Effect of inhibition of fatty acid oxidation on neonatal liver carnitine content

The hypoglycaemic agent 2-tetradecylglycidic acid (compound McN-3802) caused an increase in total liver carnitine content, this being due primarily to an increase in the free carnitine pool. In the neonatal animal, this may represent a mechanism to overcome the inhibitory effect of fatty acid oxidation by the drug.

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Carnitine in the Perinatal Metabolism of Lipids I. Relationship Between Maternal and Fetal Plasma Levels of Carnitine and Acylcarnitines

PEDIATRICS ◽

10.1542/peds.67.1.95 ◽

1981 ◽

Vol 67 (1) ◽

pp. 95-100

Author(s):

Milan Novak ◽

Ellen F. Monkus ◽

Dina Chung ◽

Maria Buch

Keyword(s):

Fatty Acid ◽

Fatty Acid Oxidation ◽

Plasma Levels ◽

Umbilical Vein ◽

Maternal Plasma ◽

Free Carnitine ◽

Acid Oxidation ◽

Limited Capacity ◽

Fetal Plasma ◽

Arterial Plasma

Since premature infants have a limited capacity for fatty acid oxidation, supplementation with carnitine may improve their utilization of fat. Documentation of the source and extent of fetal carnitine reserves should explain the possible need for exogenous carnitine in the neonate. Correlation between free carnitine concentration in maternal and umbilical arterial plasma at birth (r = .45, P < .01) indicates that the initial concentration of free carnitine in the newborn depends on the maternal level. Thin-layer chromatography shows more γ-butyrobetaine in maternal than umbilical arterial plasma indicating higher availability of the precursor of carnitine biosynthesis. Elevated fatty acid oxidation in maternal tissues seems to be reflected by larger amounts of long-chain acylcarnitines in maternal plasma. Shortchain acylcarnitines, mainly acetylcarnitine, are higher in the umbilical vein than in maternal plasma (P < .01) indicating that the conceptus (the placenta or fetus) is either producing more or utilizing less acetylcarnitine. Plasma levels of carnitine rapidly decrease in premature newborns during the first three days after birth if no exogenous carnitine is given (P < .001), while no significant changes of total carnitine were detected in adult patients on total parenteral alimentation for one week. This difference indicates lower carnitine depots or limited capacity for carnitine biosynthesis in neonates. The possibility still requires further investigation that the development of the optimal rate of fatty acid oxidation in human newborns, as well as in other newborn mammals, may depend on the supply of exogenous carnitine.

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Effects of 2-mercaptoacetate in isolated liver mitochondria in vitro. Competitive inhibition of 3-hydroxybutyrate dehydrogenase and depression of the β-oxidation pathway

Biochemical Journal ◽

10.1042/bj2060053 ◽

1982 ◽

Vol 206 (1) ◽

pp. 53-59 ◽

Cited By ~ 15

Author(s):

F Bauché ◽

D Sabourault ◽

Y Giudicelli ◽

J Nordmann ◽

R Nordmann

Keyword(s):

Fatty Acid ◽

Fatty Acid Oxidation ◽

Competitive Inhibition ◽

Liver Mitochondria ◽

Inhibitory Effect ◽

Acid Oxidation ◽

Membrane Bound ◽

Energy Dependent ◽

Isolated Liver

The effects of 2-mercaptoacetate on the respiration rates induced by different substrates were studied in vitro in isolated liver mitochondria. With palmitoyl-L-carnitine or 2-oxoglutarate as the substrate, the ADP-stimulated respiration (State 3) was dose-dependently inhibited by 2-mercaptoacetate. with glutamate or succinate as the substrate. State-3 respiration was only slightly inhibited by 2-mercaptoacetate. In contrast, the oxidation rate of 3-hydroxybutyrate was competitively inhibited by 2-mercaptoacetate in both isolated mitochondria and submitochondrial particles. In uncoupled mitochondria and in mitochondria in which ATP- and GTP-dependent acyl-CoA biosynthesis was inhibited, the inhibitory effect of 2-mercaptoacetate on palmitoyl-L-carnitine oxidation was abolished; under the same conditions, however, inhibition of 3-hydroxybutyrate oxidation by 2-mercaptoacetate still persisted. These results led to the following conclusions: 2-mercaptoacetate itself enters the mitochondrial matrix, inhibits fatty acid oxidation through a mechanism requiring an energy-dependent activation of 2-mercaptoacetate and itself inhibits 3-hydroxybutyrate oxidation through a competitive inhibition of the membrane-bound 3-hydroxybutyrate dehydrogenase. This study also strongly suggests that the compound responsible for the inhibition of fatty acid oxidation is 2-mercaptoacetyl-CoA.

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The effects of chronic trimetazidine treatment on mechanical function and fatty acid oxidation in diabetic rat hearts

Canadian Journal of Physiology and Pharmacology ◽

10.1139/y07-036 ◽

2007 ◽

Vol 85 (5) ◽

pp. 527-535 ◽

Cited By ~ 8

Author(s):

Arzu Onay-Besikci ◽

Sahika Guner ◽

Ebru Arioglu ◽

Isil Ozakca ◽

A. Tanju Ozcelikay ◽

...

Keyword(s):

Fatty Acid ◽

Fatty Acid Oxidation ◽

Coronary Flow ◽

Contractile Function ◽

Inhibitory Effect ◽

Diabetic Rats ◽

Diabetic Rat ◽

Acid Oxidation ◽

Mechanical Function ◽

Oxidation Rates

Clinical and experimental evidence suggest that increased rates of fatty acid oxidation in the myocardium result in impaired contractile function in both normal and diabetic hearts. Glucose utilization is decreased in type 1 diabetes, and fatty acid oxidation dominates for energy production at the expense of an increase in oxygen requirement. The objective of this study was to examine the effect of chronic treatment with trimetazidine (TMZ) on cardiac mechanical function and fatty acid oxidation in streptozocin (STZ)-diabetic rats. Spontaneously beating hearts from male Sprague–Dawley rats were subjected to a 60-minute aerobic perfusion period with a recirculating Krebs–Henseleit solution containing 11 mmol/L glucose, 100 μU/mL insulin, and 0.8 mmol/L palmitate prebound to 3% bovine serum albumin (BSA). Mechanical function of the hearts, as cardiac output × heart rate (in (mL/min)·(beats/min)·10–2), was deteriorated in diabetic (73 ± 4) and TMZ-treated diabetic (61 ± 7) groups compared with control (119 ± 3) and TMZ-treated controls (131 ± 6). TMZ treatment increased coronary flow in TMZ-treated control (23 ± 1 mL/min) hearts compared with untreated controls (18 ± 1 mL/min). The mRNA expression of 3-ketoacyl-CoA thiolase (3-KAT) was increased in diabetic hearts. The inhibitory effect of TMZ on fatty acid oxidation was not detected at 0.8 mmol/L palmitate in the perfusate. Addition of 1 μmol/L TMZ 30 min into the perfusion did not affect fatty acid oxidation rates, cardiac work, or coronary flow. Our results suggest that higher expression of 3-KAT in diabetic rats might require increased concentrations of TMZ for the inhibitory effect on fatty acid oxidation. A detailed kinetic analysis of 3-KAT using different concentrations of fatty acid will determine the fatty acid inhibitory concentration of TMZ in diabetic state where plasma fatty acid levels are increased.

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Effect of short-term fasting on the lipolytic response to theophylline

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.1991.261.4.e500 ◽

1991 ◽

Vol 261 (4) ◽

pp. E500-E504 ◽

Cited By ~ 4

Author(s):

E. J. Peters ◽

S. Klein ◽

R. R. Wolfe

Keyword(s):

Fatty Acid ◽

Fatty Acid Oxidation ◽

Indirect Calorimetry ◽

Adenosine Receptors ◽

Plasma Concentrations ◽

Inhibitory Effect ◽

Acid Oxidation ◽

Inhibitory Influence ◽

Receptor Blockade ◽

Short Term

We investigated the hypothesis that the increase in lipolysis that occurs in short-term (86-h) fasting is due to a decreased inhibitory influence of adenosine. In normal volunteers who fasted for 14 and 86 h, the response to adenosine receptor blockade was assessed by the infusion of theophylline at a rate sufficient to produce plasma concentrations (30 microM) that blocked adenosine receptors but that were well below the threshold for inhibition of phosphodiesterase. Lipolysis was assessed by determining the rate of appearance of glycerol using D-5-glycerol infusion. Fatty acid flux was also determined by means of [1-13C]palmitate infusion, and total fatty acid oxidation was determined by indirect calorimetry. There was a mild stimulatory effect of theophylline on lipolysis at 14 h. After the subjects fasted for 86 h, theophylline infusion caused a much greater increase in both lipolysis and fatty acid oxidation. These results suggest that the inhibitory effect of adenosine on lipolysis is increased during short-term fasting.

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ESI-MS/MS measurement of free carnitine and its precursor γ-butyrobetaine in plasma and dried blood spots from patients with organic acidurias and fatty acid oxidation disorders

Molecular Genetics and Metabolism ◽

10.1016/j.ymgme.2010.06.012 ◽

2010 ◽

Vol 101 (2-3) ◽

pp. 141-145 ◽

Cited By ~ 11

Author(s):

Sonja Primassin ◽

Ute Spiekerkoetter

Keyword(s):

Fatty Acid ◽

Fatty Acid Oxidation ◽

Dried Blood Spots ◽

Free Carnitine ◽

Acid Oxidation ◽

Organic Acidurias ◽

Fatty Acid Oxidation Disorders ◽

Esi Ms ◽

Blood Spots

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Characteristics of fatty acid oxidation in rat liver homogenates and the inhibitory effect of malonyl-CoA

Biochimica et Biophysica Acta (BBA) - Lipids and Lipid Metabolism ◽

10.1016/0005-2760(78)90150-9 ◽

1978 ◽

Vol 530 (3) ◽

pp. 305-313 ◽

Cited By ~ 37

Author(s):

J.Denis McGarry ◽

Guy P. Mannaerts ◽

Daniel W. Foster

Keyword(s):

Fatty Acid ◽

Fatty Acid Oxidation ◽

Rat Liver ◽

Inhibitory Effect ◽

Acid Oxidation ◽

Malonyl Coa ◽

Liver Homogenates

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Inhibitory effect of 2-mercaptoacetate on fatty acid oxidation in the liver

FEBS Letters ◽

10.1016/0014-5793(79)80589-x ◽

1979 ◽

Vol 108 (2) ◽

pp. 465-468 ◽

Cited By ~ 6

Author(s):

Dominique Sabourault ◽

Françoise Bauché ◽

Yves Giudicelli ◽

Joseph Nordmann ◽

Roger Nordmann

Keyword(s):

Fatty Acid ◽

Fatty Acid Oxidation ◽

Inhibitory Effect ◽

Acid Oxidation

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Beneficial effects of heat-treated Enterococcus faecalis FK-23 on high-fat diet-induced hepatic steatosis in mice

British Journal Of Nutrition ◽

10.1017/s0007114514001792 ◽

2014 ◽

Vol 112 (6) ◽

pp. 868-875 ◽

Cited By ~ 8

Author(s):

Masatoshi Kondoh ◽

Takashi Shimada ◽

Kazutake Fukada ◽

Mayuko Morita ◽

Kazuhiro Katada ◽

...

Keyword(s):

Fatty Acid ◽

Hepatic Steatosis ◽

Fatty Acid Oxidation ◽

Enterococcus Faecalis ◽

High Fat Diet ◽

Inhibitory Effect ◽

Acid Oxidation ◽

Standard Diet ◽

High Fat ◽

Expression Levels

A high-fat diet (HFD) is one of the causes of hepatic steatosis. We previously demonstrated that Enterococcus faecalis FK-23 (FK-23), a type of lactic acid bacteria, exhibits an anti-obesity effect in mice fed a HFD. In the present study, we examined the effects of FK-23 on HFD-induced hepatic steatosis. Male C57BL/6 mice were divided into four groups and given one of four treatments: standard diet (SD); standard diet supplemented with FK-23 (SD+FK); HFD; or HFD supplemented with FK-23 (HFD+FK). For the administration of FK-23, the drinking water was supplemented with FK-23 at a concentration of 2 % (w/w). After 11 weeks, histological findings revealed hepatic steatosis in the liver of HFD-fed mice; however, this effect was attenuated by the administration of FK-23. The expression levels of genes involved in fatty acid oxidation in the liver tissue were significantly reduced in the HFD group compared with the SD group, but FK-23 supplementation tended to up-regulate the expression levels of these genes. Our findings show that the inhibitory effect of FK-23 against hepatic steatosis in HFD-fed mice can be explained by the prevention of fat accumulation in the liver through the modulation of the activities of genes involved in hepatic fatty acid oxidation.

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