scholarly journals Flexibility of zonation of fatty acid oxidation in rat liver

1995 ◽  
Vol 311 (3) ◽  
pp. 853-860 ◽  
Author(s):  
M Guzmán ◽  
C Bijleveld ◽  
M J H Geelen
Keyword(s):  
Fatty Acid ◽  
Fatty Acid Oxidation ◽  
Carnitine Palmitoyltransferase ◽  
Physiological Status ◽  
Acid Oxidation ◽  
Acetyl Coa Carboxylase ◽  
Acetyl Coa ◽  
Palmitate Oxidation ◽  
Malonyl Coa ◽  
Carnitine Palmitoyltransferase I

Periportal and perivenous hepatocytes were isolated from rats subjected to different treatments that induce (starvation, cold exposure) or depress (refeeding after starvation) hepatic fatty acid oxidation. These experiments were designed to determine factors that may be involved in creating and maintaining the asymmetrical distribution of this metabolic pathway in the acinus of the liver. The uneven distribution of mitochondrial [14C]-palmitate oxidation within the acinus (i) was very flexible and changed markedly with the physiological status of the animal (periportal/perivenous ratio: 1.5, 2.0, 1.0 and 0.4 for fed, starved, refed and cold-exposed animals respectively), (ii) coincided with a similar zonation of carnitine palmitoyltransferase I activity in fed as well as in cold-exposed animals, (iii) was paralleled by a comparable zonation of mitochondrial 3-hydroxy-3-methyl-glutaryl-CoA synthase activity in starved animals, and (iv) was not determined by zonal differences in any of the following parameters: sensitivity of carnitine palmitoyltransferase I to malonyl-CoA, intracellular concentration of malonyl-CoA, fatty acid synthesizing capacity, acetyl-CoA carboxylase activity, fatty acid synthase activity or relative content of the two hepatic acetyl-CoA carboxylase isoforms. Unlike mitochondrial oxidation, peroxisomal [14C]palmitate oxidation was always zonated towards the perivenous zone of the liver irrespective of the physiological status of the animal. The data presented show that changes in the acinar distribution of mitochondrial long-chain fatty acid oxidation involve specific long-term mechanisms under different physiological conditions.

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.

Influence of malonyl-CoA and palmitate concentration on rate of palmitate oxidation in rat muscle

1998 ◽  
Vol 85 (5) ◽  
pp. 1909-1914 ◽  
Author(s):  
G. F. Merrill ◽  
E. J. Kurth ◽  
B. B. Rasmussen ◽  
W. W. Winder
Keyword(s):  
Skeletal Muscle ◽  
Fatty Acid ◽  
Protein Kinase ◽  
Fatty Acid Oxidation ◽  
Acid Oxidation ◽  
Acetyl Coa Carboxylase ◽  
Acetyl Coa ◽  
Palmitate Oxidation ◽  
Malonyl Coa ◽  
Amp Activated Protein Kinase

5-Aminoimidazole-4-carboxamide 1-β-d-ribofuranoside (AICAR) is taken up by perfused skeletal muscle and phosphorylated to form 5-aminoimidazole-4-carboxamide-1-β-d-ribofuraosyl-5′-monophosphate (analog of 5′-AMP) with consequent activation of AMP-activated protein kinase, phosphorylation of acetyl-CoA carboxylase, decrease in malonyl-CoA, and increase in fatty acid oxidation. This study was designed to determine the effect of increasing levels of palmitate on the rate of fatty acid oxidation. Malonyl-CoA concentration was manipulated with AICAR at different palmitate concentrations. Rat hindlimbs were perfused with Krebs-Henseleit bicarbonate containing 4% bovine serum albumin, washed bovine red cells, 200 μU/ml insulin, 10 mM glucose, and different concentrations of palmitate (0.1–1.0 mM) without or with AICAR (2.0 mM). Perfusion with medium containing AICAR was found to activate AMP-activated protein kinase in skeletal muscle, inactivate acetyl-CoA carboxylase, and decrease malonyl-CoA at all concentrations of palmitate. The rate of palmitate oxidation increased as a function of palmitate concentration in both the presence and absence of AICAR but was always higher in the presence of AICAR. These results provide additional evidence that malonyl-CoA is an important regulator of the rate of fatty acid oxidation at palmitate concentrations in the physiological range.

Metoprolol improves cardiac function and modulates cardiac metabolism in the streptozotocin-diabetic rat

2008 ◽  
Vol 294 (4) ◽  
pp. H1609-H1620 ◽  
Author(s):  
Vijay Sharma ◽  
Pavan Dhillon ◽  
Richard Wambolt ◽  
Hannah Parsons ◽  
Roger Brownsey ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Cardiac Function ◽  
Fatty Acid Oxidation ◽  
Heart Function ◽  
Carnitine Palmitoyltransferase ◽  
Acid Oxidation ◽  
Protein Kinase Activity ◽  
Palmitate Oxidation ◽  
Malonyl Coa ◽  
Carnitine Palmitoyltransferase I

The effects of diabetes on heart function may be initiated or compounded by the exaggerated reliance of the diabetic heart on fatty acids and ketones as metabolic fuels. β-Blocking agents such as metoprolol have been proposed to inhibit fatty acid oxidation. We hypothesized that metoprolol would improve cardiac function by inhibiting fatty acid oxidation and promoting a compensatory increase in glucose utilization. We measured ex vivo cardiac function and substrate utilization after chronic metoprolol treatment and acute metoprolol perfusion. Chronic metoprolol treatment attenuated the development of cardiac dysfunction in streptozotocin (STZ)-diabetic rats. After chronic treatment with metoprolol, palmitate oxidation was increased in control hearts but decreased in diabetic hearts without affecting myocardial energetics. Acute treatment with metoprolol during heart perfusions led to reduced rates of palmitate oxidation, stimulation of glucose oxidation, and increased tissue ATP levels. Metoprolol lowered malonyl-CoA levels in control hearts only, but no changes in acetyl-CoA carboxylase phosphorylation or AMP-activated protein kinase activity were observed. Both acute metoprolol perfusion and chronic in vivo metoprolol treatment led to decreased maximum activity and decreased sensitivity of carnitine palmitoyltransferase I to malonyl-CoA. Metoprolol also increased sarco(endo)plasmic reticulum Ca2+-ATPase expression and prevented the reexpression of atrial natriuretic peptide in diabetic hearts. These data demonstrate that metoprolol ameliorates diabetic cardiomyopathy and inhibits fatty acid oxidation in streptozotocin-induced diabetes. Since malonyl-CoA levels are not increased, the reduction in total carnitine palmitoyltransferase I activity is the most likely factor to explain the decrease in fatty acid oxidation. The metabolism changes occur in parallel with changes in gene expression.

Effect of phosphorylation by AMP-activated protein kinase on palmitoyl-CoA inhibition of skeletal muscle acetyl-CoA carboxylase

2005 ◽  
Vol 98 (4) ◽  
pp. 1221-1227 ◽  
Author(s):  
D. S. Rubink ◽  
W. W. Winder
Keyword(s):  
Skeletal Muscle ◽  
Fatty Acid ◽  
Protein Kinase ◽  
Fatty Acid Oxidation ◽  
Acid Oxidation ◽  
Acetyl Coa Carboxylase ◽  
Acetyl Coa ◽  
Oxidation Rates ◽  
Malonyl Coa ◽  
Amp Activated Protein Kinase

AMP-activated protein kinase (AMPK) has previously been demonstrated to phosphorylate and inactivate skeletal muscle acetyl-CoA carboxylase (ACC), the enzyme responsible for synthesis of malonyl-CoA, an inhibitor of carnitine palmitoyltransferase 1 and fatty acid oxidation. Contraction-induced activation of AMPK with subsequent phosphorylation/inactivation of ACC has been postulated to be responsible in part for the increase in fatty acid oxidation that occurs in muscle during exercise. These studies were designed to answer the question: Does phosphorylation of ACC by AMPK make palmitoyl-CoA a more effective inhibitor of ACC? Purified rat muscle ACC was subjected to phosphorylation by AMPK. Activity was determined on nonphosphorylated and phosphorylated ACC preparations at acetyl-CoA concentrations ranging from 2 to 500 μM and at palmitoyl-CoA concentrations ranging from 0 to 100 μM. Phosphorylation resulted in a significant decline in the substrate saturation curve at all palmitoyl-CoA concentrations. The inhibitor constant for palmitoyl-CoA inhibition of ACC was reduced from 1.7 ± 0.25 to 0.85 ± 0.13 μM as a consequence of phosphorylation. At 0.5 mM citrate, ACC activity was reduced to 13% of control values in response to the combination of phosphorylation and 10 μM palmitoyl-CoA. Skeletal muscle ACC is more potently inhibited by palmitoyl-CoA after having been phosphorylated by AMPK. This may contribute to low-muscle malonyl-CoA values and increasing fatty acid oxidation rates during long-term exercise when plasma fatty acid concentrations are elevated.

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.

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.

Malonyl CoA control of fatty acid oxidation in the newborn heart in response to increased fatty acid supply

2006 ◽  
Vol 84 (11) ◽  
pp. 1215-1222 ◽  
Author(s):  
Arzu Onay-Besikci ◽  
Nandakumar Sambandam
Keyword(s):  
Fatty Acids ◽  
Fatty Acid ◽  
Fatty Acid Oxidation ◽  
Acid Oxidation ◽  
Acetyl Coa Carboxylase ◽  
Myocardial Fatty Acid ◽  
Acetyl Coa ◽  
Tissue Levels ◽  
Post Surgery ◽  
Malonyl Coa

The concentration of fatty acids in the blood or perfusate is a major determinant of the extent of myocardial fatty acid oxidation. Increasing fatty acid supply in adult rat increases myocardial fatty acid oxidation. Plasma levels of fatty acids increase post-surgery in infants undergoing cardiac bypass operation to correct congenital heart defects. How a newborn heart responds to increased fatty acid supply remains to be determined. In this study, we examined whether the tissue levels of malonyl CoA decrease to relieve the inhibition on carnitine palmitoyltransferase (CPT) I when the myocardium is exposed to higher concentrations of long-chain fatty acids in newborn rabbit heart. We then tested the contribution of the enzymes that regulate tissue levels of malonyl CoA, acetyl CoA carboxylase (ACC), and malonyl CoA decarboxylase (MCD). Our results showed that increasing fatty acid supply from 0.4 mmol/L (physiological) to 1.2 mmol/L (pathological) resulted in an increase in cardiac fatty acid oxidation rates and this was accompanied by a decrease in tissue malonyl CoA levels. The decrease in malonyl CoA was not related to any alterations in total and phosphorylated acetyl CoA carboxylase protein or the activities of acetyl CoA carboxylase and malonyl CoA decarboxylase. Our results suggest that the regulatory role of malonyl CoA remained when the hearts were exposed to high levels of fatty acids.

Sign in / Sign up

Export Citation Format

Share Document