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PubMed2001

Deafferentation of the septo-hippocampal pathway in rats as a model of the metabolic events in Alzheimer's disease.

Changes in the metabolic activity within the brain of patients suffering from Alzheimer's disease (AD) were investigated and compared with biochemical alterations in the hippocampus induced by fimbria/fornix transection in the rat. The deafferentation of the hippocampus results in a degeneration of cholinergic septo-hippocampal terminals accompanied by a persistent decrease of choline acetyltransferase (ChAT) and acetylcholine esterase (AChE) activities similar to the cholinergic malfunction in AD. In the animal model the [3H]-cytochalasin B binding to the glucose transporters was elevated up to the day 7 after surgery as was the activity of the phosphofructokinase (PFK) on day 3. A reactive astrogliosis could be evidenced by the upregulation of glial fibrillary acidic protein (GFAP). An increase of the PFK activity was also found in AD being accompanied by enhanced level of GFAP as well. A higher concentration of mRNA for all three isoenzymes of PFK was shown by reverse transcription (RT)-real time polymerase chain reaction (PCR) amplification. However, the pattern of PFK isoenzyme proteins and mRNAs did neither change in diseased human nor in the lesioned rat brain. The activities of the mitochondrial enzymes pyruvate dehydrogenase complex (PDHC) and cytochrome c oxidase (CO) were diminished in the lesioned rat hippocampus on day 7 as well as in AD brain. Subcellular fractionation showed that the activity of these enzymes was affected in the synaptosomal as well as in the extrasynaptosomal mitochondria indicating a loss of neuronal input and also a vulnerability of intrinsic hippocampal neurons and/or non-neuronal cells. The recovery of the mitochondrial enzyme activity in the animal model at later post lesion intervals may be the result of compensatory responses of surviving cells or of sprouting of other non-affected inputs. It is concluded that common metabolic mechanisms may underlie the concurrent degenerative and repair processes in the denervated hippocampus and the diseased Alzheimer brain.

Acetylcholinesterase↗
PubMed1991

Characteristic changes on brain CT in a case of Leigh encephalopathy with deficiency of pyruvate dehydrogenase.

A girl aged 23 months of Leigh encephalopathy with pyruvate dehydrogenase complex (PDHC) deficiency was reported. Brain CT scan showed atrophy of the frontal and parietal cortex, low density in the midbrain and putamina, and rounded caudatum. CT change was showed from rounded to atrophic caudatum during a three-month period. The rounded caudatum may be an early CT finding in Leigh encephalopathy.

Brain↗
PubMed1995

Stimulation of non-oxidative glucose utilization by L-carnitine in isolated myocytes.

The effects of L-carnitine on 14CO2 release from [1-14C]pyruvate oxidation (an index of pyruvate dehydrogenase activity, PDH), [2-14C]pyruvate, and [6-14C]glucose oxidation (indices of the acetyl-CoA flux through citric acid cycle), and [U-14C]glucose (an index of both PDH activity and the flux of acetyl-CoA through the citric acid cycle), were studied using isolated rat cardiac myocytes. L-carnitine increased the release of 14CO2 from [1-14C]pyruvate, and decreased that of [2-14C]pyruvate in a time and concentration-dependent manner. At a concentration of 2.5 mM, L-carnitine produced a 50% increase of CO2 release from [1-14C]pyruvate and a 50% decrease from [2-14C]pyruvate oxidation. L-carnitine also increased CO2 release from [1-14C]pyruvate oxidation by 35%, and decreased that of [2-14C]pyruvate oxidation 30%, in isolated rat heart mitochondria. The fatty acid oxidation inhibitor, etomoxir, stimulated the release of CO2 from both [1-14]pyruvate and [2-14C]pyruvate. These results were supported by the effects of L-carnitine on the CO2 release from [6-14C]- and [U-14C]glucose oxidation. L-carnitine (5 mM) decreased the CO2 release from [6-14C]glucose by 37%, while etomoxir (50 microM) increased its release by 24%. L-carnitine had no effect on the oxidation of [U-14C]glucose. L-carnitine increased palmitate oxidation in a time- and concentration-dependent manner in myocytes. Also, it increased the rate of efflux of acetylcarnitine generated from pyruvate in myocytes. These results suggest that L-carnitine stimulates pyruvate dehydrogenase complex activity and enhances non-oxidative glucose metabolism by increasing the mitochondrial acetylcarnitine efflux in the absence of exogenous fatty acids.

Acetylcarnitine↗
PubMed1982

Dichloroacetate tissue concentrations and its relationship to hypolactatemia and pyruvate dehydrogenase activation.

Following a single oral dose of DCA to laboratory rats, peak hepatic tissue DCA concentration occurred at 3 hr. When given chronically for 7 days, DCA caused activation of the pyruvate dehydrogenase complex which returned to basal activity 24 hr following the final dose. Hepatic tissue DCA concentrations were maximally increased at 3 hr following the final dose, and the drug was eliminated slowly over 72 hr with a half-life of 9.74 hr. Liver and muscle showed similar DCA tissue concentrations following chronic administration.

Acetates↗
PubMedDate not supplied

Multiple effects of amobarbital on Ehrlich ascites tumor cells. Inhibition of pyruvate dehydrogenase.

The inhibition of the proliferation of hyperdiploid Ehrlich ascites tumor cells in suspension cultures by amobarbital is coupled to an increased glycolytic activity as shown by lactic acid production and glucose consumption; higher concentrations of amobarbital than 1 mM enhance the ATP/ADP ratio of the total cell. The actual activity of pyruvate dehydrogenase of intact cells is completely inhibited in the presence of 2 mM amobarbital as was shown by the 14CO2 evolution from [114C]pyruvate or the incorporation of 14CO2 into the total lipid fraction of the cells from [U-14C]lactate. The pyruvate dehydrogenase complex from Ehrlich ascites tumor cells is completely inhibited by 1 mM amobarbital in vitro. The activity of alpha-oxoglutarate dehydrogenase is inhibited by amobarbital, too, as well as shown by measuring the 14CO2 evolution from [1-14C]glutamate with intact cells. It is suggested that the inhibition of pyruvate dehydrogenase in the presence of amobarbital is the result of a direct action on the enzyme as well as the consequence of a change in the cellular redox state or its energy charge.

Adenosine Diphosphate↗
PubMed1993

Effects of blockade of fatty acid oxidation on whole body and tissue-specific glucose metabolism in rats.

We examined the effect of the long-chain fatty acid oxidation blocker methyl palmoxirate (methyl 2-tetradecyloxiranecarboxylate, McN-3716) on glucose metabolism in conscious rats. Fasted animals [5 h with or without hyperinsulinemia (100 mU/l) and 24 h] received methyl palmoxirate (30 or 100 mg/kg body wt po) or vehicle 30 min before a euglycemic glucose clamp. Whole body and tissue-specific glucose metabolism were calculated from 2-deoxy-[3H]-glucose kinetics and accumulation. Oxidative metabolism was assessed by respiratory gas exchange in 24-h fasted animals. Pyruvate dehydrogenase complex activation was determined in selected tissues. Methyl palmoxirate suppressed whole body lipid oxidation by 40-50% in 24-h fasted animals, whereas carbohydrate oxidation was stimulated 8- to 10-fold. Whole body glucose utilization was not significantly affected by methyl palmoxirate under any conditions; hepatic glucose output was suppressed only in the predominantly gluconeogenic 24-h fasted animals. Methyl palmoxirate stimulated glucose uptake in heart in 24-h fasted animals [15 +/- 5 vs. 220 +/- 28 (SE) mumol x 100 g-1 x min-1], with smaller effects in 5-h fasted animals with or without hyperinsulinemia. Methyl palmoxirate induced significant activation of pyruvate dehydrogenase in heart in the basal state, but not during hyperinsulinemia. In skeletal muscles, methyl palmoxirate suppressed glucose utilization in the basal state but had no effect during hyperinsulinemia; pyruvate dehydrogenase activation in skeletal muscle was not affected by methyl palmoxirate under any conditions. The responses in skeletal muscle are consistent with the operation of a mechanism similar to the Pasteur effect.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

Combinatorial autoantibodies to dihydrolipoamide acetyltransferase, the major autoantigen of primary biliary cirrhosis.

mRNA from a regional lymph node of a patient with primary biliary cirrhosis (PBC) was used to construct a combinatorial immunoglobulin library in the lambda phage vector system. Six human monoclonal IgG Fab clones (LC1-LC6) specific for the major autoantigen of PBC--dihydrolipoamide acetyltransferase, the E2 subunit of the pyruvate dehydrogenase complex (PDC-E2)--were isolated, appearing at a frequency of 0.01% in the combinatorial immunoglobulin library. These Fab clones recognize human PDC-E2 with high affinity (Ka = 10(-7)-10(-9) M-1). Using both immunoblotting and ELISA, LC1-LC6 showed little cross-reactivity to any of the other autoantigens commonly recognized by PBC sera or to other antigens commonly recognized by PBC sera or to other antigens such as histone, calf thymus DNA, and bovine serum albumin. The Fab monoclonal antibodies show a typical anti-mitochondrial staining pattern in HEp-2 cells but react strongly with the luminal aspect of biliary epithelial cells of patients with PBC. Our results demonstrate that a recombinant combinatorial immunoglobulin library can be used to isolate high-affinity Fabs against a specific autoantigen. Such reagents will facilitate the analysis of immunoglobulin gene structure, idiotype, and antigen-antibody interactions in autoimmune disease.

Acetyltransferases↗
PubMed1990

Pyruvate dehydrogenase activities and rates of lipogenesis during the fed-to-starved transition in liver and brown adipose tissue of the rat.

The percentages of pyruvate dehydrogenase complex (PDH) in the active form (PDHa) in two lipogenic tissues (liver and brown adipose tissue) in the fed state were 12.0% and 13.4% respectively. After acute (0.5 h) insulin treatment, PDHa activities had increased by 77% in liver and by 234% in brown fat. Significant decreases in PDHa activities were observed in both tissues by 5 h after the removal of food. The patterns of decline in PDHa activities in the two lipogenic tissues were similar in that the major decreases in activities were observed within the first 7 h of starvation. The significant decreases in PDHa activities observed after starvation for 6 h were accompanied by decreased rates of lipogenesis. Hepatic and brown-fat PDHa activities after acute (30 min) exposure to exogenous insulin were less in 6 h-starved than in fed rats, but the absolute increases in PDHa activities over the 30 min exposure period were similar in fed and 6 h-starved rats. Increases in PDHa activities were paralleled by increases in lipid synthesis in both tissues. Re-activation of PDH in response to insulin treatment or chow re-feeding after 48 h starvation occurred more rapidly in brown adipose tissue than in liver. The results are discussed in relation to the importance of the activity of the PDH complex as a determinant of the total rate of lipogenesis during the fed-to-starved transition and after insulin challenge or re-feeding.

Adipose Tissue, Brown↗
PubMed1999

Adult leigh syndrome: treatment with intravenous soybean oil for acute central respiratory failure.

This study reports a 38-year-old woman with adult Leigh syndrome associated with partial deficiency of the pyruvate dehydrogenase complex. The patient had intermittent diplopia, loss of vision, dystonia, central respiratory failure and unconsciousness with lactic acidosis. Treatment with an intravenous ketogenic emulsion resulted in rapid clinical and biochemical improvement. In patients with acute respiratory failure under these circumstances, intravenous ketogenic emulsion therapy is worth consideration.

Acute Disease↗
PubMed1994

Familial mitochondrial encephalopathy with fetal ultrasonographic ventriculomegaly and intracerebral calcifications.

In two sibs antenatal ultrasonography revealed identical intracranial calcification, ventricular widening and microcephaly. The first pregnancy was artificially terminated at 19 weeks. Post-mortem examination of the brain revealed destructive calcification and extracerebral neuronal heterotopia. The second sib went to term but died 48 h after birth from irreversible lactic acidosis. Autopsy showed extensive encephalopathy with cavitation and calcification in the cerebral hemispheres, polymicrogyria, multiple neuronal heterotopia, partial callosal dysgenesis, and severe Leigh syndrome, together forming a continuum of early and late brain disruption. Mitochondrial respiratory chain abnormalities, mainly affecting complexes I and IV, and deficiency of pyruvate dehydrogenase complex were detected in skeletal muscle and in liver. A normal functioning of the respiratory chain was found in the fibroblasts. Analysis of mtDNA from muscle, liver and blood revealed normal amounts of intact mtDNA without any of the known point mutations associated with MELAS, MERRF or Leigh syndromes. The early fetal disruption and necrotic changes in the brains of sibs indicate a specific genetically determined disorder which affects neuronal migration, a finding not previously associated with respiratory chain disorders. The present disorder may mimic antenatal congenital infectious encephalopathy because of the combined finding of microcephaly and destructive intracerebral calcification.

Brain↗
PubMed2003

The clinical spectrum of mitochondrial disease in 75 pediatric patients.

The clinical presentation of mitochondrial disorders in childhood is highly variable causing difficulties in diagnosis and management. We assessed records of 75 children (48 male, 27 female) with a biochemically and/or molecularly established mitochondrial disorder in a retrospective, multicentric study. The predominant biochemical defect was an isolated respiratory chain complex IV, followed by respiratory chain complex I, combined respiratory chain, and isolated pyruvate dehydrogenase complex (PDHC) deficiencies. For the 75 patients, the predominant clinical presentations were a nonspecific encephalomyopathy (n = 34) and Leigh syndrome (n = 17). Classical mitochondrial syndromes with associated mutations of the mitochondrial DNA were rare (n = 12). Eleven children had a lethal infantile mitochondrial disease (LIMD). This group comprised a considerable variety of clinical pictures, and the cohort was big enough to show the high frequency and wide spectrum of nonneuromuscular symptoms in mitochondrial disorders in childhood.

Adolescent↗
PubMed1999

Transcription factor GCN4 for control of amino acid biosynthesis also regulates the expression of the gene for lipoamide dehydrogenase.

The yeast LPD1 gene encoding lipoamide dehydrogenase is subject to the general control of amino acid biosynthesis mediated by the GCN4 transcription factor. This is striking in that it demonstrates that GCN4-mediated regulation extends much farther upstream than simply to the direct pathways for amino acid and purine biosynthesis. In yeast, lipoamide dehydrogenase functions in at least three multienzyme complexes: pyruvate dehydrogenase and 2-oxoglutarate dehydrogenase (which function in the entry of pyruvate into, and metabolism via, the citric acid cycle) and glycine decarboxylase. When wild-type cells were shifted from growth on amino acid-rich to amino acid-deficient medium, the expression of lipoamide dehydrogenase was induced approx. 2-fold. In a similar experiment no such induction was observed in isogenic gcn4 mutant cells. Northern analysis indicated that amino acid starvation affected levels of the LPD1 transcript. In the upstream region of LPD1 are three matches to the consensus for control mediated by GCN4. Directed mutagenesis of each site, and of all combinations of sites, suggests that only one site might be important for the general control response under the conditions tested. Gel-retardation analysis with GCN4 protein synthesized in vitro has indicated that GCN4 can bind in vitro to at least two of the consensus motifs.

Amino Acid Sequence↗
PubMed1998

Biotransformation of nitroso aromatic compounds and 2-oxo acids to N-hydroxy-N-arylacylamides by thiamine-dependent enzymes in rat liver.

The formation of N-hydroxy-N-arylacylamides from nitroso aromatic compounds and 2-oxo acids was investigated using rat liver subcellular fractions. Activities were found in both mitochondria and cytosol, except for activities for phenylpyruvate and glyoxylate; the former did not produce N-hydroxy-N-phenylphenylacetamide and the latter nonenzymatically produced N-hydroxy-N-phenylformamide with nitrosobenzene (NOB). The cytosolic activity of N-hydroxy-N-phenylglycolamide formation was indicated to be due to transketolase, which utilized hydroxypyruvate as a glycolic aldehyde donor to NOB. With mitochondria, 2-oxo acids (including hydroxypyruvate) served as substrates for the biotransformation of NOB to the corresponding N-hydroxy-N-phenylacylamides. The substrate preference was 2-oxobutyrate > pyruvate > 2-oxoisovalerate > 2-oxoisocaproate > 2-oxovalerate > 2-oxo-3-methylvalerate, judging from Vmax/half-saturating concentration for mitochondria values. The half-saturating concentrations for NOB were nearly constant. The mitochondrial activity was due to pyruvate dehydrogenase complex and branched-chain 2-oxo acid dehydrogenase complex (BCDHC). By using partially purified BCDHC, pyruvate and 2-oxobutyrate were found to be common substrates for both of the enzymes, and 2-oxoisovalerate was shown to be the most effective substrate for BCDHC. Analysis by the Taft equation indicated that the polar effects, rather than the steric effects, of the alkyl groups of 2-oxo acids are important for BCDHC-catalyzed formation of N-hydroxy-N-phenylacylamides. A positive Hammett constant obtained for the formation of N-hydroxy-N-arylisobutyramides indicates that an electron-withdrawing substituent makes the nitroso compounds susceptible to BCDHC-catalyzed biotransformation.

Animals↗
PubMed2002

Clinical significance of positive immunoblotting but negative immunofluorescence for antimitochondrial antibodies in patients with liver diseases other than primary biliary cirrhosis.

The serum reaction to anti-2-oxo-acid dehydrogenase complex (2-OADC) enzymes, the antigens recognized by antimitochondrial antibodies (AMA), can be detected by immunoblotting in patients with liver diseases other than primary biliary cirrhosis (PBC), who are negative for AMA by conventional indirect immunofluorescence. Whether the presence of anti-2-OADC is related to PBC or represents preclinical PBC in such patients is obscure at present. We examined the immunoreactivity of AMA by immunofluorescense, immunoblotting, and enzyme inhibition assay in serum samples from 59 patients with liver diseases other than PBC and 71 healthy subjects. We also examined the clinical course of the patients in whom a positive result was obtained to elucidate whether such reaction was a "true" or "false" phenomenon. None of the 130 sera was positive for AMA by indirect immunofluorescence or for anti-pyruvate dehydrogenase complex (PDC) by enzyme inhibition assay. However, seven of 71 (10%) sera from healthy subjects contained weak IgG class antibody to PDC-E2 (four sera) or E2 subunit of branched-chain oxo-acid dehydrogenase complex (BCOADC-E2) (three sera). Of the 59 sera from patients with liver diseases other than PBC, four (7%) reacted against 2-OADC by immunoblotting. Of these, three sera were from patients with chronic hepatitis C virus (HCV) infection, and contained IgG class autoantibody to BCOADC-E2. The serum reactivity to BCOADC-E2 detected by immunoblotting in these three patients diminished after absorption with recombinant BCOADC-E2 fusion protein. During the 3-5 year follow-up period, AMA by immunofluorescence and anti-PDC activity by enzyme inhibition assay were always negative in these three patients. The other one serum was from patient with alcoholic cirrhosis, and contained IgM class autoantibody to E3 binding protein (E3-BP). This patient did not develop PBC during the following 2 years. Our results showed that anti-2-OADC antibodies could be detected in some patients with liver diseases other than PBC, and even in healthy individuals. The clinical significance of the presence of these serum reactions is obscure at this stage, but the production of anti-BCOADC-E2 may be linked to the presence of HCV in certain patients. Further prospective studies of larger population should clarify whether anti-2-OADC reaction can precede the clinical development of PBC.

3-Methyl-2-Oxobutanoate Dehydrogenase (Lipoamide)↗
PubMed1996

Tissue-specific expression of the human pyruvate dehydrogenase alpha (Pdha-1)/chloramphenicol acetyltransferase fusion gene in transgenic mice.

A chimeric gene (-763/+33Pdha-1/CAT) containing -763/+33 nucleotides o f the human pyruvate dehydrogenase gene (Pdha-1) and the structural gene of chloramphenicol acetyltransferase (CAT) was used to generate transgenic mice. CAT activity was detected predominantly in the brain followed in decreasing order by adipose tissue, spleen, heart, kidney and liver. Developmental expression of CAT activity in the testes was similar to that of the endogenous Pdha-1 subunit expression in the testes. Dietary regulation of the transgene was comparable to the expression of endogenous pyruvate dehydrogenase complex in kidney and adipose tissue. Thus, the -763/+33 bp segment of the human Pdha-1 gene is transcriptionally active in vivo and can direct the expression of CAT in several tissues.

Adipose Tissue↗
PubMed2001

Differential effects of two mutations at arginine-234 in the alpha subunit of human pyruvate dehydrogenase.

The most common mutation in the alpha subunit of the pyruvate dehydrogenase (E1) component of the human pyruvate dehydrogenase complex (PDC) is arginine-234 to glycine and glutamine in 12 and 3 patients, respectively. Interestingly, these two mutations at the same amino acid position cause E1 (and hence PDC) deficiency by apparently different mechanisms. Recombinant human R234Q E1 had similar V(max) (25.7 +/- 4.4 units/mg E1) and apparent K(m) (101 +/- 4 nM) values for TPP as recombinant wild-type human E1, while R234G E1 had no significant change in V(max) (33.6 +/- 4.7 units/mg E1) but had a 7-fold increase in its apparent K(m) value for TPP (497 +/- 25 nM). Both of the R234 mutant proteins had similar apparent K(m) values for pyruvate. Both R234Q and R234G mutant proteins displayed similar phosphorylation rates of sites 1 and 2 by pyruvate dehydrogenase kinase 2 (PDK2) and site 3 by PDK1 compared to wild-type E1. Phosphorylated R234Q E1, R234G E1, and wild-type E1 also had similar dephosphorylation rates of sites 1 and 2 by phosphopyruvate dehydrogenase phosphatase 1. The rate of dephosphorylation of site 3 was about 50% for R234Q E1 and without a significant change for R234G E1 compared to the wild type. The data indicate that the patients with the R234G E1 mutation are symptomatic due to a decreased ability of this mutant protein to bind TPP, whereas the patients with the R234Q E1 mutation are symptomatic due to a decreased rate of dephosphorylation of site 3, hence keeping the enzyme in a phosphorylated/inactivated form.

Amino Acid Substitution↗
PubMed1998

Immunological features of patients with primary biliary cirrhosis (PBC) overlapping systemic sclerosis: a comparison with patients with PBC alone.

To characterize the immunological features of patients with primary biliary cirrhosis (PBC) overlapping systemic sclerosis (SSc), 26 patients with PBC were classified according to the presence of scleroderma-related features (Raynaud's phenomenon, sclerodactyly etc.). The patients were classified into 10 patients with PBC overlapping SSc (PBC-SSc), four patients with some scleroderma-related features although not meeting the criteria of SSc (PBC-SSc spectrum) and 12 patients with PBC alone. Sera from PBC-SSc showed a significantly higher positivity to anti-centromere antibody (P< 0.01) and to E1beta of pyruvate dehydrogenase complex (P< 0.005) than those from patients with PBC alone. The same tendency was observed in PBC-SSc spectrum patients. Patients with PBC exhibiting scleroderma-related features, in both the PBC-SSc and PBC-SSc spectrum, may comprise a subset in PBC, not only clinically, but also immunologically.

Adult↗
PubMed2003

Severe lactic acidosis due to thiamine deficiency in a patient with B-cell leukemia/lymphoma on total parenteral nutrition during high-dose methotrexate therapy.

An 11-month-old girl with B-cell leukemia/lymphoma developed profound lethargy due to severe lactic acidosis during chemotherapy and total parenteral nutrition (TPN). Initial treatment with NaHCO3 was ineffective. Treatment with a vitamin cocktail (OH-cobalamin, pyridoxine, thiamine, riboflavine, biotin, carnitine) at pharmacologic doses rapidly improved the child's clinical and laboratory status. Lactic acidosis was caused by an impairment of pyruvate dehydrogenase complex, which was due to lack of its necessary cofactor thiamine in the TPN. This case report indicates that lactic acidosis may be a front-line diagnosis in patients on TPN with lethargy and outlines the need for monitoring thiamine supply in TPN.

Acidosis, Lactic↗