PubMed Health⌕ Search

Biomedical subjects

M C Sugden

Publications and source records attributed to M C Sugden.

At least 163 records · Page 9Linked to original sources
PubMed1984

Effect of hyperthyroidism on hepatic lipogenesis in rats: studies in vivo and in vitro.

Lipogenic rates (measured with 3H2O) in hepatocytes from fed or starved euthyroid rats were similar in magnitude to those measured in livers in vivo. Hepatic lipogenesis in vivo in fed triiodothyronine (T3)-treated rats was greater than in fed control rats, but rates in vitro were only 16% of those of control rats. It is concluded that hepatic lipogenesis in vivo in T3-treated rats utilizes precursors from extrahepatic tissues. Glycogen depletion of hepatocytes from fed control rats decreased lipogenesis, and rates were then similar to those in hepatocytes from fed T3-treated rats. Addition of lactate (2 mmol/l) and pyruvate (0.2 mmol/l) had little stimulatory effect on lipogenesis in hepatocytes from fed control rats, but increased lipogenesis in glycogen-depleted hepatocytes (by 86%), hepatocytes from starved rats (by 25%) and hepatocytes from T3-treated rats (by 60%). In the presence of lactate and pyruvate, 3-mercaptopicolinate (3-MPA) (an inhibitor of gluconeogenesis) did not affect lipogenesis in hepatocytes from fed control rats but substantially increased lipogenesis in hepatocytes from starved euthyroid rats or fed hyperthyroid rats. Thus, in hepatocytes from starved euthyroid rats or fed hyperthyroid rats gluconeogenesis competes with lipogenesis for available precursors (lactate and pyruvate). In contrast, in fed rats carbon flux is predominantly towards lipogenesis. Effects of 3-MPA in the presence of lactate and pyruvate were much less in glycogen-depleted cells from fed rats than in hepatocytes from starved or T3-treated rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1984

Hormonal regulation of ketogenesis in hepatocytes from fed rats before and after glycogen depletion.

Vasopressin, angiotensin II and the catecholamines decreased ketogenesis from oleate but increased ketogenesis from butyrate in hepatocytes from fed rats. The hormones increase CO2 production from both oleate and butyrate. It is suggested that whereas the mitochondrial uptake of butyrate is linked to its rate of oxidation, that of oleate is independent of its intramitochondrial metabolism, and consequently the oxidation of oleate to CO2 occurs at the expense of ketogenesis. Effects of the hormones on ketogenesis from oleate or butyrate were not observed after pre-treatment of the hepatocytes with dibutyryl cyclic AMP for 1 hour. The insensitivity of ketogenesis to the hormones after this treatment (which mimics the effects of acute carbohydrate deprivation in vivo) questions the physiological significance of hormonal regulation of ketogenesis other than at the onset of starvation.

Angiotensin II↗
PubMed1984

Odd-carbon fatty acid metabolism in hepatocytes from starved rats.

The metabolism of odd-chain fatty acids was investigated in hepatocytes from 24 h-starved rats. Rates of glucose and 14CO2 production from [1-14C]propionate, [1-14C]valerate and [1-14C]nonanoate were maximal at 0.1 mM. Glucose production was greater with propionate as substrate than with valerate or nonanoate. Ketone body, lactate and pyruvate release were not affected by addition of the odd carbon fatty acids. It is concluded that hepatic odd-chain fatty acid metabolism in starvation is partly oxidative and partly gluconeogenic. Vasopressin and angiotensin II stimulated 14CO2 production from [1-14C] valerate and [1-14C]nonanoate but not from [1-14C]propionate and [1-14C]oleate in hepatocytes from starved rats. Nonanoate and valerate generate acetyl-CoA and propionyl-CoA, whereas oleate or propionate produce acetyl CoA and propionyl-CoA respectively. Given this stoichiometry, it is inferred that in hepatocytes from starved rats there must be an input of a tricarboxylic acid cycle intermediate to permit expression of the hormonal sensitivity.

Angiotensin II↗
PubMed1983

Adrenergic inhibition of branched-chain 2-oxo acid dehydrogenase in rat diaphragm muscle in vitro.

In theory, the complete oxidation to CO2 of amino acids that are metabolized by conversion into tricarboxylic acid-cycle intermediates may proceed via their conversion into acetyl-CoA. The possible adrenergic modulation of this oxidative pathway was investigated in isolated hemidiaphragms from 40 h-starved rats. Adrenaline (5.5 microM), phenylephrine (0.49 mM) and dibutyryl cyclic AMP (10 microM) inhibited 14CO2 production from 3 mM-[U-14C]valine by 35%, 28% and 19% respectively. At the same time, these agents stimulated glycogen mobilization (measured as a decrease in glycogen content) and glycolysis (measured as lactate release). Adrenaline, phenylephrine and dibutyryl cyclic AMP did not inhibit 14CO2 production from 3 mM-[U-14C]aspartate or 3 mM-[U-14C]glutamate, although, as in the presence of valine, the agents stimulated glycogen mobilization and glycolysis. The rate of proteolysis (measured as tyrosine release in the presence of cycloheximide) was not changed by adrenaline. The data indicate that the adrenergic inhibition of 14CO2 production from [U-14C]valine was not a consequence of radiolabel dilution. Inhibition was apparently specific for branched-chain amino acid metabolism in that the adrenergic agonists also inhibited 14CO2 production from [1-14C]valine, [1-14C]leucine and [U-14C]isoleucine. Since 14CO2 production from the 1-14C-labelled substrates is a specific measure of decarboxylation in the reaction catalysed by the branched-chain 2-oxo acid dehydrogenase complex, it is at this site that the adrenergic agents are concluded to act.

3-Methyl-2-Oxobutanoate Dehydrogenase (Lipoamide)↗
PubMed1983

Is the direct effect of naloxone on liver cell metabolism an artifact?

Proprietary naloxone hydrochloride (Narcan) acts on isolated hepatocytes from 24-h starved rats to increase 14CO2 production from [1-14C]oleate and to reverse in part the inhibitory effect of ethanol on the oxidation of [1-14C]oleate to 14CO2. The effects are attributable not to naloxone itself, but to the methyl p-hydroxybenzoate present in Narcan as a preservative. The question is posed as to whether methyl p-hydroxybenzoate and p-hydroxybenzoate contribute to the reported antagonism by proprietary naloxone of acute ethanol intoxication in vivo.

Animals↗
PubMed1983

Studies of cerebral beta-hydroxybutyrate transport by carotid injection; effects of age, diet and injectant composition.

Transport of beta-hydroxybutyrate at the blood--brain barrier was studied by the carotid-injection technique of Oldendorf. beta-hydroxybutyrate permeability declined sharply with age (80-300 g rats) and, in adult rats, increased 5-fold during one week on a high fat diet. Acetoacetate and lactate permeabilities showed age and diet dependences which were similar in direction whereas DMO, urea and mannitol did not show age and diet dependent permeabilities. There was no apparent increase of beta-hydroxybutyrate Km with age, so the decline of permeability was attributed to a decline of Vmax. beta-Hydroxybutyrate permeability was inversely related to pH of the injectant in the alkaline range but not in the acid range, suggesting that the pH dependence reflected titration of a carrier rather than titration of the permeant. Permeability was independent of [Na+], [K+], [Cl-] and [SO2-(4)]. Replacing a portion of the Na+ with ammonium enhanced beta-hydroxybutyrate uptake. This effect appeared to be due to trans alkalization, and was as expected of an A-/H+-symport or A-/OH- -antiport mechanism. Pyruvate, 4-hydroxy-alpha-cyanocinnamate and tetracaine inhibited, but SITS, DIDS, phloretin and methyl-isobutylxanthine did not. The data are consistent with transport by an A-/H+ -symporter or A-/OH- -antiporter with properties similar to those found in erythrocytes and other cells. Induction of its activity during ketosis would spare carbohydrate both by favoring ketoacid uptake and by favoring lactate output.

3-Hydroxybutyric Acid↗
PubMed1983

Stimulation of [1-14C]oleate oxidation to 14CO2 in isolated rat hepatocytes by the catecholamines, vasopressin and angiotensin. A possible mechanism of action.

Adrenaline, noradrenaline, vasopressin and angiotensin increased 14CO2 production from [1-14C]oleate by hepatocytes from fed rats but not by hepatocytes from starved rats. The hormones did not increase 14CO2 production when hepatocytes from fed rats were depleted of glycogen in vitro. Increased 14CO2 production from ]1-14C]oleate in response to the hormones was observed when hepatocytes from starved rats were incubated with 3-mercaptopicolinate, an inhibitor of phosphoenolpyruvate carboxykinase. 3-Mercaptopicolinate inhibited uptake and esterification of [1-14C]oleate, slightly increased 14CO2 production from [1-14C]oleate and greatly increased the [3-hydroxybutyrate]/[acetoacetate] ratio. In the presence of 3-mercaptopicolinate 14CO2 production in response to the catecholamines was blocked by the alpha-antagonist phentolamine and required extracellular Ca2+. The effects of vasopressin and angiotensin were also Ca2+-dependent. The actions of the hormones of 14CO2 production from [I-14C]oleate by hepatocytes from starved rats in the presence of 3-mercaptopicolinate thus have the characteristics of the response to the hormones found with hepatocytes from fed rats incubated without 3-mercaptopicolinate. The stimulatory effects of the hormones on 14CO2 production from [1-14C]oleate were not the result of decreased esterification (as the hormones increased esterification) or increased beta-oxidation. It is suggested that the effect of the hormones to increase 14CO2 production from [1-14C]oleate are mediated by CA2+-activation of NAD+-linked isocitrate dehydrogenase, the 2-oxoglutarate dehydrogenase complex, and/or electron transport. The results also demonstrate that when the supply of oxaloacetate is limited it is utilized for gluconeogenesis rather than to maintain tricarboxylic acid-cycle flux.

Angiotensin II↗
PubMed1983

Interactions between insulin and thyroid hormone in the control of lipogenesis.

1. The effects of intragastric glucose feeding and L-tri-iodothyronine (T3) administration on rates of hepatic and brown-fat lipogenesis in vivo were examined in fed and 48 h-starved rats. 2. T3 treatment increased hepatic lipogenesis in the fed but not the starved animals. Brown-fat lipogenesis was unaffected or slightly decreased by T3 treatment of fed or starved rats. 3. Intragastric glucose feeding increased hepatic lipogenesis in control or T3-treated fed rats, but did not increase hepatic lipogenesis in starved control rats. Glucose feeding increased hepatic lipogenesis if the starved rats were treated with T3. Glucose feeding increased rates of brown-fat lipogenesis in all experimental groups. The effects of glucose feeding on liver and brown-fat lipogenesis were mimicked by insulin injection. 4. The increase in hepatic lipogenesis in T3-treated 48 h-starved rats after intragastric glucose feeding was prevented by short-term insulin deficiency, but not by (-)-hydroxycitrate, an inhibitor of ATP citrate lyase. The increase in lipogenesis in brown adipose tissue in response to glucose feeding was inhibited by both short-term insulin deficiency and (-)-hydroxycitrate. 5. The results tend to preclude pyruvate kinase and acetyl-CoA carboxylase as the sites of interaction of insulin and T3 in the regulation of hepatic lipogenesis in 48 h-starved rats. Other potential sites of interaction are discussed.

Acetyl-CoA Carboxylase↗
PubMed1983

Effects of hyperthyroidism on stimulation of [1-14C]oleate oxidation to 14CO2 in isolated hepatocytes from fed rats by the catecholamines, vasopressin, and angiotensin II.

Possible effects of adrenaline, noradrenaline, vasopressin, and angiotensin II to increase 14CO2 production from [1-14C]oleate were examined in hepatocytes from fed L-triiodothyronine (T3)-treated or control rats. Rates of 14CO2 production were decreased and rates of ketogenesis increased in hepatocytes from T3-treated rats. These changes were accompanied by a marked shift of the 3-hydroxybutyrate:acetoacetate concentration ratio towards acetoacetate. Rates of glucose and lactate release were decreased. Whereas the Ca2+-mobilizing hormones increased 14CO2 production from [1-14C]oleate by 64-84% with hepatocytes from control rats, they increased 14CO2 production from [1-14C]oleate by on 24-32% with hepatocytes from T3-treated rats. The magnitude of the response to the Ca2+-mobilizing hormones in hepatocytes from T3-treated rats was increased by the addition of 3-mercaptopicolinate, an inhibitor of phosphoenolpyruvate carboxykinase, to the incubation medium (increases of 52-88%). In the presence of 3-mercaptopicolinate, the 3-hydroxybutyrate:acetoacetate concentration ratio in hepatocytes from fed, T3-treated rats was similar to that in hepatocytes from control rats in the absence of 3-mercaptopicolinate. The results demonstrate that hyperthyroidism per se does not lead to a loss of sensitivity, in terms of oleate oxidation, either to the catecholamines or to vasopressin and angiotensin II. The impaired ability of hepatocytes from T3-treated rats to respond to these hormones is a consequence of decreased net glycolytic flux or a more oxidized mitochondrial redox state.

Angiotensin II↗
PubMed1983

Inhibition of lipogenesis by vasopressin and angiotensin II in glycogen-depleted hepatocytes.

Vasopressin and angiotensin II inhibited lipogenesis (measured with 3H2O) in hepatocytes from fed rats. Inhibition was also observed with hepatocytes from fed rats which had been depleted of glycogen in vitro and incubated with lactate + pyruvate (5 mM + 0.5 mM) as substrates. The inhibitory actions of the hormones are therefore independent of hormone-mediated changes in glycogenolytic or glycolytic flux from glycogen, and thus the site(s) of hormone action must be subsequent to the formation of lactate. (-)Hydroxycitrate, a specific inhibitor of ATP-citrate lyase, decreased lipogenesis in hepatocytes from fed rats incubated with lactate + pyruvate by approx. 51% but had little effect on lipogenesis in glycogen-depleted hepatocytes similarly incubated. There was parallel inhibition of incorporation of 14C from [U-14C]lactate into fatty acid and lipogenesis as measured with 3H2O in each case. Thus depletion of glycogen, or conceivably the process of glycogen-depletion (incubation with dibutyryl cyclic AMP) causes a change in the rate-determining step(s) for lipogenesis from lactate. Vasopressin and angiotensin II also decreased lipogenesis and incorporation of 14C into fatty acids in glycogen-depleted hepatocytes provided with [U-14C]proline as opposed to [U-14C]-lactate. However, proline-stimulated lipogenesis was inhibited by (-)hydroxycitrate, and proline-stimulated lipogenesis and incorporation of 14C from [U-14C]-proline were not decreased in parallel by this inhibitor (inhibition of 52% and 85% respectively). It is inferred that lactate and proline stimulate lipogenesis by different mechanisms and incorporation of 14C from [U-14C]proline and [U-14C]lactate into fatty acid occurs via different routes.(ABSTRACT TRUNCATED AT 250 WORDS)

Angiotensin II↗
PubMed1983

Effects of dichloroacetate on fatty acid synthesis in interscapular brown adipose tissue of the rat in vivo and in vitro.

The effects of dichloroacetate (DCA) on fatty acid synthesis in interscapular brown adipose tissue of the rat were investigated. Administration of DCA to rats inhibited fatty acid synthesis in brown adipose tissue, measured in vivo using 3H2O, regardless of the nutritional state of the animals. Glucose administration increased lipogenesis in brown adipose tissue of fed and starved rats and DCA did not suppress this stimulation. DCA (1 mM or 10 mM) inhibited [1-14C]glucose incorporation into fatty acid by brown adipose tissue slices in vitro but was without effect on 14CO2 production from [1-14C]glucose. This demonstrates that DCA inhibits fatty acid synthesis directly, and the effects of DCA in vivo need not be attributed to decreased supply or utilization of lipogenic precursors.

Acetates↗
PubMed1983

Can isolated spans of the tricarboxylic acid cycle operate independently? L-proline, oleate and butyrate metabolism in rat hepatocytes.

14CO2 production from [l-14C]oleate, [l-14C]butyrate and [U-14C]proline by isolated rat hepatocytes was studied. In hepatocytes from fed rats, fatty acid and proline oxidation are stimulated in parallel by adrenaline, noradrenaline, vasopressin and angiotensin II. In contrast in hepatocytes from 24 h-starved rats these hormones stimulate proline oxidation whereas oleate and butyrate oxidation is hormone-insensitive. This suggests that 14CO2 production from [U-14C]proline and [l-14C]oleate is subject to independent endocrine control. In support of this in hepatocytes from fed rats, glucagon and dibutyryl cyclic AMP stimulate 14CO2 production from proline but inhibit 14CO2 production from [l-14C]oleate. The pathway of hepatic proline oxidation is discussed and it is suggested that 2-oxoglutarate dehydrogenase is one site of endocrine control of proline oxidation.

Angiotensin II↗
PubMed1983

Direction of carbon flux in starvation and after refeeding: in vitro and in vivo effects of 3-mercaptopicolinate.

3-Mercaptopicolinate (3-MPA) is a specific inhibitor of phosphoenolpyruvate carboxykinase (PEP CK). In vivo the hypoglycaemic action of 3-MPA in 24 h-starved rats was abolished on intragastric glucose refeeding. Nonetheless, 3-MPA decreased hepatic glycogen content and rate of synthesis in starved animals re-fed glucose. The inference is that on re-feeding after starvation hepatic glycogen is synthesised mainly de novo via glyconeogenesis involving PEP CK. 3-MPA increased hepatic lipogenesis in water- and glucose-fed normal and diabetic rats. This increase is presumed to result from inhibition of PEP CK and consequent diversion of pyruvate from gluconeogenesis to lipogenesis. In contrast, 3-MPA inhibited brown-fat lipogenesis in water- and glucose-fed rats.

Adipose Tissue, Brown↗
PubMed1982

Effects of L-alanine on ketogenesis in vitro.

Alanine (5 mM) increased 14CO2 production from [1-14C]oleate by 130% and from [1-14C]butyrate by 101%. Alanine inhibited ketone-body production by 37.5% in the presence of butyrate but did not affect ketogenesis in the presence of oleate. Alanine decreased the [3-hydroxybutyrate]/[acetoacetate] ratio when either butyrate or oleate was present. The results are discussed with reference to the hypoketonaemic action of alanine in vivo.

Alanine↗
PubMed1982

Effects of adrenaline on ketogenesis from long- and medium-chain fatty acids in starved rats.

1. Injection of adrenaline into 24 h-starved rats caused a 69% decrease in blood [ketone-body] (3-hydroxybutyrate plus acetoacetate), accompanied by a decreased [3-hydroxybutyrate]/[acetoacetate] ratio. Blood [glucose] and [lactate] increased, but [alanine] was unchanged. 2. Adrenaline also decreased [ketone-body] after intragastric feeding of both long- and medium-chain triacylglycerol. The latter decrease was observed after suppression of lipolysis with 5-methylpyrazole-3-carboxylic acid, indicating that the antiketogenic action of adrenaline was not dependent on the chain length of the precursor fatty acid. 3. The actions of adrenaline to decrease blood [ketone-body] and to increase blood [glucose] were not observed after administration of 3-mercaptopicolinate, an inhibitor of gluconeogenesis. This suggests that these effects of the hormone are related. 4. The possible clinical significance of the results is discussed with reference to the restricted ketosis often observed after surgical or orthopaedic injury.

Animals↗
PubMed1982

Brown-adipose-tissue lipogenesis in starvation: effects of insulin and (-) hydroxycitrate.

Glucose or insulin increased lipogenesis (measured in vivo using 3H2O) in brown fat of starved rats. Such increases were associated with activation of pyruvate dehydrogenase and increased use of glucose as a lipogenic precursor (monitored as an increase in the 14C/3H ratio in brown-fat fatty acids in rats injected with both 3H20 and [U-14C]glucose). (-) Hydroxycitrate did not inhibit basal rates of brown-fat lipogenesis in starved rats but suppressed the increases in lipogenesis and glucose utilization observed in response to insulin. (-)Hydroxycitrate did not, however, inhabit the increase in 14C/3H observed after insulin treatment. The results indicate that in brown fat, glucose is utilized for fatty-acid synthesis predominantly via citrate, and that insulin acts to increase lipogenesis at site(s) prior to citrate cleavage. As basal rates of lipogenesis were not inhibited by (-)hydroxycitrate, it is suggested that acetate may be a lipogenic substrate for brown fat in starvation, and experiments are described which support this suggestion.

Acetates↗
PubMed1981

Cyclic nucleotide phosphodiesterase of rat pancreatic islets. Effects of Ca2+, calmodulin and trifluoperazine.

Cyclic nucleotide phosphodiesterase activity towards cyclic AMP and cyclic GMP was studied in extracts of rat islets of Langerhans. Biphasic Eadie plots [Eadie (1942) J. Biol. Chem. 146, 85-93] were obtained with either substrate suggesting the presence of both 'high'- and 'low'-Km components. The apparent Km values were 6.2 +/- 0.5 (n = 8) microM and 103.4 +/- 13.5 (6) microM for cyclic AMP and 3.6 +/- 0.3 (12) microM and 61.4 +/- 7.5 (13) microM for cyclic GMP. With cyclic AMP as substrate, phosphodeisterase activity was increased by calmodulin and Ca2+ and decreased by trifluoperazine, a specific inhibitor of calmodulin. With cyclic GMP as substrate, phosphodiesterase activity was decreased by omission of Ca2+ or addition of trifluoperazine. Addition of exogenous calmodulin had no effect on activity. The data suggest that Ca2+ may influence the islet content of cyclic AMP and cyclic GMP via effects on calmodulin-dependent cyclic nucleotide phosphodiesterase(s).

2',3'-Cyclic-Nucleotide Phosphodiesterases↗