Effects of liver damage on ketone-body production and nitrogen balance in starved rats.
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ABSTRACT:
SUBMITTER: Flatt JP
PROVIDER: S-EPMC1163232 | biostudies-other | 1981 Jul
REPOSITORIES: biostudies-other
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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:Ketone bodies [beta-hydroxybutyrate (bHB) and acetoacetate] are mainly produced in the liver during prolonged fasting or starvation. bHB is a very efficient energy substrate for sustaining ATP production in peripheral tissues; importantly, its consumption is preferred over glucose. However, the majority of malignant cells, particularly cancer cells of neuroectodermal origin such as glioblastoma, are not able to use ketone bodies as a source of energy. Here, we report a novel observation that fenofibrate, a synthetic peroxisome proliferator-activated receptor alpha (PPARa) agonist, induces bHB production in melanoma and glioblastoma cells, as well as in neurospheres composed of non-transformed cells. Unexpectedly, this effect is not dependent on PPARa activity or its expression level. The fenofibrate-induced ketogenesis is accompanied by growth arrest and downregulation of transketolase, but the NADP/NADPH and GSH/GSSG ratios remain unaffected. Our results reveal a new, intriguing aspect of cancer cell biology and highlight the benefits of fenofibrate as a supplement to both canonical and dietary (ketogenic) therapeutic approaches against glioblastoma.
| S-EPMC4735548 | biostudies-literature
Project description:1. Rates of appearance and disappearance of total ketone bodies were determined in normal, starved and alloxan-diabetic rats by measuring specific radioactivities and concentrations of blood acetoacetate and 3-hydroxybutyrate at different times after injection of 3-hydroxy[(14)C]butyrate. 2. The mean rates of appearance were 1.7, 4.2 and 10.9mumoles/min./100g. body wt. respectively for normal, starved and alloxan-diabetic rats. The rates of disappearance were of the same order of magnitude as the rates of appearance. 3. There was a direct correlation between the rates of appearance and disappearance and the blood concentrations of the ketone bodies. 4. The results indicate that in the rat increased ketone-body production is paralleled by increased ketone-body utilization and that the raised ketone-body concentration in the blood in starvation and alloxan-diabetes is due to a slight imbalance between the rates of production and utilization. 5. The findings are discussed in relation to the concept that ketone bodies can serve as fuels of respiration when the supply of carbohydrate is limited.
| S-EPMC1187436 | biostudies-other
Project description:Hong Shan Capsule (HSC), a crude drug of 11 medicinal herbs, was used in clinical practice for the treatment of radiation injuries in China. In this study, we investigated its protection in rats against acute lethal total-body irradiation (TBI). Pre-administration of HSC reduced the radiation sickness characteristics, while increasing the 30-day survival of the irradiated rats. Administration of HSC also reduced the radiation sickness characteristics and increased the 30-day survival of mice after exposure to lethal TBI. Ultrastructural observation illustrated that the pretreatment of rats with HSC significantly attenuated the TBI-induced morphological changes in the different organs of irradiated rats. Gene expression profiles revealed the dramatic effect of HSC on alterations of gene expression caused by lethal TBI. Pretreatment with HSC prevented differential expression of 66% (1398 genes) of 2126 genes differentially expressed in response to TBI. Pathway enrichment analysis indicated that these genes were mainly involved in a total of 32 pathways, such as pathways in cancer and the mitogen-activated protein kinase (MAPK) signaling pathway. Our analysis indicated that the pretreatment of rats with HSC modulated these pathways induced by lethal TBI, such as multiple MAPK pathways, suggesting that pretreatment with HSC might provide protective effects on lethal TBI mainly or partially through the modulation of these pathways. Our data suggest that HSC has the potential to be used as an effective therapeutic or radio-protective agent to minimize irradiation damage.
| S-EPMC4581280 | biostudies-literature
Project description:1. The rates of formation of acetoacetate and beta-hydroxybutyrate by the isolated perfused rat liver were measured under various conditions. 2. The rates found after addition of butyrate, octanoate, oleate and linoleate were about 100mumoles/hr./g. wet wt. in the liver of starved rats. These rates are much higher than those found with rat liver slices. 3. The differences between the rates given by slices and by the perfused organ were much higher with the long-chain than with short-chain fatty acids. The increments caused by oleate and linoleate were 12 and 16 times as large in the perfused organ as in the slices, whereas the increments caused by butyrate and octanoate were about four times as large. 4. The rates of ketogenesis in the unsupplemented perfused liver of well-fed rats, and the increments caused by the addition of fatty acids, were about half of those in the liver from starved rats. 5. The value of the [beta-hydroxybutyrate]/[acetoacetate] ratio of the medium was raised by octanoate, oleate and linoleate. 6. Carnitine did not significantly accelerate ketogenesis from fatty acids. 7. Oleate formed up to 82% of the expected yield of ketone bodies. 8. In the liver of alloxan-diabetic rats the endogenous rates of ketogenesis were raised, in some cases as high as in the liver from starved rats, after addition of oleate. 9. On addition of either beta-hydroxybutyrate or acetoacetate to the perfusion medium the liver gradually adjusted the [beta-hydroxybutyrate]/[acetoacetate] ratio towards the normal range. 10. The [beta-hydroxybutyrate]/[acetoacetate] ratio of the medium was about 0.4 when slices were incubated, but near the physiological value of 2 when the liver was perfused. 11. The experiments demonstrate that for the study of ketogenesis slices are in many ways grossly inferior to the perfused liver.
| S-EPMC1187761 | biostudies-other
Project description:Objectives: Exogenous ketones may provide therapeutic benefit in treatment of obesity. Administration of the ketone ester (KE) R,S-1,3-butanediol acetoacetate diester (BD-AcAc2) decreases body weight in mice, but effects on energy balance have not been extensively characterized. The purpose of this investigation was to explore concentration-dependent effects of BD-AcAc2 on energy intake and expenditure in mice. Methods: Forty-two male C57BL/6J mice were randomly assigned to one of seven isocaloric diets (n = 6 per group): (1) Control (CON, 0% KE by kcals); (2) KE5 (5% KE); (3) KE10 (10% KE); (4) KE15 (15% KE); (5) KE20 (20% KE); (6) KE25 (25% KE); and (7) KE30 (30% KE) for 3 weeks. Energy intake and body weight were measured daily. Fat mass (FM), lean body mass (LBM), and energy expenditure (EE) were measured at completion of the study. Differences among groups were compared to CON using ANOVA and ANCOVA. Results: Mean energy intake was similar between CON and each concentration of KE, except KE30 which was 12% lower than CON (P < 0.01). KE25 and KE30 had lower body weight and FM compared to CON, while only KE30 had lower LBM (P < 0.03). Adjusted resting and total EE were lower in KE30 compared to CON (P < 0.03), but similar for all other groups. Conclusions: A diet comprised of 30% energy from BD-AcAc2 results in lower energy intake, coincident with lower body weight and whole animal adiposity; while KE20 and KE25 have significantly lower body weight and adiposity effects independent of changes in energy intake or expenditure.
| S-EPMC6504762 | biostudies-literature
Project description:A double-isotope procedure was used to measure the effects of insulin and glucagon on ketone-body production and utilization (i.e. turnover) in the starved rat. Somatostatin was infused during the experiment to suppress the pancreatic release of either hormone. The immediate action of insulin in terms of ketone-body turnover that was most evident was a decreased production of 3-hydroxybutyrate, with no significant change in the turnover of acetoacetate. Similarly, the significant effect of glucagon infusion was to increase the production of 3-hydroxybutyrate, with minimum increase in acetoacetate turnover. The data support a direct effect of both hormones on the distribution of acetyl units derived from fatty acid beta-oxidation.
| S-EPMC1144056 | biostudies-other
Project description:1. In short- and long-term diabetic rats there is a marked increase in size of both the small intestine and colon, which was accompanied by marked decreases (P less than 0.001) and increases (P less than 0.001) in the arterial concentrations of glutamine and ketone bodies respectively. 2. Portal-drained viscera blood flow increased by approx. 14-37% when expressed as ml/100 g body wt., but was approximately unchanged when expressed as ml/g of small intestine of diabetic rats. 3. Arteriovenous-difference measurements for ketone bodies across the gut were markedly increased in diabetic rats, and the gut extracted ketone bodies at approx. 7 and 60 nmol/min per g of small intestine in control and 42-day-diabetic rats respectively. 4. Glutamine was extracted by the gut of control rats at a rate of 49 nmol/min per g of small intestine, which was diminished by 45, 76 and 86% in 7-, 21- and 42-day-diabetic rats respectively. 5. Colonocytes isolated from 7- or 42-day-diabetic rats showed increased and decreased rates of ketone-body and glutamine metabolism respectively, whereas enterocytes of the same animals showed no apparent differences in the rates of acetoacetate utilization as compared with control animals. 6. Prolonged diabetes had no effects on the maximal activities of either glutaminase or ketone-body-utilizing enzymes of colonic tissue preparations. 7. It is concluded that, although the epithelial cells of the small intestine and the colon during streptozotocin-induced diabetes exhibit decreased rates of metabolism of glutamine, such decreases were partially compensated for by enhanced ketone-body utilization by the gut mucosa of diabetic rats.
| S-EPMC1148739 | biostudies-other
Project description:1. The effects of starvation and diabetes on brain fuel metabolism were examined by measuring arteriovenous differences for glucose, lactate, acetoacetate and 3-hydroxybutyrate across the brains of anaesthetized fed, starved and diabetic rats. 2. In fed animals glucose represented the sole oxidative fuel of the brain. 3. After 48h of starvation, ketone-body concentrations were about 2mm and ketone-body uptake accounted for 25% of the calculated O(2) consumption: the arteriovenous difference for glucose was not diminished, but lactate release was increased, suggesting inhibition of pyruvate oxidation. 4. In severe diabetic ketosis, induced by either streptozotocin or phlorrhizin (total blood ketone bodies >7mm), the uptake of ketone bodies was further increased and accounted for 45% of the brain's oxidative metabolism, and the arteriovenous difference for glucose was decreased by one-third. The arteriovenous difference for lactate was increased significantly in the phlorrhizin-treated rats. 5. Infusion of 3-hydroxybutyrate into starved rats caused marked increases in the arteriovenous differences for lactate and both ketone bodies. 6. To study the mechanisms of these changes, steady-state concentrations of intermediates and co-factors of the glycolytic pathway were determined in freeze-blown brain. 7. Starved rats had increased concentrations of acetyl-CoA. 8. Rats with diabetic ketosis had increased concentrations of fructose 6-phosphate and decreased concentrations of fructose 1,6-diphosphate, indicating an inhibition of phosphofructokinase. 9. The concentrations of acetyl-CoA, glycogen and citrate, a potent inhibitor of phosphofructokinase, were increased in the streptozotocin-treated rats. 10. The data suggest that cerebral glucose uptake is decreased in diabetic ketoacidosis owing to inhibition of phosphofructokinase as a result of the increase in brain citrate. 11. The inhibition of brain pyruvate oxidation in starvation and diabetes can be related to the accelerated rate of ketone-body metabolism; however, we found no correlation between the decrease in glucose uptake in the diabetic state and the arteriovenous difference for ketone bodies. 12. The data also suggest that the rates of acetoacetate and 3-hydroxybutyrate utilization by brain are governed by their concentrations in plasma. 13. The finding of very low concentrations of acetoacetate and 3-hydroxybutyrate in brain compared with plasma suggests that diffusion across the blood-brain barrier may be the rate-limiting step in their metabolism.
| S-EPMC1166169 | biostudies-other
Project description:The mitochondrial sirtuin SIRT3 regulates metabolic homeostasis during fasting and calorie restriction. We identified mitochondrial 3-hydroxy-3-methylglutaryl CoA synthase 2 (HMGCS2) as an acetylated protein and a possible target of SIRT3 in a proteomics survey in hepatic mitochondria from Sirt3(-/-) (SIRT3KO) mice. HMGCS2 is the rate-limiting step in ?-hydroxybutyrate synthesis and is hyperacetylated at lysines 310, 447, and 473 in the absence of SIRT3. HMGCS2 is deacetylated by SIRT3 in response to fasting in wild-type mice, but not in SIRT3KO mice. HMGCS2 is deacetylated in vitro when incubated with SIRT3 and in vivo by overexpression of SIRT3. Deacetylation of HMGCS2 lysines 310, 447, and 473 by incubation with wild-type SIRT3 or by mutation to arginine enhances its enzymatic activity. Molecular dynamics simulations show that in silico deacetylation of these three lysines causes conformational changes of HMGCS2 near the active site. Mice lacking SIRT3 show decreased ?-hydroxybutyrate levels during fasting. Our findings show SIRT3 regulates ketone body production during fasting and provide molecular insight into how protein acetylation can regulate enzymatic activity.
| S-EPMC3310379 | biostudies-literature