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Biomedical subjects

A Munnich

Publications and source records attributed to A Munnich.

At least 505 records · Page 28Linked to original sources
PubMed1985

Dependence of hepatocyte-specific gene expression on cell-cell interactions in primary culture.

In co-culture with non-parenchymal liver epithelial cells, rat hepatocytes show a marked increase in albumin and total protein synthesis when compared with cells maintained as pure populations in which an early decline in albumin secretion takes place. Analysis of the relative amounts of different mRNA sequences, determined by hybridization, indicated that the increase in protein synthesis resulted essentially from an increased level of the corresponding mRNAs. In addition, when cell-cell contacts were established between the two cell types several days after the seeding of hepatocytes, the stimulation of albumin secretion was similarly observed with a significant increase of the corresponding mRNA on days 10-14 of culture. Transcriptional assays, in which isolated nuclei were used for the study of RNA synthesis, showed that liver-specific gene transcription was significantly increased and maintained for at least 2 weeks. These results demonstrate for the first time long-term stabilization and reversibility of various specific mRNAs at high levels by adult hepatocytes in primary culture. They suggest that establishment of cell-cell contacts between hepatocytes and liver epithelial cells are essential for the maintenance of a high rate of transcription of the liver-specific genes.

Albumins↗
PubMed1985

Dietary and hormonal regulation of aldolase B gene expression.

Aldolase B is an enzyme of the glycolytic pathway whose activity and mRNA levels in the liver fluctuate according to dietary status. Both the enzyme activity and the mRNA concentration decline during fasting and increase four- to eightfold upon refeeding of a carbohydrate-rich diet. The mechanism, however, of the mRNA induction remains unknown. To elucidate the mechanisms that regulate this induction responsive to dietary stimuli, we have studied the roles of hormones and glycolytic substrates on aldolase B gene expression in three tissues that synthesize the enzyme. Using a cDNA probe complementary to rat aldolase B mRNA, we determined the amount of cytoplasmic RNAs in the liver, kidney, and small intestine of normal, adrenalectomized, thyroidectomized, diabetic, and glucagon- or cAMP-treated animals refed either a fructose-rich or a maltose-rich diet. The in vivo hormonal control of gene expression was found to be very different in the three organs tested. In the liver, cortisone and thyroid hormones were required for the induction of the specific mRNA by carbohydrates, while in the kidney none of the hormonal modifications tested altered the level of mRNA induction. In the liver, but not in the kidney, diabetes and glucagon administration abolished the induction of aldolase B mRNAs in animals refed the maltose-rich diets. In the small intestine, only diabetes and thyroidectomy affected the gene expression. Finally, no induction occurred when normal fasted rats were given any of the hormones. Thus, the in vivo hormonal control of liver aldolase B gene expression differs significantly from that of kidney and small intestine. In the liver, the mRNA induction requires the presence of dietary carbohydrates, of permissive hormones, and the cessation of glucagon release, while in the kidney, the induction of the mRNAs by fructose occurs regardless of the hormonal status of the animals. The hormonal control of aldolase B mRNA levels in the small intestine is intermediate.

Adrenalectomy↗
PubMed1984

Cyclic AMP as a transcriptional inhibitor of upper eukaryotic gene transcription.

Recently, glucagon and its second messenger, cyclic AMP, have been shown to stimulate the transcription rate of several upper eukaryotic genes (1-5). We show here that glucagon can also block gene transcription. Both glucagon and cyclic AMP were found to inhibit the transcription of the genes encoding three liver glycolytic enzymes, including L-type pyruvate kinase and aldolase B. Thus, cyclic AMP proves to be not only an activator but also an inhibitor of gene transcription in eukaryotes.

Animals↗
PubMed1984

In vivo hormonal control of L-type pyruvate kinase gene expression. Effects of glucagon, cyclic AMP, insulin, cortisone, and thyroid hormones on the dietary induction of mRNAs in the liver.

Using a cDNA probe complementary to rat L-type pyruvate kinase mRNAs, we studied the respective roles of glucocorticoids, thyroid hormones, glucagon, and insulin in the induction of specific mRNAs in the liver of animals refed either a maltose-rich or a fructose-rich diet. Neither adrenalectomized nor thyroidectomized nor diabetic animals could express L-type pyruvate kinase mRNAs in their liver when refed the carbohydrate-rich diets. When the animals were given the missing hormone, the level of hybridizable mRNAs returned to normal values but administration of the hormone alone failed to induce mRNA synthesis in fasted animals. Both glucagon and cyclic AMP abolished the induction of L-type pyruvate kinase mRNAs in refed animals. Exogenous insulin, whatever the dose, could not reverse the inhibitory action of glucagon. Insulin has usually been regarded as the main regulator of L-type pyruvate kinase gene expression. It appears now that glucagon, beside regulating the enzyme activity by phosphorylation mechanisms, may also modulate L-type pyruvate kinase synthesis at a pre-translational level. Consequently, our results show that three conditions are required for the synthesis of liver L-type pyruvate kinase mRNAs: (i) the presence of dietary carbohydrates, (ii) the cessation of glucagon release, and (iii) the presence of permissive hormones, including insulin.

Adrenalectomy↗
PubMed1984

Abnormal galactoside excretion in urine of a patient with early myoclonic epileptic encephalopathy.

An abnormal carbohydrate pattern was found in urine of a patient with early myoclonic epileptic encephalopathy. Three major oligosaccharides have been isolated from the urine; structural studies including sugar analyses, methylation procedure and enzymatic hydrolysis allow us to propose the following structures: beta-Gal-(1 leads to 3)-Gal beta-Gal-(1 leads to 3)-beta-Gal-(1 leads to 3)-Glc beta-Gal-(1 leads to 3)-beta-Gal-(1 leads to 3)-Gal Such oligosaccharide structures have not previously been described in any biological fluid. The origin of these compounds, and the possibility of a specific metabolic defect are discussed.

Chemical Phenomena↗
PubMed1984

Hudson memorial lecture. Neonatal management of organic acidurias. Clinical update.

Therapeutic guidelines have been obtained from a retrospective review of 41 patients affected with organic acidaemias, 16 patients with neonatal maple syrup urine disease (MSUD), 11 methylmalonic acidaemia, (MMA) seven propionic acidaemias (PA) and seven isovaleric acidaemias (IVA), and by comparing this personal series with similar reported cases. The emergency treatment of these organic acidurias in the neonate has to main goals: toxin removal and anabolism. Anabolism is always promoted by early diet therapy. The best method of toxin removal depends on the nature of the defect; peritoneal dialysis with exchange transfusions or multiple or prolonged exchange transfusions in MSUD and in PA, diuresis and exchange transfusions in MMA and glycine supplementation in IVA. Vitamin supplementation (thiamine 20 mg, biotin 10 mg, B12 2 mg and riboflavin 100 mg) should be tried in all cases although the neonatal forms of these defects are very rarely vitamin responsive. Additional treatments such as carnitine or insulin may prove to be useful.

Acids↗
PubMed1983

Biotin dependent carboxylase activities in normal human and multicarboxylase deficient patient fibroblasts: relationship to the biotin content of the culture medium.

Three mitochondrial carboxylase activities can be depleted in skin fibroblasts from patients with the neonatal form of multiple carboxylase deficiency when the biotin content of the culture medium is lowered to 25 nmol/l. On the other hand this depletion can be achieved in control fibroblasts or in fibroblasts from patients with the late onset form of the deficiency when avidin (50 U/l) is added to the culture medium. The kinetics of the carboxylase activity decrease are nevertheless identical for control and for both types of fibroblasts. After depletion, control and late onset form fibroblasts recover their carboxylase activities at the same rate, whereas fibroblasts with the neonatal form of deficiency need longer times or higher concentrations of biotin to restore their carboxylase activities. These results are consistent with previous hypotheses concerning the origin of both forms of the deficiency. In addition, this technique provides a convenient access to human apocarboxylases, i.e. substrates for in vitro holocarboxylase synthetase investigation.

Biotin↗
PubMed1983

Absence of functional messenger RNA for glycogen phosphorylase in the muscle of two patients with McArdle's disease.

(1) Two unrelated cases of McArdle's disease (glycogen storage disease type V, deficiency in muscle-type glycogen phosphorylase, EC.2.4.1.1) with no detectable inactive protein, and two heterozygous relatives of one patient, have been investigated for the presence or absence of functional messenger RNA. Methods were developed and scaled down to be compatible with clinical-size biopsies. (2) Total muscle RNA was prepared and translated in a rabbit reticulocyte cell-free system. Neosynthesized products were isolated by immunoaffinity microchromatography. Phosphorylase was compared with control enzymes neosynthesized and purified under the same conditions. (3) No functional mRNA for phosphorylase could be detected in the muscles of the two patients. A decreased amount of messenger for phosphorylase, compared with the control enzymes, was found in the muscles of the two heterozygotes. (4) Exploration of functional messenger RNA in clinical enzymopathies should be readily adaptable to a number of enzymatic diseases.

Adolescent↗
PubMed1982

Biotin-responsive immunoregulatory dysfunction in multiple carboxylase deficiency.

The immunoregulatory system has recently been shown to require prostaglandins (PG) for its activation in man. We report here an impairment of immunoregulatory function, due to defective PGE monocytic production, in a 12-month-old boy with multiple carboxylase deficiency (MCD). The abnormal immune-response was corrected in vitro by adding PGE to the medium. Moreover, PGE deficiency and immunoregulatory dysfunction responded to biotin administration in vivo. It is suggested that the PGE deficiency in MCD could result from an impaired activity of a biotin enzyme, acetyl CoA carboxylase, since the product of this enzyme reaction, malonyl CoA, is required for prostaglandin synthesis.

Biotin↗