Jean-Pierre Draye

The glyconeogenicity of fatty acids in mammals

Although excess glucose can be readily converted to fatty acids in mammals, most textbooks state that glucose cannot be formed from fatty acids. Whilst this remains largely true, several pathways have now been discovered in mammals in which fatty acids are potentially gluconeogenic.

Comparison between the formation and the oxidation of dicarboxylylcarnitine esters in rat liver and skeletal muscle: possible implications for human inborn disorders of mitochondrial beta-oxidation.

SummaryThe activity of dicarboxylyl-CoA synthetase previously reported in rat liver was detected, in the presence of added detergents, in rat skeletal muscle. In both tissues, carnitine dicarboxylyltransferase activities were recorded but their substrate chain length specificity was, however, different. In rat skeletal muscle, but not liver, a carnitine-dependent oxidation by intact mitochondria of dodecanedioyl-CoA was easily detected by the spectrophotometric measurement of the substrate-dependent ferricyanide reduction.The implications of the present data for the pathogenesis of disorders with excess urine dicarboxylylcarnitine esters are discussed.

Peroxisomal Disorders of Lipid Catabolism

Peroxisomes are subcellular organelles which contain a series of enzymes generating H2O2 as well as catalase, to destroy this peroxide. Their morphology is most variable from organ to organ, as well as their content in H2O2-generating oxidases. They possess a few enzymes necessary for lipid synthesis, as the key enzymes for initiating the formation of etherlipids (see previous chapters), 3-hydroxy-3-methylglutaryl- CoA reductase, and they are able to form dolichol. Their role in lipid catabolism will be summarized here. In addition mammalian peroxisomes possess a D-aminoacid oxidase and participate, among others, in the intermediary metabolism of L-aminoacids. For instance, they contain alanine:glyoxylate transaminase, the deficiency of which is responsible for hyperoxaluria type I (Danpure & Jennings 1987). Another characteristic of these organelles is their response to several physiological or pathological conditions, to hypolipidaemic drugs and various xenobiotics. This response consists usually in the proliferation of the peroxisomal population with enhancement of its beta-oxidizing capacity. An excellent book on peroxisomes in biology and medicine has been edited recently by Fahimi and Sies (1987).

Beta-Oxidation of Omega-Hydroxymonocarboxylic Acids in Rat Liver Peroxisomes and Mitochondria

The long- and medium- chain omega-hydroxymonocarboxylic acids, intermediates in the omega-oxidation of fatty acids, were activated by rat liver homogenates into their acyl-CoA derivatives. The omega-hydroxymonocarboxylyl-CoAs were substrates for both rat liver mitochondrial carnitine-dependent (oxygen uptake) and peroxisomal (1st step: hydrogen peroxide production; 3rd step: NAD+ reduction) fatty acid oxidation. Medium-chain omegahydroxymonocarboxylic acids were oxidized by rat liver coupled but not uncoupled mitochondria. The subcellular distribution of omega-hydroxyacyl-CoA oxidase and dehydrogenase reactions were studied in Percoll fractions demonstrating that both peroxisomes and mitochondria contain oxidoreductases active on omega-hydroxyfatty acids. The mitochondrial but not the peroxisomal oxidation of omega hydroxyacids was strongly reduced by millimolar concentrations of valproic acid. The pathogenesis of several inborn errors of metabolism caracterised by dicarboxylicaciduria could be explained by the beta-oxidizing fate of the omegaoxidation intermediates and products, here reported.

Mammalian Metabolism of Phytanic Acid : Recent Findings

Phytanic acid, a xenobiotic compound, is a saturated C20 branched chain fatty acid which, because of the existence of a beta-methyl substitution cannot directly undergo beta-oxidation. A preliminary alpha-oxidizing decarboxylation takes place, after which the methyl group occupies the alpha position (1–4). The alpha-oxidation of phytanic acid is catalysed by phytanate oxidase and consists of the alpha-hydroxylation of phytanic acid into L-2-hydroxyphytanic acid which is further converted to pristanic acid and carbon dioxide (scheme 1). Conversely to phytanic acid (3,7,11-15-tetramethylhexadecanoic acid), pristanic acid (2,6,10,14-etramethylpentadecanoic acid) is a substrate for beta-oxidation.

The Metabolism of Dicarboxylic Acids in Rat Liver

In mammals, the beta-oxidation of fatty acids was thought to be the prerogative of mitochondria until the demonstration by Lazarow and de Duve (1) that rat liver peroxisomes also contain beta-oxidizing enzymes. The distinction between mitochondrial and peroxisomal fatty acid oxidation includes the specialisation of the latter system in the shortening of very long-chain acids (2–4), the oxidation of polyunsaturated fatty acids (5–7), cleavage of the cholesterol side chain (8–10) and the catabolism of prostaglandins (11,12). Conversely to beta-oxidation, the omega-oxidation of fatty acids does not require coenzyme A (13). It consists of the omega-hydroxylation of fatty acids followed by the oxidation of the resulting alcohol group to a carboxyl group (14–16). In vivo studies disclosed that omega-oxidation of long-chain monocarboxylic acids and beta-oxidation of the corresponding dicarboxylic acids are the basis of medium-chain dicarboxylicaciduria (17–18). We have previously demonstrated that rat liver contains a dicarboxylyl-CoA synthetase active on substrates having more than five carbon atoms (19). This paper deals with the respective contributions of peroxisomes and mitochondria to the catabolism of long-chain saturated dicarboxylyl-CoA esters. Arguments for the involvement of both organelles in the breakdown of long-chain dicarboxylates are presented.