term effects of surgical stress to decrease ketonaemia via inhibition of ketogenesis at site(s) distal to CPT I.
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PMID:Ketone-body metabolism after surgical stress or partial hepatectomy. Evidence for decreased ketogenesis and a site of control distal to carnitine palmitoyltransferase I. 359 3

The effects of various inhibitors of carnitine palmitoyltransferase I were examined in mitochondria from rat liver and skeletal muscle. Three types of inhibitors were used: malonyl-CoA (reversible), tetradecylglycidyl-CoA and three of its analogues (irreversible), and 2-bromopalmitoyl-CoA (essentially irreversible when added with carnitine). Competitive binding studies between labeled and unlabeled ligands together with electrophoretic analysis of sodium dodecyl sulfate-solubilized membranes revealed that in mitochondria from both tissues all of the inhibitors interacted with a single protein. While the binding capacity for inhibitors was similar in liver and muscle (6-8 pmol/mg of mitochondrial protein) the proteins involved were of different monomeric size (Mr 94,000 and 86,000, respectively). Treatment of mitochondria with the detergent, octyl glucoside, yielded a soluble form of carnitine palmitoyltransferase and residual membranes that were devoid of enzyme activity. The solubilized enzyme displayed the same activity regardless of whether carnitine palmitoyltransferase I of the original mitochondria had first been exposed to an irreversible inhibitor or destroyed by chymotrypsin. It eluted as a single activity peak through four purification steps. The final product from both liver and muscle migrated as single band on sodium dodecyl sulfate-polyacrylamide electrophoresis with Mr of approximately 80,000. The data are consistent with the following model. The inhibitor binding protein is carnitine palmitoyltransferase I itself (as opposed to a regulatory subunit). The hepatic monomer is larger than the muscle enzyme. Each inhibitor interacts via its thioester group at the palmitoyl-CoA binding site of the enzyme but also at a second locus that is probably different for each agent and dictated by the chemical substituent on carbon 2. Disruption of the mitochondrial inner membrane by octyl glucoside causes inactivation of carnitine palmitoyltransferase I while releasing carnitine palmitoyltransferase II in active form. The latter is readily purified, is a smaller protein than carnitine palmitoyltransferase I, and has the same molecular weight in liver and muscle. It is insensitive to inhibitors where on or off the mitochondrial membrane.
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PMID:Characterization of the mitochondrial carnitine palmitoyltransferase enzyme system. I. Use of inhibitors. 359 41

Exposure of rat liver mitochondrial membranes to octyl glucoside, Triton X-100, or Tween 20 solubilized an active and tetradecylglycidyl-CoA (TG-CoA)-insensitive carnitine palmitoyltransferase (presumed to be carnitine palmitoyltransferase II). The residual membranes after octyl glucoside or Triton X-100 treatment were devoid of all transferase activity. By contrast, Tween 20-extracted membranes were still rich in transferase; this was completely blocked by TG-CoA and thus was presumed to be carnitine palmitoyltransferase I. The residual carnitine palmitoyltransferase activity disappeared from the membranes upon subsequent addition of octyl glucoside or Triton X-100 and could not be recovered in the supernatant fraction. Antibody raised against purified rat liver transferase II (Mr 80,000) recognized only this protein in immunoblots from untreated liver mitochondrial membranes containing both transferases I and II. Tween 20-extracted membranes, which contained only transferase I, did not react with the antibody. Purified transferase II from skeletal muscle (also of Mr 80,000) was readily recognized by the antiserum, suggesting antigenic similarity with the liver enzyme. These and other studies on the effects of detergents on the mitochondrial [3H]TG-CoA binding protein provide further support for the model of carnitine palmitoyltransferase proposed in the preceding paper. They suggest that: 1) carnitine palmitoyltransferases I and II in rat liver are immunologically distinct proteins; 2) transferase I is more firmly anchored into its membrane environment than transferase II; 3) association of carnitine palmitoyltransferase I with a membrane component(s) is necessary for catalytic activity. While carnitine palmitoyltransferase I is a different protein in liver and muscle, it seems likely that both tissues share the same transferase II.
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PMID:Characterization of the mitochondrial carnitine palmitoyltransferase enzyme system. II. Use of detergents and antibodies. 359 42

Livers of genetically obese Zucker rats showed, compared with lean controls, hypertrophy and enrichment in triacylglycerols, indicating that fatty acid metabolism was directed towards lipogenesis and esterification rather than towards fatty acid oxidation. Mitochondrial activities of cytochrome c oxidase and monoamine oxidase were significantly lower when expressed per g wet wt. of liver, whereas peroxisomal activities of urate oxidase and palmitoyl-CoA-dependent NAD+ reduction were unchanged. Liver mitochondria were able to oxidize oleic acid at the same rate in both obese and lean rats. For reactions occurring inside the mitochondria, e.g. octanoate oxidation and palmitoyl-CoA dehydrogenase, no difference was found between both phenotypes. Total carnitine palmitoyl-, octanoyl- and acetyl-transferase activities were slightly higher in mitochondria from obese rats, whereas the carnitine content of both liver tissue and mitochondria was significantly lower in obese rats compared with their lean littermates. The carnitine palmitoyltransferase I activity was slightly higher in liver mitochondria from obese rats, but this enzyme was more sensitive to malonyl-CoA inhibition in obese than in lean rats. The above results strongly suggest that the impaired fatty acid oxidation observed in the whole liver of obese rats is due to the diminished transport of fatty acids across the mitochondrial inner membrane via the carnitine palmitoyltransferase I. This effect could be reinforced by the decreased mitochondrial content per g wet wt. of liver. The depressed fatty acid oxidation may explain in part the lipid infiltration of liver observed in obese Zucker rats.
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PMID:Study of some factors controlling fatty acid oxidation in liver mitochondria of obese Zucker rats. 380 Sep 70


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