Ketone-body metabolism after partial hepatectomy in the rat.
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ABSTRACT:
SUBMITTER: Schofield PS
PROVIDER: S-EPMC1152730 | biostudies-other | 1985 Oct
REPOSITORIES: biostudies-other
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Project description:The aim of this work was to investigate the use of 13 C-labelled acetoacetate and ?-hydroxybutyrate as novel hyperpolarized substrates in the study of cardiac metabolism. [1-13 C]Acetoacetate was synthesized by catalysed hydrolysis, and both it and [1-13 C]?-hydroxybutyrate were hyperpolarized by dissolution dynamic nuclear polarization (DNP). Their metabolism was studied in isolated, perfused rat hearts. Hyperpolarized [1-13 C]acetoacetate metabolism was also studied in the in vivo rat heart in the fed and fasted states. Hyperpolarization of [1-13 C]acetoacetate and [1-13 C]?-hydroxybutyrate provided liquid state polarizations of 8 ± 2% and 3 ± 1%, respectively. The hyperpolarized T1 values for the two substrates were 28 ± 3 s (acetoacetate) and 20 ± 1 s (?-hydroxybutyrate). Multiple downstream metabolites were observed within the perfused heart, including acetylcarnitine, citrate and glutamate. In the in vivo heart, an increase in acetylcarnitine production from acetoacetate was observed in the fed state, as well as a potential reduction in glutamate. In this work, methods for the generation of hyperpolarized [1-13 C]acetoacetate and [1-13 C]?-hydroxybutyrate were investigated, and their metabolism was assessed in both isolated, perfused rat hearts and in the in vivo rat heart. These preliminary investigations show that DNP can be used as an effective in vivo probe of ketone body metabolism in the heart.
| S-EPMC6001529 | biostudies-other
Project description:Rats were subjected to laparotomy, or laparotomy and partial hepatectomy, at 0-48 h before administration of water or medium-chain-length triacylglycerol, having been starved post-operatively. Functional hepatectomies were performed at intervals after the intragastric load. Blood ketone-body concentrations after medium-chain triacylglycerol administration and/or functional hepatectomy of these rats were compared with values obtained in starved control rats. Decreased ketonaemia in response to medium-chain triacylglycerol was observed for up to 48 h after partial hepatectomy and at 1 and 2 h after laparotomy, but not at 24 or 48 h after laparotomy. Rates of ketone-body clearance after functional hepatectomy were unaffected by prior laparotomy or partial hepatectomy. Ketonaemia after medium-chain-triacylglycerol administration was only partially blocked by inhibition of CPT I (carnitine palmitoyltransferase I). The results demonstrate sustained effects of partial hepatectomy and short-term effects of surgical stress to decrease ketonaemia via inhibition of ketogenesis at site(s) distal to CPT I.
| S-EPMC1147585 | biostudies-other
Project description:1. Folate metabolism was studied during the early phases of liver regeneration after partial hepatectomy in rats accustomed to eating during the first 8h of a daily 12h dark period. 2. The content of 5-CH(3)-H(4)folate was drastically decreased during the first hours of regeneration. 3. The total HCO-H(4)folate coenzymes showed a constant decrease during the first 3 days of regeneration, and a continuous interconversion between 5-HCO-H(4)folate and 10-HCO-H(4)folate. 4. 10-HCO-H(4)folate synthetase, serine hydroxymethyl-transferase and 5,10-CH(2)-H(4)folate dehydrogenase activities were relatively low during the first hours after the operation, and increased only several hours later. 5. The increase in enzyme activities showed a stepwise pattern, apparently due to an interaction between the regeneration process and the controlled feeding schedules.
| S-EPMC1172464 | biostudies-other
Project description:Paracrine interactions are critical to liver physiology, particularly during regeneration, although physiological involvement of extracellular ATP, a crucial intercellular messenger, remains unclear. The physiological release of ATP into extracellular milieu and its impact on regeneration after partial hepatectomy were investigated in this study.Hepatic ATP release after hepatectomy was examined in the rat and in human living donors for liver transplantation. Quinacrine was used for in vivo staining of ATP-enriched compartments in rat liver sections and isolated hepatocytes. Rats were treated with an antagonist for purinergic receptors (Phosphate-6-azo(benzene-2,4-disulfonic acid), PPADS), and liver regeneration after hepatectomy was analyzed.A robust and transient ATP release due to acute portal hyperpressure was observed immediately after hepatectomy in rats and humans. Clodronate liposomal pre-treatment partly inhibited ATP release in rats. Quinacrine-stained vesicles, co-labeled with a lysosomal marker in liver sections and isolated hepatocytes, were predominantly detected in periportal areas. These vesicles significantly disappeared after hepatectomy, in parallel with a decrease in liver ATP content. PPADS treatment inhibited hepatocyte cell cycle progression after hepatectomy, as revealed by a reduction in bromodeoxyuridine incorporation, phosphorylated histone 3 immunostaining, cyclin D1 and A expression and immediate early gene induction.Extracellular ATP is released immediately after hepatectomy from hepatocytes and Kupffer cells under mechanical stress and promotes liver regeneration in the rat. We suggest that in hepatocytes, ATP is released from a lysosomal compartment. Finally, observations made in living donors suggest that purinergic signalling could be critical for human liver regeneration.
| S-EPMC3625734 | biostudies-literature
Project description:Friedreich's ataxia (FRDA) is an autosomal recessive neurodegenerative disease caused by the deficiency of mitochondrial protein frataxin, which plays a crucial role in iron-sulphur cluster formation and ATP production. The cellular function of frataxin is not entirely known. Here, we demonstrate that frataxin controls ketone body metabolism through regulation of 3-Oxoacid CoA-Transferase 1 (OXCT1), a rate limiting enzyme catalyzing the conversion of ketone bodies to acetoacetyl-CoA that is then fed into the Krebs cycle. Biochemical studies show a physical interaction between frataxin and OXCT1 both in vivo and in vitro. Frataxin overexpression also increases OXCT1 protein levels in human skin fibroblasts while frataxin deficiency decreases OXCT1 in multiple cell types including cerebellum and skeletal muscle both acutely and chronically, suggesting that frataxin directly regulates OXCT1. This regulation is mediated by frataxin-dependent suppression of ubiquitin-proteasome system (UPS)-dependent OXCT1 degradation. Concomitantly, plasma ketone bodies are significantly elevated in frataxin deficient knock-in/knockout (KIKO) mice with no change in the levels of other enzymes involved in ketone body production. In addition, ketone bodies fail to be metabolized to acetyl-CoA accompanied by increased succinyl-CoA in vitro in frataxin deficient cells, suggesting that ketone body elevation is caused by frataxin-dependent reduction of OXCT1 leading to deficits in tissue utilization of ketone bodies. Considering the potential role of metabolic abnormalities and deficiency of ATP production in FRDA, our results suggest a new role for frataxin in ketone body metabolism and also suggest modulation of OXCT1 may be a potential therapeutic approach for FRDA.
| S-EPMC9396447 | biostudies-literature
Project description:Postoperative fatigue syndrome is a general complication after surgery. However, there is no ''gold standard'' for fatigue assessment due to the lack of objective biomarkers. In this study, a rodent model of postoperative fatigue syndrome based on partial hepatectomy was firstly established and serum metabonomic method based on ultra-high performance liquid chromatography coupled with Q-TOF mass spectrometry was applied. Partial least-squares discriminant analysis was used to identify the differential metabolites in 70% partial hepatectomy rats relative to sham rats and 30% partial hepatectomy rats, which showed 70% partial hepatectomy group was significantly distinguishable from 30% partial hepatectomy group and sham group. Eighteen serum metabolites responsible for the discrimination were identified. The levels of hypoxanthine, kynurenine, tryptophan, uric acid, phenylalanine, palmitic acid, arachidonic acid and oleic acid showed progressive elevation from sham group to 30% partial hepatectomy group to 70% partial hepatectomy group, and levels of valine, tyrosine, isoleucine, linoleyl carnitine, palmitoylcarnitine, lysophosphatidylcholine (16:0), lysophosphatidylcholine (20:3), citric acid, succinic acid and hippuric acid showed progressive declining trend from sham group to 30% partial hepatectomy group to 70% partial hepatectomy group. These potential biomarkers help to understand of etiology, pathophysiology and treatment of postoperative fatigue syndrome.
| S-EPMC4865597 | biostudies-literature
Project description:Epidermal growth factor (EGF), a multifunctional growth factor, is a regulator in a wide variety of physiological processes. EGF plays an important role in the regulation of liver regeneration. This study was aimed at investigating the methylation level of EGF gene throughout liver regeneration. DNA of liver tissue from control rats and partial hepatectomy (PH) rats at 10 time points was extracted and a 354 bp fragment including 10 CpG sites from the transcription start was amplified after DNA was modified by sodium bisulfate. The result of sequencing suggested that methylation ratio of four CpG sites was found to be significantly changed when PH group was compared to control group, in particular two of them were extremely striking. mRNA expression of EGF was down-regulated in total during liver regeneration. We think that the rat EGF promoter region is regulated by variation in DNA methylation during liver regeneration.
| S-EPMC4094617 | biostudies-literature
Project description:During starvation for 72 h, tumour-bearing rats showed accelerated ketonaemia and marked ketonuria. Total blood [ketone bodies] were 8.53 mM and 3.34 mM in tumour-bearing and control (non-tumour-bearing) rats respectively (P less than 0.001). The [3-hydroxybutyrate]/[acetoacetate] ratio was 1.3 in the tumour-bearing rats, compared with 3.2 in the controls at 72 h (P less than 0.001). Blood [glucose] and hepatic [glycogen] were lower at the start of starvation in tumour-bearing rats, whereas plasma [non-esterified fatty acids] were not increased above those in the control rats during starvation. After functional hepatectomy, blood [acetoacetate], but not [3-hydroxybutyrate], decreased rapidly in tumour-bearing rats, whereas both ketone bodies decreased, and at a slower rate, in the control rats. Blood [glucose] decreased more rapidly in the hepatectomized control rats. Hepatocytes prepared from 72 h-starved tumour-bearing and control rats showed similar rates of ketogenesis from palmitate, and the distribution of [1-14C] palmitate between oxidation (ketone bodies and CO2) and esterification was also unaffected by tumour-bearing, as was the rate of gluconeogenesis from lactate. The carcinoma itself showed rapid rates of glycolysis and a poor ability to metabolize ketone bodies in vitro. The results are consistent with the peripheral, normal, tissues in tumour-bearing rats having increased ketone-body and decreased glucose metabolic turnover rates.
| S-EPMC1153051 | biostudies-other
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:Ketone bodies, including β-hydroxybutyrate and acetoacetate, are important alternative energy sources during energy shortage. β-Hydroxybutyrate also acts as a signaling molecule via specific G protein-coupled receptors (GPCRs); however, the specific associated GPCRs and physiological functions of acetoacetate remain unknown. Here we identified acetoacetate as an endogenous agonist for short-chain fatty acid (SCFA) receptor GPR43 by ligand screening in a heterologous expression system. Under ketogenic conditions, such as starvation and low-carbohydrate diets, plasma acetoacetate levels increased markedly, whereas plasma and cecal SCFA levels decreased dramatically, along with an altered gut microbiota composition. In addition, Gpr43-deficient mice showed reduced weight loss and suppressed plasma lipoprotein lipase activity during fasting and eucaloric ketogenic diet feeding. Moreover, Gpr43-deficient mice exhibited minimal weight decrease after intermittent fasting. These observations provide insight into the role of ketone bodies in energy metabolism under shifts in nutrition and may contribute to the development of preventive medicine via diet and foods.
| S-EPMC6876247 | biostudies-literature