Regulation of myocardial ketone body metabolism by the gut microbiota during nutrient deprivation.
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ABSTRACT:
SUBMITTER: Crawford PA
PROVIDER: S-EPMC2700149 | biostudies-literature |
REPOSITORIES: biostudies-literature
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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.
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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.
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Project description:Starvation is probably the most common stressful situation in nature. In vertebrates, elevation of the biogenic amine norepinephrine levels is common during starvation. However, the precise role of norepinephrine in nutrient deprivation remains largely unknown. We report that in the free-living nematode Caenorhabditis elegans, up-regulation of the biosynthesis of octopamine, the invertebrate counterpart of norepinephrine, serves as a mechanism to adapt to starvation. During nutrient deprivation, the nuclear receptor DAF-12, known to sense nutritional cues, up-regulates the expression of tbh-1 that encodes tyramine ?-hydroxylase, a key enzyme for octopamine biosynthesis, in the RIC neurons. Octopamine induces the expression of the lipase gene lips-6 via its receptor SER-3 in the intestine. LIPS-6, in turn, elicits lipid mobilization. Our findings reveal that octopamine acts as an endocrine regulator linking nutrient cues to lipolysis to maintain energy homeostasis, and suggest that such a mechanism may be evolutionally conserved in diverse organisms.
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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.
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Project description:Mechanisms that coordinate different metabolic pathways, such as glucose and lipid, have been recognized. However, a potential interaction between amino acid and lipid metabolism remains largely elusive. Here we show that during starvation of Caenorhabditis elegans, proline catabolism is coupled with lipid metabolism by SKN-1. Mutation of alh-6, a conserved proline catabolic enzyme, accelerates fat mobilization, enhances the expression of genes involved in fatty acid oxidation and reduces survival in response to fasting. This metabolic coordination is mediated by the activation of the transcription factor SKN-1/Nrf2, possibly due to the accumulation of the alh-6 substrate P5C, and also requires the transcriptional co-regulator MDT-15. Constitutive activation of SKN-1 induces a similar transcriptional response, which protects animals from fat accumulation when fed a high carbohydrate diet. In human cells, an orthologous alh-6 enzyme, ALDH4A1, is also linked to the activity of Nrf2, the human orthologue of SKN-1, and regulates the expression of lipid metabolic genes. Our findings identify a link between proline catabolism and lipid metabolism, and uncover a physiological role for SKN-1 in metabolism.
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Project description:Background:Metabolic remodeling plays a vital role in the development of heart failure. The trimetazidine can optimize fatty acid and glucose oxidation via inhibition of long-chain 3-ketoacyl CoA thiolase in the heart. So, trimetazidine commonly used in cardiovascular therapy as a myocardial metabolic drug. This study was conducted to assess the effects and mechanisms of trimetazidine on ketone body metabolism in heart failure rats. Methods:A rat model of heart failure was established by continuous subcutaneous injection of isoproterenol in 10 mg/kg/d. We examined body weight, heart weight index, and tested B-type natriuretic peptide by kit. We detected the structure and function of the heart. Hematoxylin-eosin staining and Masson's trichrome staining was performed to assess myocardial tissue morphology. To evaluate apoptosis, we used Tunel staining. Metabolic substrate contents of glucose, free fatty acid, ketone bodies, lactic acid, and pyruvate and ATP levels in myocardial tissues were measured with the corresponding kit. We detected the levels of protein expressions related to myocardial substrate uptake and utilization by Western blot. Results:Trimetazidine remarkably reduced the heart weight index and B-type natriuretic peptide levels. Besides, trimetazidine increased the level of blood pressure and decreased heart rate. Moreover, trimetazidine inhibited decreases in left ventricular ejection fraction and left ventricular fractional shortening. Further, trimetazidine decreased the levels of collagen volume fraction and promoted ATP production in myocardial tissues. Trimetazidine also reduced the levels of free fatty acid, ketone bodies, lactic acid, and increased glucose and pyruvate levels in myocardial tissues. Furthermore, trimetazidine markedly inhibited apoptosis. More importantly, the protein expression levels related to myocardial substrate uptake and utilization increased dramatically in the trimetazidine group. In particular, the protein expressions related to ketone body utilization were prominent. Conclusions:Trimetazidine could attenuate metabolic remodeling and improve cardiac function in heart failure rats. The potential mechanism for the cardioprotective effect of trimetazidine may be highly associated with its regulation of adenosine monophosphate-activated protein kinase, and peroxisome proliferator activated receptor ? expressions. Along with the regulation, myocardial substrate utilization was improved, especially the utilization of ketone bodies.
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Project description:IntroductionEriocitrin, found in lemon fruit, has shown a wide range of biological properties. Herein, we investigated the intestinal metabolic profile of eriocitrin in colon, and the regulation of dietary intervention of eriocitrin on gut microbiota.MethodsWe performed ultra performance liquid chromatography-electrospray ionization-tandem mass spectrometry (UPLC-ESI-MS/MS), 16S rDNA gene sequencing and gas chromatography-mass (GC-MS) on colon contents from the eriocitrin group (n=6), and compared them with control participants (n=6).ResultsA total of 136 flavonoids were found in colon contents, including eriocitrin and its six metabolites (eriodictyol, homoeriodictyol, hesperetin, eriodictyol-3'-O-glucoside, hesperetin-7-O-glucoside and eriodictyol-7-O-(6″-O-galloyl) glucoside). Moreover, dietary intervention of eriocitrin significantly alters the beta diversity of the gut microbiota, the probiotics such as Lachnospiraceae_UCG_006 were significantly enriched, and the production of butyrate, valerate and hexanoate in the colon pool of short-chain fatty acids were significant increased. The spearman's association analysis performed some intestinal bacteria may be involved in the metabolism of eriocitrin.DiscussionCollectively, our results preliminarily suggest the metabolism of eriocitrin in the gut, demonstrating alterations of eriocitrin in gut microbiota, which warrants further investigation to determine its potential use in food and biomedical applications.
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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:Weaning transition usually impairs intestinal architecture and functions and results in gut-associated disorders in pigs. Understanding the changes in intestinal transcriptome and gut microbiota during weaning transition is important for elucidating the underlying mechanism of weaning stress. In the present study, we performed RNA-seq to determine the changes in intestinal transcriptome and 16S rRNA sequencing to measure the gut microbiota changes in the weaning transition. Transcriptome results indicated that weaning transition altered intestinal gene expression involved in nutrient transport and metabolism. Regarding fatty metabolism, fatty acid-binding protein 1 (FABP1), acyl-CoA dehydrogenase (ACADSB), and carnitine palmitoyltransferase 2 (CPT2) expression in the intestine was decreased by weaning. Genes related to bile acid metabolism were increased by weaning, including FABP6, farnesoid X receptor (FXR or NR1H4) and organic solute transporter-? (SLC51A). In addition, genes associated with oxidative stress were altered by weaning transition, including decreased catalase (CAT) and lactate dehydrogenase (LDHA) and increased glutathione peroxidase 2 (GPX2) and superoxide dismutase 3 (SOD3). Results of microbiota composition showed that the Firmicutes abundance and Firmicutes/Bacteroidetes ratio were increased and that the Proteobacteria abundance in the fecal microbiota was decreased by the weaning process; during the weaning transition, the Bacteroides and Fusobacterium abundances decreased markedly, and these bacteria nearly disappeared, while the Prevotella abundance showed a marked increase. Moreover, the levels of the microbial metabolites butyrate and acetate increased with changes in gut microbiota composition. In addition, predictive metagenome by PICRUSt analysis showed that the pathways related to D-glutamine and D-glutamate metabolism, citrate cycle (TCA cycle), peroxisome proliferators-activated receptor (PPAR) signaling, alpha-linolenic acid metabolism were decreased and the pathway related to retinol metabolism was increased in the gut microbiota of piglets during weaning transition. Our results showed that early weaning alters intestinal gene expression involved in nutrient metabolism, which may be due to the changes in microbiota composition.
| S-EPMC7181064 | biostudies-literature
Project description:Eriocitrin, found in lemon fruit, has shown a wide range of biological properties. Herein, to evaluate the intestinal metabolic profile of eriocitrin in colon, the flavonoids in mice colon contents were identified by ultra performance liquid chromatography-electrospray ionization-tandem mass spectrometry (UPLC-ESI-MS/MS), and a total of 136 flavonoids were found, including eriocitrin and its six metabolites (eriodictyol, homoeriodictyol, hesperetin, eriodictyol-3'-O-glucoside, hesperetin-7-O-glucoside and eriodictyol-7-O-(6''-O-galloyl) glucoside). Mice colon contents were used for 16S rDNA gene sequencing and gas chromatography-mass (GC-MS). Resultu showed that eriocitrin significantly alters the beta diversity of the gut microbiota, the probiotics such as Lachnospiraceae_UCG_006 were significantly enriched, and the production of butyrate, valerate and hexanoate in the colon pool of short-chain fatty acids (SCFAs) were significant increased. The spearman's association analysis performed some intestinal bacteria may be involved in the metabolism of eriocitrin. Collectively, our results preliminarily suggesting the metabolism of eriocitrin in the gut, demonstrate alterations of eriocitrin on gut microbiota, which warrants further investigation to determine its potential use in food and biomedical applications.
2022-11-30 | GSE218729 | GEO