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Biomedical subjects

E D Saggerson

Publications and source records attributed to E D Saggerson.

At least 37 records · Page 2Linked to original sources
PubMed1994

Platelet function in patients with hypercholesterolaemia.

Platelets and plasma lipoproteins, particularly low density lipoprotein, have important roles in atherogenesis. Evidence from several sources suggests that important interactions occur between these individual components of the atherogeneic process. Here we review work from our own laboratory on platelet function in normal individuals and patients heterozygous for familial hypercholesterolaemia (FH). Data is presented on the role of platelet noradrenaline and also on altered cellular signalling in platelets from FH individuals who have plasma low density lipoprotein concentrations which are approximately double those seen in normal subjects.

Blood Platelets↗
PubMed1993

Malonyl-CoA metabolism in cardiac myocytes and its relevance to the control of fatty acid oxidation.

1. Viable myocytes were obtained from rat hearts. Oxidation of [1-14C]palmitate by these cells could be decreased by the addition of glucose (5 mM) or lactate (2 mM). In the presence of glucose, insulin decreased and adrenaline increased palmitate oxidation. 2. The myocytes contained activities of ATP citrate-lyase, acetyl-CoA carboxylase and the condensing enzyme of the fatty acid elongation system. No fatty acid synthase activity was demonstrable in myocytes. 3. In rat hearts perfused with 5 mM glucose, malonyl-CoA content was acutely raised by insulin. In the presence of glucose+insulin, perfusion with palmitate or adrenaline decreased the malonyl-CoA content. 4. It is concluded that malonyl-CoA can be synthesized within cardiac myocytes and that the level of this metabolite can be acutely regulated. This is likely to have consequences for the regulation of carnitine palmitoyltransferase in the heart.

Acetyltransferases↗
PubMed1993

Altered cellular signalling and decreased platelet sensitivity to adenosine in insulin-dependent diabetic patients with proliferative retinopathy.

Platelets from patients with insulin-dependent diabetes with proliferative retinopathy showed the same reactivity to ADP as those from control subjects. Responsiveness of platelets to the aggregation inhibitor adenosine and to the analogue N-ethylcarboxamidoadenosine was decreased in diabetes. In contrast, responsiveness to the anti-aggregatory effects of prostaglandin I2 was not significantly altered in diabetes. Platelets from diabetic patients exhibited decreased formation of cyclic AMP in response to N-ethylcarboxamidoadenosine compared with those from control subjects. In contrast, when adenylyl cyclase was stimulated by prostaglandin I2 or by forskolin, no differences in cyclic AMP formation were observed between control and diabetic platelets. Diabetes was associated with an apparent loss of high-affinity binding of [3H]N-ethylcarboxamidoadenosine to platelet membranes. Possible mechanisms that could contribute to this diabetes-induced change in signalling through the platelet A2 adenosine receptor are discussed.

Adenosine↗
PubMed1993

Decreased sensitivity to adenosine in platelets from patients with familial hypercholesterolaemia--a change reversed by cholestyramine treatment.

Platelet-rich plasma was obtained from patients with untreated heterozygous familial hypercholesterolaemia (FH), from FH patients treated with cholestyramine and from control subjects. Responsiveness of platelets to the aggregation inhibitors adenosine, its analogue N-ethylcarboxamidoadenosine (NECA) and prostaglandin I2 was decreased in FH. Patients on cholestyramine therapy showed normal responsiveness to adenosine and NECA. There were only minor changes in the binding of [3H]NECA to high-affinity binding sites on platelet membranes from untreated FH or cholestyramine-treated FH patients. The initial rate of cyclic AMP formation in response to a high concentration of NECA was severely decreased in platelets from FH patients. By contrast, the rate of cyclic AMP formation in response to forskolin or a high concentration of prostaglandin I2 was unchanged. These data point to a defect in the coupling of the platelet A2 adenosine receptor to adenylyl cyclase in untreated FH patients.

Adenosine↗
PubMed1992

Malarial toxic antigens synergistically enhance insulin signalling.

Hypoglycaemia is a major complication of severe malaria [(1990) Trans. Roy. Soc. Trop. Med. 84 (suppl. 2) 1-65], especially cerebral malaria, in which it is associated with increased mortality [(1990) Lancet 336, 1039-1043; (1989) Quart. J. Med. (New series) 71, 441-459]; however, the mechanisms responsible have not been fully explained. Preparations containing toxic malaria antigens (TMA) released by blood stage Plasmodium yoelii malaria parasites have been shown to induce hypoglycaemia in mice lasting at least 8 h [(1992) Clin. Exp. Immunol. (in press)]. Here we report that TMAs can act synergistically with insulin in both stimulating lipogenesis and inhibiting lipolysis in rat adipocytes in vitro, and, furthermore, that they act synergistically with insulin in the induction of hypoglycaemia in vivo.

Adipose Tissue↗
PubMed1992

Treatment with triiodothyronine decreases the abundance of the alpha-subunits of Gi1 and Gi2 in the cerebral cortex.

Treatment of rats for 3 days with T3 halved the abundance of the alpha-subunits of Gi1 and Gi2 in synaptosomal membranes isolated from the cerebral cortex. It is suggested that these changes could contribute to behavioural abnormalities in hyperthyroidism. Similar T3 treatment did not alter abundance of Gi1 alpha or Gi2 alpha in the medulla oblongata nor did it alter abundance of G(o) alpha-subunits in three tested brain regions.

Amino Acid Sequence↗
PubMed1991

A study of properties and abundance of the components of liver carnitine palmitoyltransferases in mitochondrial inner and outer membranes. Effects of hypothyroidism, fasting and a ketotic diabetic state.

1. Liver mitochondrial outer and inner membranes were isolated from normal, 48 h-fasted, streptozotocin-diabetic and hypothyroid rats. 2. Relative to membrane protein, fasting and diabetes substantially increased the activity of carnitine palmitoyltransferase (CPT) in outer membranes. Inner-membrane CPT specific activity was only slightly altered, being increased in diabetes and decreased in hypothyroidism. Abundance of an inner-membrane Mr-68,000 polypeptide that cross-reacted with an anti-CPT serum was significantly increased in diabetes and hypothyroidism. Relative to inner-membrane CPT activity, this cross-reactivity was increased by 37% in diabetes and by 400% in hypothyroidism, suggesting modification of the intrinsic activity of the CPT in these states. 3. CPT in outer membranes was inhibitable by malonyl-CoA, whereas inner-membrane CPT was insensitive to malonyl-CoA. Fasting and diabetes increased the IC50 (concentration of malonyl-CoA causing 50% inhibition) for outer-membrane CPT, whereas the IC50 was decreased in hypothyroidism. 4. Binding of [14C]malonyl-CoA was observed with both outer and inner membranes and was fitted to two-site models in each case. Fasting, diabetes and hypothyroidism changed the KD for binding at the higher-affinity site in outer membranes in a manner that correlated closely with changes in IC50 for inhibition of outer-membrane CPT by malonyl-CoA. Fasting and diabetes increased the abundance of this outer-membrane high-affinity malonyl-CoA-binding site, whereas hypothyroidism decreased its abundance.

Animals↗
PubMed1991

Activities of enzymes of glycerolipid synthesis in brown adipose tissue after treatment of rats with the adrenergic agonists BRL 26830A and phenylephrine, after exposure to cold and in streptozotocin-diabetes.

1. Measurements were made, relative to tissue DNA, of the activities of enzymes of glycerolipid synthesis in homogenates of interscapular brown adipose tissue. These were: mitochondrial and microsomal forms of glycerolphosphate acyltransferase (GPAT), Mg(2+)-dependent phosphatidate phosphohydrolase (PPH) and fatty acyl-CoA synthetase (FAS). 2. In normal animals, 3 days of cold-exposure (4 degrees C) increased all activities. The increase in mitochondrial GPAT activity was particularly pronounced (5-fold). Administration of the beta-adrenergic agonist BRL 26830A mimicked the effect of cold on microsomal GPAT activity. Mitochondrial GPAT, PPH and FAS activities were unresponsive to BRL 26830A. The alpha-adrenergic agonist phenylephrine significantly decreased activities of GPAT and PPH. 3. Streptozotocin-diabetes decreased mitochondrial GPAT activity, but did not abolish the effect of cold to increase this activity or the activity of microsomal GPAT. Diabetes abolished the effect of cold on PPH and FAS activities. 4. The findings are relevant to signals that drive early events in mitochondriogenesis and cell proliferation in brown adipose tissue on exposure to cold.

Adipose Tissue, Brown↗
PubMed1990

Concurrent up-regulation of guanine-nucleotide-binding proteins Gi1 alpha, Gi2 alpha and Gi3 alpha in adipocytes of hypothyroid rats.

Rat white adipocytes express three distinct 'Gi-like' guanine-nucleotide-binding proteins (G-proteins) [Mitchell, Griffiths, Saggerson, Houslay, Knowler & Milligan (1989) Biochem. J. 262, 403-408]. We have previously noted elevated levels of Gi in membranes of adipocytes from hypothyroid rats [Milligan, Spiegel, Unson & Saggerson (1987) Biochem. J. 247, 223-227]. Using a series of anti-peptide antisera able to discriminate between the individual gene products we have examined levels of each Gi-like G-protein in adipocyte membranes of hypothyroid rats compared with euthyroid controls. We demonstrate that up-regulation of Gi in adipocytes of hypothyroid rats is not restricted to a single subtype of Gi but that each of Gi1 alpha, Gi2 alpha and Gi3 alpha is present at markedly higher levels compared with euthyroid animals. In contrast, levels of both the 45 and 42 kDa forms of Gs alpha were not altered substantially in the hypothyroid state.

Adenosine Diphosphate Ribose↗
PubMed1990

The relationship of rat liver overt carnitine palmitoyltransferase to the mitochondrial malonyl-CoA binding entity and to the latent palmitoyltransferase.

1. Confirming previous work [Murthy & Pande (1987) Proc. Natl. Acad. Sci. U.S.A. 84, 378-382], malonyl-CoA-inhibitable carnitine palmitoyltransferase (CPT1) from rat liver was found to be localized in outer rather than in inner mitochondrial membranes. 2. Antisera were raised against a liver mitochondrial CPT of Mr 68,000, which was presumed to be the latent from of the enzyme (CPT2). These antisera cross-reacted with solubilized CPT extracted from liver inner mitochondrial membranes and with polypeptides of Mr 68,000 and 60,000 in immunoblots of both inner and outer mitochondrial membranes. The antisera also precipitated CPT activity from detergent-treated total membrane and outer-membrane preparations. 3. The antisera did not precipitate [14C]malonyl-CoA binding material obtained either from total membranes or from outer membranes. 4. It was concluded that liver CPT1 and CPT2 have some epitopes in common and may have a similar subunit size. In addition, CPT1 and the entity that binds malonyl-CoA must be separated polypeptides.

Animals↗
PubMed1990

Carnitine palmitoyltransferase (CPT2) from liver mitochondrial inner membrane becomes inhibitable by malonyl-CoA if reconstituted with outer membrane malonyl-CoA binding protein.

A soluble extract was obtained on treatment of rat liver mitochondrial outer membranes with cholate which bound [14C]malonyl-CoA but was essentially free of carnitine palmitoyltransferase (CPT) activity. Extraction of mitochondrial inner membranes with cholate readily solubilized a CPT activity which was insensitive to malonyl-CoA. Combination of these two extracts caused the CPT derived from inner membranes to become inhibitable by malonyl-CoA.

Acyl Coenzyme A↗
PubMed1990

Differences in the properties of A1-type adenosine receptors in rat white and brown adipocytes.

1. White adipocytes were found to be more responsive than brown adipocytes to inhibition of lipolysis by the A1 adenosine receptor agonist phenylisopropyladenosine. 2. Radioligand binding studies with plasma membranes isolated from the two adipocyte types indicated differences in the properties of the A1 receptors. Kd values (high and low affinity) for phenylisopropyladenosine were higher in membranes from brown adipocytes. The Kd values for the antagonist dipropylcyclopentylxanthine were also higher in brown adipocyte membranes. 3. The effects of guanine nucleotides in converting adipocyte A1 receptors into a low-affinity state were enhanced by dithiothreitol.

Adenosine↗
PubMed1989

Inhibition of adenylate cyclase in rat brain synaptosomal membranes by GTP and phenylisopropyladenosine is enhanced in hypothyroidism.

1. Synaptosomal membranes were isolated from rats made hypothyroid by treatment with propylthiouracil and a low iodine diet. 2. When assayed in the presence of 100 mM-Na+, inhibition of forskolin-stimulated adenylate cyclase by GTP was enhanced in membranes from hypothyroid animals. 3. Hypothyroidism also enhanced inhibition of adenylate cyclase by phenylisopropyladenosine (with 100 mM-Na+ and 10 microM-GTP present). 4. Hypothyroidism did not increase binding of the A1 adenosine receptor agonist phenylisopropyladenosine to synaptosomal membranes; rather, the maximum binding was slightly decreased without any change in the KD. 5. The effect of GTP in modifying the displacement of the antagonist [3H]diethylphenylxanthine from synaptosomal membranes by unlabelled phenylisopropyladenosine was more pronounced in the hypothyroid state. 6. These findings are consistent with hypothyroidism causing modification of the brain adenylate cyclase system at the level of the coupling protein Gi.

Adenosine↗
PubMed1989

Effects of hypothyroidism and hyperthyroidism on GDP binding to brown-adipocyte mitochondria from rats.

1. Rats were made hypothyroid by giving them a low-iodine diet with propylthiouracil for 4 weeks, or were made hyperthyroid by injection with tri-iodothyronine (T3) over a 3-day period. 2. Brown adipocytes were isolated from the interscapular depots of these animals or from their euthyroid controls, followed by isolation of mitochondria from the cells. 3. Relative to cell DNA content, hypothyroidism decreased the maximum binding (Bmax.) of [3H]GDP to mitochondria by 50%. T3 treatment increased binding by 37%. 4. These findings, which are discussed in relation to previously observed changes in brown adipose tissue after alteration of thyroid status, suggest that mitochondrial uncoupling for thermogenesis is less or more effective in hypothyroidism or hyperthyroidism respectively.

Adipose Tissue, Brown↗
PubMed1989

Guanine-nucleotide-binding proteins expressed in rat white adipose tissue. Identification of both mRNAs and proteins corresponding to Gi1, Gi2 and Gi3.

Considerable debate has focused on the molecular identity of the guanine-nucleotide-binding proteins (G-proteins) in adipose tissue which can be detected following pertussis-toxin-catalysed ADP-ribosylation [Rapiejko, Northup, Evans, Brown & Malbon (1986) Biochem. J. 240, 35-40; Hinsch, Rosenthal, Spicher, Binder, Gausepohl, Frank, Schultz & Joost (1988) FEBS Lett. 238, 191-196]. We have used a panel of selective anti-peptide antisera which are able to discriminate between the different pertussis-toxin-sensitive G-proteins to assess which of these are expressed in rat adipose tissue. We demonstrate that plasma membranes of rat white adipocytes contain alpha subunits corresponding to each of Gi1, Gi2 and Gi3. Furthermore, using synthetic oligonucleotides complimentary to unique regions of each of the three polypeptides, we demonstrate that the mRNAs for the three G-protein alpha subunits can also be detected in adipose tissue.

Adipose Tissue↗
PubMed1989

Effect of noradrenaline on triacylglycerol synthesis in rat brown adipocytes.

Incubation of rat brown adipocytes with noradrenaline in the presence of insulin and palmitate caused a decrease in the rate of triacylglycerol synthesis as measured by [U-14C]glucose incorporation into acylglycerol glycerol. Concomitantly, the ratio of [1-14C]palmitate oxidized to CO2 to that esterified was increased. This alteration in the rate of triacylglycerol synthesis by noradrenaline was not observed when fatty acid oxidation was inhibited by etomoxir. Noradrenaline did not cause any acute inactivation of enzymes of the triacylglycerol-synthesis pathway. It is suggested that the decrease in triacylglycerol synthesis seen with noradrenaline is secondary to activation of fatty acid oxidation.

Adipose Tissue, Brown↗
PubMed1989

Differentiation of rapid and slower-acting effects of insulin on mitochondrial processes in brown adipose tissue from streptozotocin-diabetic rats.

Insulin treatment of streptozotocin-diabetic rats restores the depressed palmitoyl-group oxidation observed in brown-adipose-tissue mitochondria from diabetic rats. A relatively rapid effect of insulin (5 h) to increase carnitine-dependent oxidation of palmitoyl-CoA and to increase overt carnitine palmitoyltransferase activity is differentiated from a slower effect of the hormone (1 day) to increase palmitoylcarnitine oxidation.

Adipose Tissue, Brown↗