Index

A-Oxidation of phytanic acid, 273-281 peroxisomal, 283-299 ABC transporters, 262-263, 290 in a-oxidation of phytanic acid, 275-276 Acetoacetate, 2, 155, 233 effect of valproic acid on circulating levels, 180 Acetoacetyl-CoA inhibitor of 2-enoyl-CoA hydratase, 135 substrate for hydroxymethylglutaryl-CoA synthase, 235-236 Acetoacetyl-CoA thiolase, 150 in ketogenesis, 243 Acetyl-carnitine, 147, 149,155-159, 164 Acetyl-CoA, ix, 145, 147, 148, 149, 162, 163, 399 inhibitor of carnitine palmitoyl...

Discussion

MCAD deficiency is one of the most common inborn errors of metabolism. It is generally believed that treatment of this condition is simple and prognosis is good once diagnosis is established. A study of 120 cases showed that no patient died after diagnosis, however there were significant sequelae in those patients who survived the initial episode of decompensation.2 Early recognition through newborn screening programs aimed to prevent mortality and reduce sequelae of the disease. However, two...

Effects Of Scad Deficiency On Other Metabolic Pathways

As mentioned, human patients with acyl-CoA dehydrogenase deficiencies share the disease features of hypoglycemia, hyperammonemia, tissue fatty change, hypoketonemia, carnitine deficiency and organic acidemia due to apparent disruption of normal fatty acid, glucose and urea metabolism. Most of the acute clinical episodes occur in young children. These episodes are precipitated by fasting and are often fatal with the in vivo mechanisms essentially unknown. Since the genes of the rate controlling...

Studies To Investigate Mechanisms Of Disease

In human patients with SCAD or MCAD deficiency the common features include hypoglycemia, hyperammonemia, metabolic acidosis, organic acidemia and a fatty change of liver.4,15,16,17 As stated previously there are no overt clinical signs reported in these mice however, they do show several biochemical and pathological features. We have found that upon fasting SCAD deficient mice under 8 weeks of age that the blood glucose will drop in half as compared to normal controls.3 In our experience,...

Glucocorticoids and Fat Mobilisation a Response to Stress

We can more easily understand the logic of the synergistic interactions of the GR and PPAR RXR signal pathways on mHS gene expression, when we realise that one of the functions of glucocorticoid release into the blood is in the response of starvation stress.21 Starvation partly parallels the situations of the suckling neonate or the adult on a high fat low carbohydrate diet in that all three situations result in elevated plasma free fatty acid concentrations.22,23 In the case of starvation,...

References

Beinert H. (1963) Acyl-CoA dehydrogenases, Boyer PD, Lardy H. & Myrback K. eds. The Enzymes, Academic Press New York. 7 447-66. 2. Kelly D.P., Kim J.-J.P., Bffladello J.J., Hainline B.E., Chu T.W. & Strauss A.W. (1987) Nucleotide sequence of medium-chain acyl-coenzyme A dehydrogenase mRNA and its expression in enzyme-deficient human tissue. Proc Natl Acad Sci 84 4068-72. 3. Matsubara Y., Krauss J.P., Ozasa H., Glassberg R., Finocchiaro G., Ikeda Y. & Mole J. et al. (1987) Molecular...

Results And Discussion

Biochemical studies in fibroblasts from the index patient showed that the rate of -oxidation of myristate and palmitate was severely decreased to less than 5 of the controls Table 1 . Enzyme measurements of the very-long chain acyl-CoA dehydrogenase, enoyl-CoA hydratase, 3-hydroxyacyl-CoA dehydrogenase, thiolase, carnitine palmitoyltransferase I and II showed normal activities not shown . The severe deficiency of long chain fatty acid oxidation was explained by the complete deficiency of CAC...

Molecular Genetic Considerations

In our opinion, the model of choice to study a genetic deficiency is a knockout model. This implies that the model animal has to be a mouse,31 since only in murine embryonic stem cells it has been possible to efficiently create the desired genetic alterations while pertaining these cells pluripotent, a prerequisite for proper embryonic development. Thus, in contrast to transgenic model systems, which in principle can be generated in any mammalian species by means of oocyte microinjection, the...

Info

Only defects in the liver-type enzyme are documented. ' ' ' In these patients hepatic problems dominate, i.e., hypoketotic hypoglycemia under circumstances where an increase in P-oxidation is called upon. These primary metabolic consequences in L-CPT1 defects can lead to hepatomegaly, encephalopathy, coma, and sudden death. Apart from malfunctioning of other organ systems, transient cardiac arrhythmia,20 tachycardia21 and cardiomegaly21,22 in cases of L-CPT1 deficiency have been observed. These...

Transport Of Fatty Acylcarnitine Across The Liver Microsomal Membrane

Having CATa and CATB on either side of the microsomal membrane appears to serve no obvious purpose unless, by analogy with the well-characterized mitochondrial system,14-18 these are linked to some form of transport system to move fatty acylcarnitines across the membrane. It is impractical to study directly the transport of radiolabelled long-chain fatty acylcarnitines into or out of sealed microsomal vesicles because these metabolites bind non-specifically to many cellular proteins. We,...

Confocal Laser Scanning Microscopy Of Human Skin Fibroblasts Showing Transient Expression Of A Green Fluorescent

Roelofsen1, K. E. Niezen-Koning, E. A. A. Nollen2, and J. R. G. Kuipers Department of Pediatrics department of Internal Medicine Department of Radiobiology Groningen Utrecht Institute for Drug Exploration Groningen University, Groningen The Netherlands The mitochondrial outer membrane enzyme carnitine palmitoyltransferase 1 CPT1 is a main site of regulation of intracellular long-chain fatty acid transport. At least two isoforms of CPT1 are expressed in the body L-CPT1...

T

T increased compared to controls unchanged compared to controls i decreased compared to controls ND not determined T increased compared to controls unchanged compared to controls i decreased compared to controls ND not determined these effects on lipogenesis, and consequently TG-biosynthesis, is not self-evident. On one hand, an inhibition of two of the enzymes involved in fatty acid synthesis is consistent with a retarded lipogenesis. On the other hand, the finding that the activity of the...

Fatty Acids Regulate the Mitochondrial Synthase Gene Expression Mediated by PPAR Localization of the PPRE

There is considerable evidence that fatty acids can activate PPAR as potently as peroxisome proliferators do.15-17 On the other hand, previous results in our laboratory revealed that fatty acids induce an increase in the mitochondrial HMG-CoA synthase mRNA levels18 and gene transcription.19 We were therefore interested in determining whether fatty acids could have a role in the regulation of the mitochondrial HMG-CoA synthase gene expression mediated by PPAR. Figure 1 shows that the highest...