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F Demaugre

Publications and source records attributed to F Demaugre.

45 records · Page 3Linked to original sources
PubMed1982

Oxidation of fatty acids in cultured fibroblasts: a model system for the detection and study of defects in oxidation.

A number of recently described inherited disorders interfere with the oxidation of fatty acids. In these disorders at least three different metabolic steps may be affected: (1) transport of long chain fatty acids into the mitochondria as in carnitine deficiency and carnitine palmitoyl transferase deficiency (CPT); (2) multiple acyl CoA dehydrogenase deficiency or glutaric aciduria type II (GAII) due presumably to a defective common electron transfering flavoprotein or iron sulfur flavoprotein; (3) specific long or medium chain fatty acyl CoA dehydrogenase deficiency as in inherited dicarboxylic aciduria. In order to develop a system for the detection and the study of the consequences of defects such as these on the oxidation of fatty acids, we investigated the metabolism of oleate (18 carbons), octanoate (eight carbons) and butyrate (four carbons) in intact cultured fibroblasts from patients with CPT deficiency, GAII, and dicarboxylic aciduria. In CPT deficient cells there was a markedly deficient ability to oxidize [1-14C] and [U-14C] oleate (19 and 5% of normal, respectively), whereas oxidations of [1-14C] octanoate and [1,4-14C] succinate were significantly increased (150 and 222%, respectively), and [1-14C] butyrate oxidation was normal. GAII cells displayed a nearly complete defect in the oxidation of [1-14C] and [U-14C] oleate (8 and 1%, respectively), as well as of [1-14C] octanoate and [1-14C] butyrate (8 and 5% of normal, respectively). The oxidation of [1,4-14C] succinate by GAII cells was normal. Cells from a patient with dicarboxylic aciduria showed a significant reduction in [14CO2] production from [U-14C] oleate (57%) and [1-14C] octanoate (31%) and a normal oxidation of [1-14C] oleate, [1-14C] butyrate, and [1,4-14C] succinate. These observations are consistent with available information on the normal metabolism of fatty acids in liver and muscle and also with the hypothesis about the molecular localization of the defects in GAII and inherited dicarboxylic aciduria. They demonstrate that intact cultured skin fibroblasts represent a reliable and convenient model for the investigation of fatty acid oxidation in man. Many aspects of the human acyl CoA dehydrogenases and their physiologic functions remain unknown, among them the problem of their acyl chain length specificity. Studies in cultured fibroblasts from patients with presumed mutations affecting the metabolism of fatty acids provide a means for the elucidation of these defects and at the same time give information on normal metabolic functions. It appears likely that a number of previously unrecognized defects in this area of metabolism remain to be found. The availability of a model system for their study in cultured fibroblasts should facilitate their discovery.

Carnitine O-Palmitoyltransferase↗
PubMed1981

Metabolic consequences of pyruvate kinase inhibition by oxalate in intact rat hepatocytes.

The effects of oxalate on glycolysis and glucose production from trioses were studied in hepatocytes isolated from fed and fasted rats. 1--In cells from fed rats oxalate inhibited glycolysis at the pyruvate kinase step, as shown by an increased phosphoenolpyruvate concentration, a decreased lactate and pyruvate production and a reduction of the glycolytic flux estimated by the rate of detritiation of [6-3H] glucose. The plot of 1/lactate production versus oxalate concentration showed that pyruvate kinase is a limiting step of glycolysis and allowed to determine the apparent inhibition constant for oxalate: about 3035 microM which is near the physiological concentration of blood oxalate. Under conditions where both pyruvate kinase and glycolytic flux are inhibited, oxalate had no effect on the synthesis of [14C] glucose from [14C] triose. 2--In hepatocytes prepared from fasted rats and incubated with lactate and pyruvate, oxalate decreased gluconeogenesis. In cells isolated from fasted rats and incubated with dihydroxyacetone, oxalate decreased lactate and pyruvate production whereas glucose synthesis remained unchanged. It is concluded that the inhibition of pyruvate kinase cannot by itself increase the gluconeogenic flux from triose.

Animals↗
PubMed1980

The metabolic effects of oxalate on intact red blood cells.

The metabolic effects of oxalate on pyruvate kinase were studied in intact human red blood cells and compared to the spontaneous modifications induced by congenital pyruvate kinase deficiency. In normal cells, oxalate (2-3 . 10(-4) M) produces a large increase of the monophosphoglycerates, phosphoenolpyruvate pool and decrease of pyruvate concentrations as a result of pyruvate kinase inhibition; it does not significantly modify 2,3-diphosphoglycerate level, ATP formation or overall glycolytic activity. Those effects of oxalate are not due to Mg2+ chelation. A similar metabolite pattern is observed in vivo in erythrocytes with congenital pyruvate kinase deficiency, in which ATP concentration and glycolytic activity are described. These cells are more sensitive to oxalate than normal ones. Results are discussed with reference to the rate-limiting character of normal or congenitally deficient pyruvate kinase.

Erythrocytes↗
PubMed1980

[Effects of dichloroacetate and 2-chloropropionate on carbohydrate metabolism of isolated hepatocytes. Therapeutic applications].

In isolated hepatocytes, dichloroacetate directly activates pyruvate dehydrogenase whereas its biotransformation product, oxalate, inhibits pyruvate carboxylase and pyruvate kinase. Dichloroacetate, which decreases blood lactate very efficiently, has been sucessfully tested in the acute treatment of congenital lactic acidosis, but its transformation into oxalate and potential chronic toxicity prompt to replace it by 2-chloropropionate as a therapeutic agent.

Acetates↗
PubMed1978

The effects of pyruvate concentration, dichloroacetate and alpha-cyano-4-hydroxycinnamate on gluconeogenesis, ketogenesis and [3-hydroxybutyrate]/[3-oxobutyrate] ratios in isolated rat hepatocytes.

1. In isolated rat hepatocytes incubated with pyruvate, ketogenesis increased with increasing pyruvate concentrations and decreased under the influence of 1 mM-alpha-cyano-4-hydroxycinnamate, a known inhibitor of pyruvate transport. Ketogenesis from pyruvate was higher by 30% in hepatocytes prepared from starved than from fed rats. 2. With pyruvate as substrate, 2 mM-dichloroacetate had no effect on ketogenesis of starved-rat hepatocytes, but increased ketogenesis of fed-rat hepatocytes to the 'starved' value. Gluconeogenesis from pyruvate, lactate and alanine, but not from glycerol, was inhibited by dichloroacetate. Both increased ketogenesis and decreased gluconeogenesis may result from an inhibition of pyruvate carboxylase by dichloroacetate. 3. Mitochondria were rapidly isolated from incubated hepatocytes, and [3-hydroxybutyrate]/[3-oxobutyrate] ratios were measured in the mitochondrial pellet ('mitochondrial' ratios) and in whole-cell suspensions ('total' ratios). Increasing pyruvate concentrations increased mitochondrial and decreased total ratios. In the presence of pyruvate (2 to 10 mM), dichloroacetate decreased mitochondrial and increased total ratios.

Acetoacetates↗
PubMedDate not supplied

[Heterogeneity of carnitine palmitoyltransferase deficiencies. Deficiency of CPT I in the hepatic form and CPT II in the muscular form].

Carnitine Palmitoyl Transferase (CPT) deficiencies are found in 2 different clinical forms: muscular and hepatic. The study of fibroblasts of 2 patients corresponding to each of these situations showed that these phenotypes are associated with different abnormalities of CPT, CPT I in the hepatic type and CPT II in the muscular type. The functional consequences of both abnormalities are different. In the hepatic type, CPT I deficiency induces a lack of long chain fatty acid (LCFA) oxidation in fibroblasts as well as, probably, in the patient's liver. In the muscular type, CPT II deficiency has no functional consequences in the fibroblast, contrary to what is observed in the patient's muscle. It is postulated that control of the mitochondrial LCFA oxidation in the liver and in the fibroblasts depends on CPT I, while it depends on CPT II in the muscle.

Acyltransferases↗