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

Increase in the density of liver lysosomes after leupeptin administration was marked in starved rats but only slight in starved-refed rats. The levels of several intracellular enzymes in the liver lysosome fraction purified from leupeptin-treated rats were about 10 to 30 times more in starved rats than in refed rats. However, there was no difference between the intralysosomal levels of endocytosed FITC-labeled asialofetuin in starved and refed rats, indicating that refeeding after starvation markedly suppressed autophagy but not heterophagy in vivo. Immunohistochemical studies with cathepsin B and asialofetuin Fab'-peroxidase conjugates showed that refeeding after starvation markedly altered the cellular distribution of cathepsin B in the liver, resulting in a linear arrangement of the enzyme only on the periphery of hepatocytes. In contrast, endocytosed asialofetuin was found only in the periphery of hepatocytes of both starved and starved-refed rats. These results indicate that autophagy and heterophagy are regulated by different mechanisms in vivo.
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PMID:Effect of starvation and refeeding on autophagy and heterophagy in rat liver. 243 Sep 55

The specific activity of cardiac cathepsin B is significantly decreased by starvation and corticosteroid treatment in vivo, and by exposure of the heart in vitro to insulin, hydrocortisone and cycloheximide. Increases in cathepsin B activity occur following isoproterenol-induced cardiac damage in vivo and exposure in vitro to sucrose. Cathepsin B activity in heart is not changed during normal aging or in thyrotoxicosis. These responses are different from simultaneous changes in cardiac cathepsin D activity in several instances (starvation, corticosteroid treatment, aging and thyrotoxicosis). In the past, measurements of cathepsin D activity in heart have sometimes been considered to be representative of lysosomal proteinase activity in general and used as an index of cardiac lysosomal proteolytic capacity. The present results suggest that changes in cathepsin D do not necessarily reflect alterations in other lysosomal proteinases and may not serve as a valid indicator of overall lysosomal proteolytic capacity under all conditions.
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PMID:Changes in cardiac cathepsin B activity in response to interventions that alter heart size or protein metabolism: comparison with cathepsin D. 623 80

In vivo proteolytic modification of liver aldolase on administration of leupeptin, a thiol proteinase inhibitor of microbial origin, is reported. When leupeptin was injected into rats, the activity of aldolase in the liver decreased to 40% of that in control rats. Molecular properties of aldolase isolated from the livers of control rats and leupeptin-treated rats indicated that a decrease of aldolase activity is attributable to hydrolysis of a peptide linkage(s) near the carboxyterminal of the enzyme. Injection of leupeptin also caused marked increase in the activities of free lysosomal proteinases, such as cathepsin A and cathepsin D and moderate increase of cathepsin B and cathepsin L. Increase in free activity of cathepsin A returned to the level of control rats by 12 hr after injection of leupeptin, whereas 36 hr was required for recovery of decreased aldolase activity. When insulin was coinjected with leupeptin, increase in the activity of free cathepsin A and decrease of activity of aldolase produced by the injection of leupeptin was prevented. These findings indicate that modification of aldolase may be due to action of a lysosomal protease(s). Incubation of the purified aldolase with the lysosomal fraction produced the same changes in properties of aldolase as those observed in vivo on injection of leupeptin. The aldolase inactivating proteinase in the lysosomal fraction was inhibited by PMSF and leupeptin and not by pepstatin. Purified cathepsin A (a serine proteinase), cathepsin B and cathepsin L (thiol proteinase) are potent inactivators of aldolase but cathepsin H and cathepsin D are not. Cathepsin A, B and L are involved in inactivation of aldolase in lysosomes. Endogenous thiol proteinase inhibitor which inhibits lysosomal thiol proteinases (cathepsin B, L and H) is found in the cytosol fraction of liver. The level of thiol proteinase inhibitor actually decreased to 60% of that in control rats in leupeptin-treated rats, suggesting that non-thiol proteinase cathepsin A is a major factor in inactivation of aldolase in lysosomes. Not only leupeptin but also other proteinase inhibitors (antipain, E-64-D, chloroquine) caused increase of labilization of the lysosomes and decrease in aldolase activity. Physiological stimuli which are known to induce the labilization of the lysosomal membrane, such as starvation and glucagon, caused slight or no significant increase of activities of free cathepsin A and D and resulted in no apparent change in aldolase activity.
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PMID:Modification of rat liver fructose biphosphate aldolase by lysosomal proteinases. 705 71

1. The loss of liver protein occurring in rats starved for 24 h was largely prevented by the administration of repeated doses of cycloheximide, an inhibitor of protein synthesis. Similar effects were produced on tubulin, a 'fixed' liver protein. 2. Starvation accelerated, whereas cycloheximide markedly lowered, the rate of protein radioactivity decay after labelling with [3H]valine or [14C]bicarbonate, indicating that changes in catabolic rates played an important role in the above regulations of liver protein mass. 3. The total activity of several lysosomal hydrolases showed little change in livers of starved rats, but a marked progressive decline developed after the administration of cycloheximide, particularly in the activities of cathepsins B, D and L as well as acid ribonuclease. There was no evidence that these changes might be due to endogenous inhibitors (at least for cathepsin B activity, which fell to less than 30% of the control values) or enzyme leakage into the bloodstream; rather, plasma beta-galactosidase and beta-N-acetylglucosaminidase activities fell progressively during the cycloheximide treatment. 4. Endogenous proteolytic rates, measured in vitro by incubating subcellular preparations from livers prelabelled in vivo with [3H]valine, were markedly decreased in cycloheximide-treated animals. 5. The osmotic fragility of hepatic lysosomes, appreciably enhanced in starved animals, after cycloheximide treatment was found to be even lower than in fed controls. 6. The present data are consistent with the view that in starved animals the loss of liver protein is mostly accounted for by increased breakdown, due, in part at least, to enhanced autophagocytosis. 7. Cycloheximide largely counteracted these effects of starvation, altering the liver from being 'poised' in a proteolytic direction to a protein-sparing condition. The present data suggest that, besides suppression of the autophagic processes, a decrease in the lysosomal proteolytic enzyme system may also play a role in this regulation, and they seem to provide further circumstantial evidence for the existence of co-ordinating mechanisms between protein synthesis and degradation.
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PMID:Control of cell protein catabolism in rat liver. Effects of starvation and administration of cycloheximide. 715 Feb 50

Prolonged starvation mimics chronic negative nitrogen balance observed in many physiopathological situations. During starvation, an initial decrease in protein utilization (phase I) is followed by a long period of protein sparing (phase II) that ends with a marked rise in nitrogen excretion (phase III). Variations in protein metabolism during starvation are determined by changes in protein synthesis and degradation rates (Cherel, Y., Attaix, D. Rosolowska-Huszcz, D., Belkhou, R., Robin, J.P., Arnal, M. and Le Maho, Y. (1991) Clin. Sci. 81, 611-619), but little information is available on expression of proteolytic systems. In this study, cathepsin B, H and L activities were compared in hindlimb muscles and liver at various phases of starvation in thyroidectomized and sham-operated rats. In muscle, cathepsin activities fell from the fed state to phase II, which suggests that cathepsins may play a role in the curtailment of muscle proteolysis during protein sparing phase. This decrease of muscle cathepsin activities was reproduced by thyroidectomy alone. In contrast, liver cathepsin B and H activities fell during starvation, but were not affected by thyroidectomy alone. Liver cathepsin L decreased only during starvation in thyroidectomized animals. These observations emphasize that different mechanisms modulate cathepsin expression in skeletal muscle and liver.
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PMID:Effect of fasting and thyroidectomy on cysteine proteinase activities in liver and muscle. 812 68

The activities of cathepsin B, L, J and H in rat liver were significantly increased by starvation if compared with normal diet rats. Furthermore, the activity of cathepsin L increased with glucagon treatment, and the activities of cathepsin L and H decreased significantly with insulin treatment. The changes in cathepsin B and J activities showed the same tendencies as those of cathepsin L and H, but the differences were not statistically significant. The changes in the activities of cathepsin B and L on starvation corresponded with the changes of enzyme protein amounts judged from Western blotting analysis. The levels of the lysosomal cysteine proteinases and amino acid deaminases in the liver changed in parallel with the hormonal and dietary conditions. The increases of alanine amino transferase activity (AAT) started from a much earlier stage than those of cathepsins under the starvation condition. Although administration of prednisolone caused marked induction of the deamination enzymes such as AAT, the levels of cathepsins in the liver were not changed.
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PMID:Hormonal and dietary regulation of lysosomal cysteine proteinases in liver under gluconeogenesis conditions. 892 90

Tumor cells exposed to a growth stress such as low pH, glucose starvation and hypoxia have been shown to exhibit a transient increase in experimental metastatic potential, particularly when allowed to recover under normal growth conditions for a period of 24-48 h. In this study we examined whether this increase in metastatic ability could be explained by changes in the expression of a number of different metastasis-associated genes, when the cells were exposed to similar conditions (24-48 h exposure to the stress condition followed by 0-48 h recovery under normal growth conditions). Although the cell lines used (KHT fibrosarcoma, SCC VII squamous cell carcinoma, and B16F1 melanoma) demonstrated altered metastatic ability after the treatment, no overall temporal correlation between changes in the mRNA levels for cathepsin B, cathepsin L, nm23, TIMP-1, osteopontin, or VEGF and metastatic ability in the three cell lines was observed. The production of gelatinase A (72 kDa collagenase) and gelatinase B (92 kDa collagenase) was also measured by gelatin zymography. There was an increase in production of these enzymes with increasing recovery time, but it did not parallel changes in metastatic potential. Although these results suggest that the products of most of the genes studied may not be involved in the transient metastatic changes, further studies are required to establish whether changes in protein levels track with changes in mRNA levels for these genes.
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PMID:An examination of the effects of hypoxia, acidosis, and glucose starvation on the expression of metastasis-associated genes in murine tumor cells. 924 50

A 48-h starvation period resulted in a great increase in muscle proteolysis-as measured following the release of tyrosine into the medium-in incubated isolated rat extensor digitorum longus (EDL) muscles. We have quantified the contribution of the different proteolytic systems to the increased protein degradation and observed a considerable activation in the ATP-dependent proteolytic (60%) and in the calcium-dependent (125%) systems, while no increases were observed in lysosomal proteolysis. The addition of 10 mM leucine to the incubation medium did not result in any changes in either total proteolytic rate or the activity rates of any of the different systems studied. In addition, the presence of the amino acid did not influence the levels of mRNA for the different genes studied-ubiquitin, C8 proteasome subunit, E2 conjugating enzyme, m-calpain, and cathepsin B. In a similar way, as observed during starvation, tumor growth resulted in increased protein degradation in incubated isolated EDL muscles from animals bearing the Yoshida AH-130 ascites hepatoma. The increased rate of protein degradation affected all the proteolytic systems studied: ATP- and calcium-dependent and lysosomal. Finally, leucine addition (10 mM), although not able to revert the increased proteolytic rate, resulted in a decrease in the gene expression for ubiquitin, C8 proteasome subunit and cathepsin B.
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PMID:Branched-chain amino acids: a role in skeletal muscle proteolysis in catabolic states? 1201 23

In early starvation tissue protein degradation increases, however in later starvation proteolysis declines so as to pace gradual atrophy during synthetic failure. Secondary decline of proteolytic pathways under progressive nutritional desperation is unexplained. After several days of starvation tissue GSH is partly depleted and GSSG/GSH is increased, followed by onset of ketonemia from fat breakdown. Ketone bodies inexplicably delay net muscle protein loss. Recent studies identify a proteome subset of more than 200 proteins with reactive sulfhydryl sites as candidates for coordinate redox control of diverse cell functions. Ketones cause protein sulfhydryl oxidation and protein S-glutathionylation. Here, redox-responsive proteolytic pathways were bio-assayed by release of [3H]leucine from rat myocardium under non-recirculating perfusion. More than 75% of myocardial protein degradation was inhibited and defined by infusion of diamide (100 microM) under constant physiologic concentrations of complete amino acids. Diamide-inhibitable proteolysis includes all lysosomal and some extra-lysosomal proteolysis. Following diamide washout, the reversal of proteolytic inhibitory action was greatly enhanced by artificial repletion of GSH by supra-physiologic extra-cellular GSH (1mM) exposure. Therefore, GSH maintains much of constitutive protein degradation in a primary tissue bioassay. Physiologic acetoacetate infusion (5mM) inhibited redox-responsive protein degradation. Uniformly [3H]leucine labeled 3T3 cells exhibited similar redox-dependent and redox-independent subcomponents of protein degradation. Independent of ketones, steady state cathepsin B reaction rate ex vivo was graded in proportion to the GSH concentration without GSSG, and inversely proportional to the GSSG/GSH redox ratio with inhibitory threshold at 0.5% oxidized. Linkage of some cysteine protease reaction rates to the interplay between GSH-GSSG/GSH status and ketonemia is suggested among transcendent mechanisms coordinating and pacing proteome turnover under prolonged starvation. The possibility of pre-emptive, redox coordination of distinct proteolytic pathways is speculatively discussed.
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PMID:Redox pacing of proteome turnover: influences of glutathione and ketonemia. 1294

Hundreds of cell proteins undergo reversible transitions among redox states. Coordinate control and common functions served by redox-modified proteins are unknown. The suspect "redox code" integrating metabolome, proteome, and genome remains undefined. Protein redox control involves coupling of the population redox partition to transfer of reductive energy from source to sink. Lessons in metabolic programs under redox coordination might be found in nutritional desperation where reductive transfer from fuel fails to feed pathways to protein reduction. Upon nutritional interruption, proteolysis initially increases. However, catabolism secondarily declines in later starvation so as to postpone loss of the minimal proteome under synthetic failure and delay death. Integrated proteome turnover is paced by reductive transfer coupled to redox states of proteins serving diverse functions. Some continuing proteolysis is redox-independent. Cathepsin B is a model, redox-responsive, catabolic machine among proteins involved in turnover. The CysHis pair is simultaneously a redox-responsive site, an inhibitory metal-binding site, and a peptidolytic reaction mechanism. Pro-region cleavage generates permissive reaction conditions, but not necessarily the maximal peptidolytic rate. Mature cathepsin B can be inactivated by partition into multiple oxidation states. Cathepsin B can be reductively activated by glutathione or disulfhydryl reductases, and redox-buffered by glutathione homodisulfide/glutathione. Topics in protease regulation include: (a) the rate of total cell transfer of nutrient reductive energy from NADPH source potential to reductive pathways, (b) the distribution of reductive energy routed through parallel interactive pathways to protease, (c) the rate of transfer from protease through pathways to oxygen (reactive oxygen species) acceptor at sink potential, and (d) the linkage of protease state partition to relative rates of reductions and oxidations. Cell iron, sulfur, and oxygen redox are inseparable. The interaction of the CysHis site with iron provides a sensor, integrator, and effector switch coupling cathepsin B to metal-sulfuroxygen redox. Artificial metal-redox-proton switching is a new concept in protein engineering; however, nature has already applied "nanotechnology" to protein redox control.
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PMID:The transfer of reductive energy and pace of proteome turnover: a theory of integrated catabolic control. 1599 53


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