Influence of neonatal hypothyroidism on the development of ketone-body-metabolizing enzymes in rat brain.
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ABSTRACT:
SUBMITTER: Patel MS
PROVIDER: S-EPMC1161688 | biostudies-other | 1979 Oct
REPOSITORIES: biostudies-other
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Project description:1. Rats (4 weeks old) were made hypothyroid by treatment with propylthiouracil and a low-iodine diet for a further period of 4 weeks. Synaptosomal membranes, myelin and 105,000 g soluble fractions were obtained from six regions of the brain. 2. Hypothyroidism resulted in 2-5-fold increases in membrane-bound 5'-nucleotidase activity in synaptosomal fractions obtained from cerebellum, cortex, striatum and hippocampus. By contrast, myelin 5'-nucleotidase activity was slightly increased only in the medulla oblongata. 3. Hypothyroidism did not change adenosine deaminase activity, but decreased adenosine kinase activity by approx. 40% in soluble fractions obtained from cerebellum, hippocampus, striatum and hypothalamus. 4. It is suggested that these changes in hypothyroidism, in particular the increases in 5'-nucleotidase activity, could enhance the neuromodulatory effect of adenosine to decrease neurotransmitter release.
| S-EPMC1138875 | biostudies-other
Project description:BACKGROUND:Dietary n-3 polyunsaturated fatty acid (PUFA) deprivation increases expression of arachidonic acid (AA 20:4n-6)-selective cytosolic phospholipase A(2) (cPLA(2)) IVA and cyclooxygenase (COX)-2 in rat brain, while decreasing expression of docosahexaenoic acid (DHA 22:6n-3)-selective calcium-independent iPLA(2) VIA. Assuming that these enzyme changes represent brain homeostatic responses to deprivation, we hypothesized that dietary n-6 PUFA deprivation would produce changes in the opposite directions. METHODS:Brain expression of PUFA-metabolizing enzymes and their transcription factors was quantified in male rats fed an n-6 PUFA adequate or deficient diet for 15weeks post-weaning. RESULTS:The deficient compared with adequate diet increased brain mRNA, protein and activity of iPLA(2) VIA and 15-lipoxygenase (LOX), but decreased cPLA(2) IVA and COX-2 expression. The brain protein level of the iPLA(2) transcription factor SREBP-1 was elevated, while protein levels were decreased for AP-2? and NF-?B p65, cPLA(2) and COX-2 transcription factors, respectively. CONCLUSIONS:With dietary n-6 PUFA deprivation, rat brain PUFA metabolizing enzymes and some of their transcription factors change in a way that would homeostatically dampen reductions in brain n-6 PUFA concentrations and metabolism, while n-3 PUFA metabolizing enzyme expression is increased. The changes correspond to reported in vitro enzyme selectivities for AA compared with DHA.
| S-EPMC3018563 | biostudies-literature
Project description:Neonatal heart undergoes metabolic conversion and cell cycle arrest preparing for the increased workload during adulthood. Herein, we report that neonatal ketone body elevation is a critical regulatory factor for postnatal heart development. Through multiomics screening, we found that the expression of 3-hydroxy-3-methylglutaryl-CoA synthase 2 (HMGCS2), the rate-limiting enzyme of ketogenesis, was transiently induced by colostrum in the neonatal heart. Hmgcs2 knockout caused mitochondrial maturation defects. Meanwhile, postnatal heart development was compromised and cardiomyocytes reacquired proliferation capacity in Hmgcs2 knockout mice. Consequently, over 40% of newborn Hmgcs2 knockout mice died before weaning. The heart function of surviving Hmgcs2 knockout mice was also impaired, which could be rescued by ketone body supplementation during the suckling stage. Mechanistically, ketone body deficiency inhibited β-hydroxybutyrylation but enhanced acetylation of mitochondrial proteins, which might be responsible for the inhibition of the enzyme activity in mitochondria. These observations suggest that ketone body is critical for postnatal heart development through regulating mitochondrial maturation and metabolic reprogramming.
| S-EPMC9553951 | biostudies-literature
Project description:To compensate for the energetic deficit elicited by reduced carbohydrate intake, mammals convert energy stored in ketone bodies to high energy phosphates. Ketone bodies provide fuel particularly to brain, heart, and skeletal muscle in states that include starvation, adherence to low carbohydrate diets, and the neonatal period. Here, we use novel Oxct1(-/-) mice, which lack the ketolytic enzyme succinyl-CoA:3-oxo-acid CoA-transferase (SCOT), to demonstrate that ketone body oxidation is required for postnatal survival in mice. Although Oxct1(-/-) mice exhibit normal prenatal development, all develop ketoacidosis, hypoglycemia, and reduced plasma lactate concentrations within the first 48 h of birth. In vivo oxidation of (13)C-labeled β-hydroxybutyrate in neonatal Oxct1(-/-) mice, measured using NMR, reveals intact oxidation to acetoacetate but no contribution of ketone bodies to the tricarboxylic acid cycle. Accumulation of acetoacetate yields a markedly reduced β-hydroxybutyrate:acetoacetate ratio of 1:3, compared with 3:1 in Oxct1(+) littermates. Frequent exogenous glucose administration to actively suckling Oxct1(-/-) mice delayed, but could not prevent, lethality. Brains of newborn SCOT-deficient mice demonstrate evidence of adaptive energy acquisition, with increased phosphorylation of AMP-activated protein kinase α, increased autophagy, and 2.4-fold increased in vivo oxidative metabolism of [(13)C]glucose. Furthermore, [(13)C]lactate oxidation is increased 1.7-fold in skeletal muscle of Oxct1(-/-) mice but not in brain. These results indicate the critical metabolic roles of ketone bodies in neonatal metabolism and suggest that distinct tissues exhibit specific metabolic responses to loss of ketone body oxidation.
| S-EPMC3044945 | biostudies-literature
Project description:1. The activities of hydroxymethylglutaryl-CoA synthase and lyase in rat liver were found to be two- to 15-fold greater than those reported by other authors under similar conditions. 2. When expressed on the basis of body weight, no appreciable differences were found between the activities of hydroxymethylglutaryl-CoA synthase in whole homogenates of livers from normal and starved rats. The synthase activity increased by 70% and 140% in livers of alloxan-diabetic rats and rats fed on a high-fat diet respectively. 3. Hydroxymethylglutaryl-CoA lyase activity showed no significant increases in starvation or alloxan-diabetes, but a 40% increase was found in fat-fed rats. 4. Less than 12% of the activities of both enzymes were found in the cytoplasmic fraction of normal liver. The cytoplasmic activity doubled in alloxan-diabetes and starvation; on feeding with a high-fat diet the increase, though significant, was less marked. 6. The intracellular distribution of glutamate dehydrogenase indicated that the changes in the cytoplasmic activities observed were not due to leakage from the mitochondria. 7. Feeding with a normal or high-fat diet after 48hr. starvation caused within 24hr. a decrease in the cytoplasmic activity of hydroxymethylglutaryl-CoA synthase to values lower than those found in rats fed on a corresponding diet for a longer period of time. 8. Acetoacetyl-CoA deacylase activity in liver was about 20% of that of hydroxymethylglutaryl-CoA synthase and was primarily located in the cytoplasm. Starvation or alloxan-diabetes did not alter the acetoacetyl-CoA deacylase activity. 9. It is concluded that variations in the concentrations of enzymes involved in acetoacetate synthesis play no major role in the regulation of ketone-body formation in starvation and alloxan-diabetes. The changes in the cytoplasmic activities of hydroxymethylglutaryl-CoA synthase and lyase suggest that acetoacetate synthesis can occur in the cytoplasm. This may play a role in the disposal of surplus acetyl-CoA arising in the cytoplasm when lipogenesis is inhibited.
| S-EPMC1198819 | biostudies-other
Project description:1. Ketone-body utilization in fed and starved adult and suckling rats has been investigated by measuring arterio-venous differences across the brain. Venous blood was collected from the confluence of sinuses and arterial blood from the femoral artery in adult rats and by cardiac puncture in suckling rats. 2. During starvation the arterio-venous difference of ketone bodies increased in proportion to their concentrations in the blood and reached a value of 0.16mm at 48h. At a given concentration of the respective ketone bodies the arterio-venous differences of acetoacetate were about twice those of 3-hydroxybutyrate. 3. Fed rats in which the concentrations of ketone bodies were raised by intravenous infusion of sodium acetoacetate had the same arterio-venous differences as starved rats at corresponding ketone-body concentrations. Thus the ability of the rat brain to utilize ketone bodies is independent of the nutritional state. 4. The concentrations of glucose, acetoacetate and 3-hydroxybutyrate were much lower in the brain than in the arterial blood. The measured (blood concentration)/(brain concentration) ratio was 4.4 for glucose, 4.5 for acetoacetate and 8.1 for 3-hydroxybutyrate in 48h-starved rats. 5. The mean arterio-venous difference of glucose across the brain was 0.51mm in fed rats and 0.43mm in 96h-starved rats. 6. Conversion of glucose into lactate rose from negligible values in the fed state to 0.2mm after 48h starvation and decreased to zero after 96h starvation. 7. In 16-22-day-old suckling rats the arterio-venous differences of ketone bodies across the brain were also proportional to the ketone-body concentration, but they were about 3-4 times greater than in adult rats at the same blood ketone-body concentration. 8. Arterio-venous differences of glucose were about the same in adult and suckling rats. 9. The brain of fed suckling rats formed more lactate from glucose than fed adult rats. 10. The results indicate that ketone bodies are major metabolic fuels of the brain of the suckling rat under normal conditions.
| S-EPMC1176682 | biostudies-other
Project description:In contrast to considerable data demonstrating a decrease in cytochrome P450 (CYP) activity in inflammation and infection, clinically, traumatic brain injury (TBI) results in an increase in CYP and UDP glucuronosyltransferase (UGT) activity. The objective of this study was to determine the effects of TBI alone and with treatment with erythropoietin (EPO) or anakinra on the gene expression of hepatic inflammatory proteins, drug-metabolizing enzymes, and transporters in a cortical contusion impact (CCI) injury model. Microarray-based transcriptional profiling was used to determine the effect on gene expression at 24 h, 72 h, and 7 days post-CCI. Plasma cytokine and liver protein concentrations of CYP2D4, CYP3A1, EPHX1, and UGT2B7 were determined. There was no effect of TBI, TBI + EPO, or TBI + anakinra on gene expression of the inflammatory factors shown to be associated with decreased expression of hepatic metabolic enzymes in models of infection and inflammation. IL-6 plasma concentrations were increased in TBI animals and decreased with EPO and anakinra treatment. There was no significant effect of TBI and/or anakinra on gene expression of enzymes or transporters known to be involved in drug disposition. TBI + EPO treatment decreased the gene expression of Cyp2d4 at 72 h with a corresponding decrease in CYP2D4 protein at 72 h and 7 days. CYP3A1 protein was decreased at 24 h. In conclusion, EPO treatment may result in a significant decrease in the metabolism of Cyp-metabolized drugs. In contrast to clinical TBI, there was not a significant effect of experimental TBI on CYP or UGT metabolic enzymes.
| S-EPMC4540723 | biostudies-literature
Project description:1. The activities of 3-hydroxybutyrate dehydrogenase and 3-oxo acid CoA-transferase in rat brain at birth were found to be about two-thirds of those of adult rat brain, expressed per g wet wt. The activities rose throughout the suckling period and at the time of weaning reached values about three times higher than those for adult brain. Later they gradually declined. 2. At birth the activity of acetoacetyl-CoA thiolase in rat brain was about 60% higher than in the adult. During the suckling period there was no significant change in activity. 3. In rat kidney the activities of the three enzymes at birth were less than one-third of those at maturity. They gradually rose and after 5 weeks approached the adult value. Similar results were obtained with rat heart. 4. The activity of glutamate dehydrogenase (a mitochondrial enzyme like 3-hydroxybutyrate dehydrogenase and 3-oxo acid CoA-transferase) also rose in brain and kidney during the suckling period, but at no stage did it exceed the adult value. 5. Throughout the suckling period the total ketone-body concentration in the blood was about six times higher than in adult fed rats, and the concentration of free fatty acids in the blood was three to four times higher. 6. It is concluded that the rate of ketone-body utilization in brains of suckling rats is determined by both the greater amounts of the key enzymes in the tissue and the high concentrations of ketone bodies in the blood. In addition, the low activities of the relevant enzymes in kidney and heart of suckling rats may make available more ketone bodies for the brain.
| S-EPMC1176485 | biostudies-other
Project description:1. The activity of rat liver microsomal drug-metabolizing enzymes was determined at various ages between 6 and 100 days post natum. The enzymes studied were: aromatic hydroxylases by using as substrate biphenyl, which is metabolized by oxidation to 2- and 4-hydroxybiphenyl; nitroreductase by using p-nitrobenzoate as substrate, which is metabolized by reduction to p-aminobenzoate; glucuronyl synthetase by using 4-methylumbelliferone as the substrate, which is conjugated to give 4-methylumbelliferone glucuronide, and cytochrome P-450, which is regarded as the major terminal mixed-function oxidase in hepatic microsomal hydroxylations. 2. The activity of biphenyl 2-hydroxylase reached a peak at 21 days, biphenyl 4-hydroxylase and 4-methyl glucuronyl transferase at 24 days, cytochrome P-450 at 31 days, and p-nitrobenzoate reductase at 38 days of age. After the peak activity had been reached, the activity of each enzyme decreased with age, and in the case of biphenyl 2-hydroxylase the activity fell to a negligible value at 52 days of age. 3. Neither the addition of Triton X-100 to the incubation medium nor the treatment of the animals with phenobarbital resulted in any increase in the activity of biphenyl 2-hydroxylase at 52 days of age. 4. The activity of biphenyl 2-hydroxylase was threefold higher in rats fed on a synthetic diet than in rats fed on a commercial stock diet. 5. These findings are discussed.
| S-EPMC1177108 | biostudies-other
Project description:1. The highest blood concentrations of ketone bodies were found at 5 days of age, after which time the concentration fell to reach the adult value by 30 days of age. 2. Both mitochondrial and cytoplasmic hydroxymethylglutaryl-CoA synthase activities were detected, with highest activities being found in the mitochondria at all stages of development. Activity of the mitochondrial enzyme increases rapidly immediately after birth, showing a maximum at 15 days of age, thereafter falling to adult values. The cytoplasmic enzyme, on the other hand, increased steadily in activity after birth to reach a maximum at 40 days of age, after which time activity fell to adult values. 3. Both mitochondrial and cytoplasmic aceto-acetyl-CoA thiolase activities were detected, with the mitochondrial enzyme having considerably higher activities at all stages of development. The developmental patterns for both enzymes were very similar to those for the corresponding hydroxymethylglutaryl-CoA synthases. 4. The activity of heart acetoacetyl-CoA transferase remains constant from late foetal life until the end of the suckling period, after which time there is a gradual threefold increase in activity to reach the adult values. The activity of brain 3-oxo acid CoA-transferase increases steadily after birth, reaching a maximum at 30 days of age, thereafter decreasing to adult values, which are similar to foetal activities. Although at all stages of development the specific activity of the heart enzyme is higher than that of brain, the total enzymic capacity of the brain is higher than that of the heart during the suckling period.
| S-EPMC1177134 | biostudies-other