scholarly journals Induction of ketogenesis and fatty acid oxidation by glucagon and cyclic AMP in cultured hepatocytes from rabbit fetuses. Evidence for a decreased sensitivity of carnitine palmitoyltransferase I to malonyl-CoA inhibition after glucagon or cyclic AMP treatment

1989 ◽  
Vol 264 (1) ◽  
pp. 93-100 ◽  
Author(s):  
J P Pégorier ◽  
M V Garcia-Garcia ◽  
C Prip-Buus ◽  
P H Duée ◽  
C Kohl ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Cyclic Amp ◽  
Fatty Acid Oxidation ◽  
Acid Oxidation ◽  
Cultured Hepatocytes ◽  
Long Chain Fatty Acid ◽  
Fetal Hepatocytes ◽  
Malonyl Coa ◽  
Carnitine Palmitoyltransferase I ◽  
Cpt I

The effects of pancreatic hormones and cyclic AMP on the induction of ketogenesis and long-chain fatty acid oxidation were studied in primary cultures of hepatocytes from fetal and newborn rabbits. Hepatocytes were cultivated during 4 days in the presence of glucagon (10(-6) M), forskolin (2 x 10(-5) M), dibutyryl cyclic AMP (10(-4) M), 8-bromo cyclic AMP (10(-4) M) or insulin (10(-7) M). Ketogenesis and fatty acid metabolism were measured using [1-14C]oleate (0.5 mM). In hepatocytes from fetuses at term, the rate of ketogenesis remained very low during the 4 days of culture. In hepatocytes from 24-h-old newborn, the rate of ketogenesis was high during the first 48 h of culture and then rapidly decreased to reach a low value similar to that measured in cultured hepatocytes from term fetuses. A 48 h exposure to glucagon, forskolin or cyclic AMP derivatives is necessary to induce ketone body production in cultured fetal hepatocytes at a rate similar to that found in cultured hepatocytes from newborn rabbits. In fetal liver cells, the induction of ketogenesis by glucagon or cyclic AMP results from changes in the partitioning of long-chain fatty acid from esterification towards oxidation. Indeed, glucagon, forskolin and cyclic AMP enhance oleate oxidation (basal, 12.7 +/- 1.6; glucagon, 50.0 +/- 5.5; forskolin, 70.6 +/- 5.4; cyclic AMP, 77.5 +/- 3.4% of oleate metabolized) at the expense of oleate esterification. In cultured fetal hepatocytes, the rate of fatty acid oxidation in the presence of cyclic AMP is similar to the rate of oleate oxidation present at the time of plating (85.1 +/- 2.6% of oleate metabolized) in newborn rabbit hepatocytes. In hepatocytes from term fetuses, the presence of insulin antagonizes in a dose-dependent fashion the glucagon-induced oleate oxidation. Neither glucagon nor cyclic AMP affect the activity of carnitine palmitoyltransferase I (CPT I). The malonyl-CoA concentration inducing 50% inhibition of CPT I (IC50) is 14-fold higher in mitochondria isolated from cultured newborn hepatocytes (0.95 microM) compared with fetal hepatocytes (0.07 microM), indicating that the sensitivity of CPT I decreases markedly in the first 24 h after birth. The addition of glucagon or cyclic AMP into cultured fetal hepatocytes decreased by 80% and 90% respectively the sensitivity of CPT I to malonyl-CoA inhibition. In the presence of cyclic AMP, the sensitivity of CPT I to malonyl-CoA inhibition in cultured fetal hepatocytes is very similar to that measured in cultured hepatocytes from 24-h-old newborns.

scholarly journals Evidence that the sensitivity of carnitine palmitoyltransferase I to inhibition by malonyl-CoA is an important site of regulation of hepatic fatty acid oxidation in the fetal and newborn rabbit. Perinatal development and effects of pancreatic hormones in cultured rabbit hepatocytes

1990 ◽  
Vol 269 (2) ◽  
pp. 409-415 ◽  
Author(s):  
C Prip-Buus ◽  
J P Pegorier ◽  
P H Duee ◽  
C Kohl ◽  
J Girard
Keyword(s):  
Fatty Acid ◽  
Cyclic Amp ◽  
Fatty Acid Oxidation ◽  
Carnitine Palmitoyltransferase ◽  
Acid Oxidation ◽  
Fetal Hepatocytes ◽  
Malonyl Coa ◽  
Carnitine Palmitoyltransferase I ◽  
Cpt I ◽  
Hepatic Fatty Acid Oxidation

The temporal changes in oleate oxidation, lipogenesis, malonyl-CoA concentration and sensitivity of carnitine palmitoyltransferase I (CPT 1) to malonyl-CoA inhibition were studied in isolated rabbit hepatocytes and mitochondria as a function of time after birth of the animal or time in culture after exposure to glucagon, cyclic AMP or insulin. (1) Oleate oxidation was very low during the first 6 h after birth, whereas lipogenesis rate and malonyl-CoA concentration decreased rapidly during this period to reach levels as low as those found in 24-h-old newborns that show active oleate oxidation. (2) The changes in the activity of CPT I and the IC50 (concn. causing 50% inhibition) for malonyl-CoA paralleled those of oleate oxidation. (3) In cultured fetal hepatocytes, the addition of glucagon or cyclic AMP reproduced the changes that occur spontaneously after birth. A 12 h exposure to glucagon or cyclic AMP was sufficient to inhibit lipogenesis totally and to cause a decrease in malonyl-CoA concentration, but a 24 h exposure was required to induce oleate oxidation. (4) The induction of oleate oxidation by glucagon or cyclic AMP is triggered by the fall in the malonyl-CoA sensitivity of CPT I. (5) In cultured hepatocytes from 24 h-old newborns, the addition of insulin inhibits no more than 30% of the high oleate oxidation, whereas it stimulates lipogenesis and increases malonyl-CoA concentration by 4-fold more than in fetal cells (no oleate oxidation). This poor effect of insulin on oleate oxidation seems to be due to the inability of the hormone to increase the sensitivity of CPT I sufficiently. Altogether, these results suggest that the malonyl-CoA sensitivity of CPT I is the major site of regulation during the induction of fatty acid oxidation in the fetal rabbit liver.

Regulation of cardiac malonyl-CoA content and fatty acid oxidation during increased cardiac power

2005 ◽  
Vol 289 (3) ◽  
pp. H1033-H1037 ◽  
Author(s):  
Kristen L. King ◽  
Isidore C. Okere ◽  
Naveen Sharma ◽  
Jason R. B. Dyck ◽  
Aneta E. Reszko ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Protein Kinase ◽  
Fatty Acid Oxidation ◽  
Acid Oxidation ◽  
Cardiac Power ◽  
Malonyl Coa ◽  
Ampk Activity ◽  
Carnitine Palmitoyltransferase I ◽  
Cpt I ◽  
Amp Activated Protein Kinase

Myocardial fatty acid oxidation is regulated by carnitine palmitoyltransferase I (CPT I), which is inhibited by malonyl-CoA. Increased cardiac power causes a fall in malonyl-CoA content and accelerated fatty acid oxidation; however, the mechanism for the decrease in malonyl-CoA is unclear. Malonyl-CoA is formed by acetyl-CoA carboxylase (ACC) and degraded by malonyl-CoA decarboxylase (MCD); thus a fall in malonyl-CoA could be due to activation of MCD, inhibition of ACC, or both. This study assessed the effects of increased cardiac power on malonyl-CoA content and ACC and MCD activities. Anesthetized pigs were studied under control conditions and during increased cardiac power in response to dobutamine infusion and aortic constriction alone, under hyperglycemic conditions, or with the CPT I inhibitor oxfenicine. An increase in cardiac power was accompanied by increased myocardial O2 consumption, decreased malonyl-CoA concentration, and increased fatty acid oxidation. There were no differences among groups in activity of ACC or AMP-activated protein kinase (AMPK), which physiologically inhibits ACC. There also were no differences in Vmax or Km of MCD. Previous studies have demonstrated that AMPK can be inhibited by protein kinase B (PKB); however, PKB was activated by dobutamine and the elevated insulin that accompanied hyperglycemia, but there was no effect on AMPK activity. In conclusion, the fall in malonyl-CoA and increase in fatty acid oxidization that occur with increased cardiac work were not due to inhibition of ACC or activation of MCD, suggesting alternative regulatory mechanisms for the work-induced decrease in malonyl-CoA concentration.

scholarly journals 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

1988 ◽  
Vol 252 (2) ◽  
pp. 409-414 ◽  
Author(s):  
P S Foxworthy ◽  
P I Eacho
Keyword(s):  
Fatty Acid ◽  
Fatty Acid Oxidation ◽  
Carnitine Palmitoyltransferase ◽  
Acid Oxidation ◽  
Beta Oxidation ◽  
Mitochondrial Inner Membrane ◽  
Malonyl Coa ◽  
Carnitine Palmitoyltransferase I ◽  
Cpt I

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.

scholarly journals Effect of pH on malonyl-CoA inhibition of carnitine palmitoyltransferase I

1983 ◽  
Vol 212 (2) ◽  
pp. 521-524 ◽  
Author(s):  
T W Stephens ◽  
G A Cook ◽  
R A Harris
Keyword(s):  
Fatty Acid ◽  
Fatty Acid Oxidation ◽  
Intracellular Ph ◽  
Carnitine Palmitoyltransferase ◽  
Acid Oxidation ◽  
Effect Of Ph ◽  
Malonyl Coa ◽  
Carnitine Palmitoyltransferase I ◽  
Ph Dependent ◽  
Hepatic Fatty Acid Oxidation

Malonyl-CoA inhibition of carnitine palmitoyltransferase I was found to be very pH-dependent. Malonyl-CoA concentrations causing 50% inhibition (I50) at pH 6.0, 6.5, 7.0, 7.5 and 8.0 were 0.04, 1, 9, 40 and 200 microM respectively. It is suggested that a lowering of intracellular pH, such as might occur in ketoacidosis, may attenuate hepatic fatty acid oxidation by increasing malonyl-CoA sensitivity of carnitine palmitoyltransferase I.

scholarly journals Two mechanisms produce tissue-specific inhibition of fatty acid oxidation by oxfenicine

1985 ◽  
Vol 227 (2) ◽  
pp. 651-660 ◽  
Author(s):  
T W Stephens ◽  
A J Higgins ◽  
G A Cook ◽  
R A Harris
Keyword(s):  
Fatty Acid ◽  
Amino Acid ◽  
Fatty Acid Oxidation ◽  
Carnitine Palmitoyltransferase ◽  
Partial Purification ◽  
Acid Oxidation ◽  
Branched Chain Amino Acid ◽  
Malonyl Coa ◽  
Carnitine Palmitoyltransferase I ◽  
Branched Chain

Oxfenicine [S-2-(4-hydroxyphenyl)glycine] is transaminated in heart and liver to 4-hydroxyphenylglyoxylate, an inhibitor of fatty acid oxidation shown in this study to act at the level of carnitine palmitoyltransferase I (EC 2.3.1.21). Oxfenicine was an effective inhibitor of fatty acid oxidation in heart, but not in liver. Tissue specificity of oxfenicine inhibition of fatty acid oxidation was due to greater oxfenicine transaminase activity in heart and to greater sensitivity of heart carnitine palmitoyltransferase I to inhibition by 4-hydroxyphenylglyoxylate [I50 (concentration giving 50% inhibition) of 11 and 510 microM for the enzymes of heart and liver mitochondria, respectively]. Branched-chain-amino-acid aminotransferase (isoenzyme I, EC 2.6.1.42) was responsible for the transamination of oxfenicine in heart. A positive correlation was found between the capacity of various tissues to transaminate oxfenicine and the known content of branched-chain-amino-acid aminotransferase in these tissues. Out of three observed liver oxfenicine aminotransferase activities, one may correspond to asparagine aminotransferase, but the major activity could not be identified by partial purification and characterization. As reported previously for malonyl-CoA inhibition of carnitine palmitoyltransferase I, 4-hydroxyphenylglyoxylate inhibition of this enzyme was found to be very pH-dependent. In striking contrast with the kinetics of malonyl-CoA inhibition, 4-hydroxyphenylglyoxylate inhibition was not affected by oleoyl-CoA concentration, but was partially reversed by increasing carnitine concentrations.

Metabolic response to an acute jump in cardiac workload: effects on malonyl-CoA, mechanical efficiency, and fatty acid oxidation

2008 ◽  
Vol 294 (2) ◽  
pp. H954-H960 ◽  
Author(s):  
Lufang Zhou ◽  
Hazel Huang ◽  
Celvie L. Yuan ◽  
Wendy Keung ◽  
Gary D. Lopaschuk ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Energy Expenditure ◽  
Fatty Acid Oxidation ◽  
Mechanical Efficiency ◽  
Acid Oxidation ◽  
Acetyl Coa Carboxylase ◽  
Acetyl Coa ◽  
Malonyl Coa ◽  
High Workload ◽  
Carnitine Palmitoyltransferase I

Inhibition of myocardial fatty acid oxidation can improve left ventricular (LV) mechanical efficiency by increasing LV power for a given rate of myocardial energy expenditure. This phenomenon has not been assessed at high workloads in nonischemic myocardium; therefore, we subjected in vivo pig hearts to a high workload for 5 min and assessed whether blocking mitochondrial fatty acid oxidation with the carnitine palmitoyltransferase-I inhibitor oxfenicine would improve LV mechanical efficiency. In addition, the cardiac content of malonyl-CoA (an endogenous inhibitor of carnitine palmitoyltransferase-I) and activity of acetyl-CoA carboxylase (which synthesizes malonyl-CoA) were assessed. Increased workload was induced by aortic constriction and dobutamine infusion, and LV efficiency was calculated from the LV pressure-volume loop and LV energy expenditure. In untreated pigs, the increase in LV power resulted in a 2.5-fold increase in fatty acid oxidation and cardiac malonyl-CoA content but did not affect the activation state of acetyl-CoA carboxylase. The activation state of the acetyl-CoA carboxylase inhibitory kinase AMP-activated protein kinase decreased by 40% with increased cardiac workload. Pretreatment with oxfenicine inhibited fatty acid oxidation by 75% and had no effect on cardiac energy expenditure but significantly increased LV power and LV efficiency (37 ± 5% vs. 26 ± 5%, P < 0.05) at high workload. In conclusion, 1) myocardial fatty acid oxidation increases with a short-term increase in cardiac workload, despite an increase in malonyl-CoA concentration, and 2) inhibition of fatty acid oxidation improves LV mechanical efficiency by increasing LV power without affecting cardiac energy expenditure.

scholarly journals The role of changes in the sensitivity of hepatic mitochondrial overt carnitine palmitoyltransferase in determining the onset of the ketosis of starvation in the rat

1996 ◽  
Vol 318 (3) ◽  
pp. 767-770 ◽  
Author(s):  
Lesley DRYNAN ◽  
Patti A. QUANT ◽  
Victor A. ZAMMIT
Keyword(s):  
Fatty Acid ◽  
Fatty Acid Oxidation ◽  
Time Course ◽  
Ketone Body ◽  
Serum Insulin ◽  
Carnitine Palmitoyltransferase ◽  
Acid Oxidation ◽  
Malonyl Coa ◽  
Cpt I ◽  
Body Concentration

The relationships between the increase in blood ketone-body concentrations and several parameters that can potentially influence the rate of hepatic fatty acid oxidation were studied during progressive starvation (up to 24 h) in the rat in order to discover whether the sensitivity of mitochondrial overt carnitine palmitoyltransferase (CPT I) to malonyl-CoA plays an important part in determining the intrahepatic potential for fatty acid oxidation during the onset of ketogenic conditions. A rapid increase in blood ketone-body concentration occurred between 12 and 16 h of starvation, several hours after the marked fall in hepatic malonyl-CoA and in serum insulin concentrations and doubling of plasma non-esterfied fatty acid (NEFA) concentration. Consequently, both the changes in hepatic malonyl-CoA and serum NEFA preceded the increase in blood ketone-body concentration by several hours. The maximal activity of CPT I increased gradually throughout the 24 h period of starvation, but the increases did not become significant before 18 h of starvation. By contrast, the sensitivity of CPT I to malonyl-CoA and the increase in blood ketone-body concentration followed an identical time course, demonstrating the central importance of this parameter in determining the ketogenic response of the liver to the onset of the starved state.

Carnitine palmitoyltransferase I control of acetogenesis, the major pathway of fatty acid β-oxidation in liver of neonatal swine

2010 ◽  
Vol 298 (5) ◽  
pp. R1435-R1443 ◽  
Author(s):  
Xi Lin ◽  
Kwanseob Shim ◽  
Jack Odle
Keyword(s):  
Fatty Acid ◽  
Ketone Bodies ◽  
Carnitine Palmitoyltransferase ◽  
Acid Oxidation ◽  
Major Pathway ◽  
Malonyl Coa ◽  
Suckling Piglets ◽  
Carnitine Palmitoyltransferase I ◽  
Newborn Pigs ◽  
Cpt I

To examine the regulation of hepatic acetogenesis in neonatal swine, carnitine palmitoyltransferase I (CPT I) activity was measured in the presence of varying palmitoyl-CoA (substrate) and malonyl-CoA (inhibitor) concentrations, and [1-14C]-palmitate oxidation was simultaneously measured. Accumulation rates of 14C-labeled acetate, ketone bodies, and citric acid cycle intermediates within the acid-soluble products were determined using radio-HPLC. Measurements were conducted in mitochondria isolated from newborn, 24-h (fed or fasted), and 5-mo-old pigs. Acetate rather than ketone bodies was the predominant radiolabeled product, and its production increased twofold with increasing fatty acid oxidation during the first 24-h suckling period. The rate of acetogenesis was directly proportional to CPT I activity. The high activity of CPT I in 24-h-suckling piglets was not attributable to an increase in CPT I gene expression, but rather to a large decrease in the sensitivity of CPT I to malonyl-CoA inhibition, which offset a developmental decrease in affinity of CPT I for palmitoyl-CoA. Specifically, the IC50 for malonyl-CoA inhibition and Km value for palmitoyl-CoA measured in 24-h-suckling pigs were 1.8- and 2.7-fold higher than measured in newborn pigs. The addition of anaplerotic carbon from malate (10 mM) significantly reduced 14C accumulation in acetate ( P < 0.003); moreover, the reduction was much greater in newborn (80%) than in 24-h-fed (72%) and 5-mo-old pigs (55%). The results demonstrate that acetate is the primary product of hepatic mitochondrial β-oxidation in Sus scrofa and that regulation during early development is mediated primarily via kinetic modulation of CPT I.

Sign in / Sign up

Export Citation Format

Share Document