Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0038187 (starvation)
 24,951 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effect of insulin on the properties of liver carnitine palmitoyltransferase I (CPT I) was assessed in conscious starved rats with the euglycemic hyperinsulinemic clamp. A 24-hour clamp was necessary to fully reverse the effect of starvation on liver malonyl-CoA concentration, CPT I maximal activity, and apparent km and Ki for malonyl-CoA. Since glucagon was not decreased during the clamp, insulin is the major factor involved in the regulation of CPT I.
 ...
PMID:Effect of insulin on the properties of liver carnitine palmitoyltransferase in the starved rat: assessment by the euglycemic hyperinsulinemic clamp. 186 36

To determine the respective part of modifications of glucose appearance and disappearance rates in the hypoglycemic action of a compound (B 827-33) inhibiting carnitine palmitoyl transferase (CPT I), we measured glucose kinetics ([6,6(2)H2]glucose) in normal and diabetic (streptozocin) rats before and after injection of either saline or B 827-33. Studies were initiated 4 hours (postabsorptive groups) and 24 hours (fasted groups) after food withdrawal. In all groups, there was evidence of inhibition of fatty acids oxidation (sharp decrease of ketone bodies [KB] and increase of plasma nonesterified fatty acids [NEFA]) after B 827-33 injection. Glucose levels decreased also in all groups after B 827-33 administration, the decrease being more important in starved than in postabsorptive groups and, whatever the nutritional status, in diabetic than in normal rats. In all groups, the evolution of plasma insulin was comparable after saline or B 827-33 injection. The mechanisms responsible for the decrease in glucose levels appeared dependent on the nutritional status. In postabsorptive normal and diabetic rats, compared with saline-injected rats, we observed a moderate inhibitory action (P less than .05) of B 827-33 on glucose production without stimulation of glucose utilization rate. After 24 hours of starvation, the decrease in glucose levels of normal rats was entirely due to a stimulation of glucose utilization (P less than .05), whereas glucose production was unexpectedly increased (P less than .05) above values of saline-injected rats.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Mechanisms of the glucose lowering effect of a carnitine palmitoyl transferase inhibitor in normal and diabetic rats. 201 Oct 84

1. A permeabilized isolated rat liver cell preparation was developed to achieve selective permeabilization of the cell membrane to metabolites and to allow the assay of mitochondrial overt carnitine palmitoyltransferase (CPT I) activity in situ. By performing the digitonin-induced permeabilization in the presence of fluoride and bivalent-metal-cation sequestrants, it was possible to demonstrate that the activity of other enzymes, which are regulated by reversible phosphorylation, was preserved during the procedure and subsequent washing of cells before assay. 2. CPT activity at a sub-optimal palmitoyl-CoA concentration was almost totally (approximately 90%) inhibited by malonyl-CoA, indicating that mitochondrial CPT I was largely measured in this preparation. 3. The palmitoyl-CoA-saturation and malonyl-CoA-inhibition curves for CPT activity in permeabilized cells were very similar to those obtained previously for the enzyme in isolated liver mitochondria. Moreover, starvation and diabetes had the same effects on enzyme activity, affinity for palmitoyl-CoA and malonyl-CoA sensitivity of CPT I in isolated cells as found in isolated mitochondria. These physiologically induced changes persisted through the cell preparation and incubation period. 4. Neither incubation of cells with glucagon or insulin nor incubation with pyruvate and lactate before permeabilization resulted in alterations of these parameters of CPT I in isolated cells. 5. The results are discussed in relation to the temporal relationships of changes in the activity and properties of CPT I in vivo in relation to the effects of insulin and glucagon on fatty acid metabolism in vivo.
 ...
PMID:Use of a selectively permeabilized isolated rat hepatocyte preparation to study changes in the properties of overt carnitine palmitoyltransferase activity in situ. 328 53

The effects of the ingestion of a meal on the partitioning of hepatic fatty acids between oxidation and esterification were studied in vivo for meal-fed rats. The time course for the reversal of the starved state was extremely rapid and the process was complete within 2 h, in marked contrast with the reversal of the effects of starvation in rats fed ad libitum [A. M. B. Moir and V. A. Zammit (1993) Biochem. J. 289, 49-55]. This rapid reversal occurred in spite of the fact that, in the liver of the meal-fed animals before feeding, a similar degree of partitioning of fatty acids in favour of oxidation was observed as in 24 h-starved rats (previously fed ad libitum). This suggested that the lower degree of ketonaemia observed in meal-fed rats before a meal is not due to the inability of acylcarnitine formation to compete successfully with esterification of fatty acids to the glycerol moiety. Investigation of the possible mechanisms that could contribute towards the rapid switching-off of fatty acid oxidation revealed that this was correlated with a very rapid rise and overshoot in hepatic malonyl-CoA concentration, but not with any change in the activity, or sensitivity to malonyl-CoA, of the mitochondrial overt carnitine palmitoyltransferase (CPT I). The role of these two parameters in the reversal of fasting-induced hepatic fatty acid oxidation was thus the inverse of that observed previously for refed 24 h-starved rats. The rapid increase in [malonyl-CoA] was accompanied by an immediate and complete reversion of the kinetic characteristics (Ka for citrate, expressed/total activity ratio) of acetyl-CoA carboxylase to those found in the post-meal animals, again in contrast with the time course observed in refed 24 h-starved rats [A. M. B. Moir and V. A. Zammit (1990) Biochem. J. 272, 511-517]. The rapidity with which these changes occurred was specific to the partitioning of acyl-CoA; the meal-induced diversion of glycerolipids towards phospholipid synthesis and the acute inhibition of the fractional rate of triacylglycerol secretion occurred with very similar time courses to those observed upon refeeding of 24 h-starved rats. The results confirm the central role played by differences in the dynamics of changes in hepatic malonyl-CoA concentration, and CPT I sensitivity to it, in determining the route through which ingested glucose is converted into hepatic glycogen upon refeeding of starved rats which had previously been meal-fed or fed ad libitum.
 ...
PMID:Rapid switch of hepatic fatty acid metabolism from oxidation to esterification during diurnal feeding of meal-fed rats correlates with changes in the properties of acetyl-CoA carboxylase, but not of carnitine palmitoyltransferase I. 809 87

1. The technique of selective labelling of hepatic fatty acids in vivo [Moir and Zammit (1992) Biochem. J. 283, 145-149] has been used to monitor non-invasively the metabolism of fatty acids in the livers of awake unrestrained rats during the starved-to-refed transition. Values for the incorporation of labelled fatty acid into liver and plasma glycerolipids and into exhaled carbon dioxide after injection of labelled lipoprotein and Triton WR 1339 into rats with chronically cannulated jugular veins were obtained for successive 1 h periods from the start of refeeding of 24 h-starved rats. 2. Starvation for 24 h resulted in marked and reciprocal changes in the incorporation of label into glycerolipids and exhaled 14CO2, such that a 4-fold higher value was obtained for the oxidation/esterification ratio in livers of starved rats compared with fed animals. 3. Refeeding of starved rats did not return this ratio to the value observed for fed animals for at least 7 h; during the first 3 h of refeeding the ratio was at least as high as that for starved rats. Between 4 h and 6 h of refeeding the ratio was still approx. 70% of that in starved animals, and 2.5-fold higher than in fed rats. 4. These data support the hypothesis that the capacity of the liver to oxidize fatty acids is maintained at a high level during the initial stages of refeeding [Grantham and Zammit (1986) Biochem. J. 239, 485-488] and that control of the flux of hepatic fatty acids into the oxidative pathway is largely lost from the reaction catalysed by mitochondrial overt carnitine palmitoyltransferase (CPT I) during this phase of recovery from the starved state. 5. Refeeding also resulted in a rapid (< 1 h) increase in hepatic malonyl-CoA concentrations to values intermediate between those in livers of fed and starved animals. The sensitivity of CPT I to malonyl-CoA inhibition in isolated liver mitochondria was only partially reversed even after 5 h of refeeding. 6. Refeeding resulted in an acute 35% inhibition of the fraction of synthesized triacylglycerol that was secreted into the plasma; the maximal effect occurred 2-3 h after the start of refeeding. The inhibition of the fractional secretion rate was fully reversed after 5 h of refeeding. 7. The amount of 14C label that was incorporated into phospholipids as a fraction of total glycerolipid synthesis was doubled within 2 h of the start of refeeding.(ABSTRACT TRUNCATED AT 400 WORDS)
 ...
PMID:Monitoring of changes in hepatic fatty acid and glycerolipid metabolism during the starved-to-fed transition in vivo. Studies on awake, unrestrained rats. 842 71

The relationships between the increase in blood ketone-body concentrations and several parameters that can potentially influence the rate of hepatic fatty acid oxidation were studied during progressive starvation (up to 24 h) in the rat in order to discover whether the sensitivity of mitochondrial overt carnitine palmitoyltransferase (CPT I) to malonyl-CoA plays an important part in determining the intrahepatic potential for fatty acid oxidation during the onset of ketogenic conditions. A rapid increase in blood ketone-body concentration occurred between 12 and 16 h of starvation, several hours after the marked fall in hepatic malonyl-CoA and in serum insulin concentrations and doubling of plasma non-esterfied fatty acid (NEFA) concentration. Consequently, both the changes in hepatic malonyl-CoA and serum NEFA preceded the increase in blood ketone-body concentration by several hours. The maximal activity of CPT I increased gradually throughout the 24 h period of starvation, but the increases did not become significant before 18 h of starvation. By contrast, the sensitivity of CPT I to malonyl-CoA and the increase in blood ketone-body concentration followed an identical time course, demonstrating the central importance of this parameter in determining the ketogenic response of the liver to the onset of the starved state.
 ...
PMID:The role of changes in the sensitivity of hepatic mitochondrial overt carnitine palmitoyltransferase in determining the onset of the ketosis of starvation in the rat. 883 17

The fatty acid composition of the diet has been found to influence the activity and sensitivity of mitochondrial carnitine palmitoyltransferase I (CPT I; EC 2.3.1.21) to inhibition by malonyl CoA in rat heart and skeletal muscle. The nutritional state of rats has been shown to have less influence on the activity and metabolic control of mitochondrial CPT I in heart and skeletal muscle tissue than in the liver, a tissue in which CPT I activity and sensitivity to inhibition by malonyl CoA can be shown to be regulated acutely under different nutritional conditions. However, because manipulation of the nutritional state in these previous studies was restricted mainly to examining the effect of starvation, this study was undertaken to determine whether, as in liver, the fatty acid content and composition of the diet can regulate the activity and metabolic control of CPT I in heart and skeletal muscle. Rats were fed for up to 10 wk either a nonpurified low fat diet (30 g fat/kg) or a high fat diet (200 g fat/kg) containing one of the following five oil types: hydrogenated coconut oil (HCO), olive oil (OO), safflower oil (SO), evening primrose oil (EPO) or menhaden (fish) oil (MO). Feeding a diet enriched in MO had the most pronounced effect. Rats fed MO had a significantly greater skeletal muscle CPT I specific activity and tissue capacity, and a lower sensitivity of CPT I to malonyl CoA inhibition compared with rats fed a low fat diet, but the duration of feeding required to modulate this sensitivity was longer than that observed previously for the liver enzyme. Progressively greater sensitivity of heart CPT I to malonyl CoA occurred with feeding duration in all groups. These studies indicate that the fatty acid composition of the diet is involved in the regulation of mitochondrial CPT I activity in heart and skeletal muscle.
 ...
PMID:Dietary fatty acids influence the activity and metabolic control of mitochondrial carnitine palmitoyltransferase I in rat heart and skeletal muscle. 934 40

Fasting elicits a progressive increase in lipid metabolism within skeletal muscle. To determine the effects of fasting on the transcriptional regulation of genes important for metabolic control in skeletal muscle composed of different fiber types, nuclei from control and fasted (24 and 72 h) rats were subjected to nuclear run-on analysis using an RT-PCR-based technique. Fasting increased (P < 0.05) transcription rate of the muscle-specific uncoupling protein-3 gene (UCP3) 14.3- to 21.1-fold in white gastrocnemius (WG; fast-twitch glycolytic) and 5.5- to 7.5-fold in red gastrocnemius (RG; fast-twitch oxidative) and plantaris (PL; mixed) muscles. No change occurred in soleus (slow-twitch oxidative) muscle. Fasting also increased transcription rate of the lipoprotein lipase (LPL), muscle carnitine palmitoyltransferase I (CPT I), and long-chain acyl-CoA dehydrogenase (LCAD) genes 1.7- to 3.7-fold in WG, RG, and PL muscles. Transcription rate responses were similar after 24 and 72 h of fasting. Surprisingly, increasing metabolic demand during the initial 8 h of starvation (two 2-h bouts of treadmill running) attenuated the 24-h fasting-induced transcriptional activation of UCP3, LPL, CPT I, and LCAD in RG and PL muscles, suggesting the presence of opposing regulatory mechanisms. These data demonstrate that fasting elicits a fiber type-specific coordinate increase in the transcription rate of several genes involved in and/or required for lipid metabolism and indicate that exercise may attenuate the fasting-induced transcriptional activation of specific metabolic genes.
 ...
PMID:Exercise attenuates the fasting-induced transcriptional activation of metabolic genes in skeletal muscle. 1082 11

Glucose and fatty acid metabolism (oxidation versus esterification) has been measured in hepatocytes isolated from 24 h starved peroxisome proliferator-activated receptor-alpha (PPARalpha) null and wild-type mice. In PPARalpha null mice, the development of hypoglycemia during starvation was due to a reduced capacity for hepatic gluconeogenesis secondary to a 70% lower rate of fatty acid oxidation. This was not due to inappropriate expression of the hepatic CPT I gene, which was similar in both genotypes, but to impaired mitochondrial hydroxymethylglutaryl-CoA synthase gene expression in the PPARalpha null mouse liver. We also demonstrate that hepatic steatosis of fasting PPARalpha null mice was not due to enhanced triglyceride synthesis.
 ...
PMID:Reduced hepatic fatty acid oxidation in fasting PPARalpha null mice is due to impaired mitochondrial hydroxymethylglutaryl-CoA synthase gene expression. 1086 48

Liver carnitine palmitoyltransferase I catalyzes the transfer of long-chain fatty acids into mitochondria. L-CPT I is considered the rate-controlling enzyme in fatty acid oxidation. Expression of the L-CPT I gene is induced by starvation in response to glucagon secretion from the pancreas, an effect mediated by cAMP. Here, the molecular mechanisms underlying the induction of L-CPT I gene expression by cAMP were characterized. We demonstrate that the cAMP response unit of the L-CPT I gene is composed of a cAMP-response element motif and a DR1 sequence located 3 kb upstream of the transcription start site. Our data strongly suggest that the coactivator PGC-1 is involved in the regulation of this gene expression by cAMP in combination with HNF4 alpha and cAMP-response element-binding protein (CREB). Indeed, (i) cotransfection of CREB or HNF4 alpha dominant negative mutants completely abolishes the effect of cAMP on the L-CPT I promoter, and (ii) the cAMP-responsive unit binds HNF4 alpha and CREB through the DR1 and the cAMP-response element sequences, respectively. Moreover, cotransfection of PGC-1 strongly activates the L-CPT I promoter through HNF4 alpha bound at the DR1 element. Finally, we show that the transcriptional induction of the PGC-1 gene by glucagon through cAMP in hepatocytes precedes that of L-CPT-1. In addition to the key role that PGC-1 plays in glucose homeostasis, it may also be critical for lipid homeostasis. Taken together these observations suggest that PGC-1 acts to coordinate the process of metabolic adaptation in the liver.
 ...
PMID:The coactivator PGC-1 is involved in the regulation of the liver carnitine palmitoyltransferase I gene expression by cAMP in combination with HNF4 alpha and cAMP-response element-binding protein (CREB). 1210 81


1 2 Next >>