Stimulation by glucocorticoids of protein degradation in hepatocyte monolayers

Hopgood, M F; Clark, Michael G.; Ballard, F. J.

doi:10.1042/bj1960033

Cited by 46 publications

(14 citation statements)

References 56 publications

(37 reference statements)

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“…In primary cultures of hepatocytes, dexamethasone stimulated RNA degradation rates significantly after a 6-h incubation period whereas this effect was no more significant after a 24-h incubation period (unpublished results). Our results are in accordance with Hopgood et al [7] who have reported up-regulation of dexamethasone on the breakdown of long-lived protein in hepatocytes in primary culture. Miller [8] reported that, in isolated liver from adrenalectomized rats, hydrocortisone failed to increase protein catabolism but potentiated the stimulating effect of glucagon on proteolysis.…”

Section: Discussionsupporting

confidence: 83%

“…Besides amino acids, other factors related more specifically to the acute-phase response induced by turpentine might also be considered. Thus, glucocorticoids are particularly interesting since they are able to modulate macromolecular degradation in the liver [7][8][9][10] and often mediate the effects of cytokines on protein metabolism in the liver [11][12] and in muscle [13]. Using RU 38486, a glucocorticoid receptor antagonist, we analysed the consequences of in vivo suppression of glucocorticoid activity on RNA breakdown in turpentine-treated rats.…”

Section: Introductionmentioning

confidence: 99%

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Down-regulation of liver RNA breakdown by turpentine administration in the starved rat: Autophagy and relevant factors

Saadane¹,

Delautier²,

Lestriez³

et al. 1999

Inflamm. res.

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Section: Discussionsupporting

confidence: 83%

Section: Introductionmentioning

confidence: 99%

Down-regulation of liver RNA breakdown by turpentine administration in the starved rat: Autophagy and relevant factors

Saadane¹,

Delautier²,

Lestriez³

et al. 1999

Inflamm. res.

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“…21,43,44 Glucocorticoids are also described to stimulate autophagy, increase protein degradation, and decrease mitochondrial content in hepatocyte monolayers, perhaps by stimulating synthesis of autophagic proteins. 34,35,45 Other evidence suggests that dexamethasone delays hepatocyte dedifferentiation in culture, 4,46 and for this reason we routinely included dexamethasone in the hepatocyte culture medium. We considered using transfection and siRNA techniques to elucidate mechanisms underlying hepatocyte remodeling further, but such approaches require 1 to 3 days to produce the desired effects on gene expression.…”

Section: Discussionmentioning

confidence: 99%

Roles of mitophagy and the mitochondrial permeability transition in remodeling of cultured rat hepatocytes

Rodrı́guez-Enrı́quez

Kai²,

Maldonado³

et al. 2009

Autophagy

102

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In primary culture, hepatocytes dedifferentiate, and their cytoplasm undergoes remodeling. Here, our aim was to characterize changes of mitochondria during remodeling. Hepatocytes were cultured one to five days in complete serum-containing Waymouth’s medium. In rat hepatocytes loaded with MitoTracker Green (MTG), tetramethylrhodamine methylester (TMRM), and/or LysoTracker Red (LTR), confocal microscopy revealed that mitochondria number and mass decreased by approximately 50% between Day 1 and Day 3 of culture. As mitochondria disappeared, lysosomes/autophagosomes proliferated five-fold. Decreased mitochondrial content correlated with (a) decreased cytochrome c oxidase activity and mitochondrial number observed by electron microscopy and (b) a profound decrease of PGC-1α mRNA expression. By contrast, mtDNA content per cell remained constant from the first to the third day of culture, although ethidium bromide (de novo mtDNA synthesis inhibitor) caused mtDNA to decrease by half from the first to the third culture day. As mitochondria disappeared, their MTG label moved into LTR-labeled lysosomes, which was indicative of autophagic degradation. A multiwell fluorescence assay revealed a 2.5-fold increase of autophagy on Day 3 of culture, which was decreased by 3-methyladenine, an inhibitor of autophagy, and also by cyclosporin A and NIM811, both selective inhibitors of the mitochondrial permeability transition (MPT). These findings indicate that mitochondrial autophagy (mitophagy) and the MPT underlie mitochondrial remodeling in cultured hepatocytes.

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“…Ref. I), freshly isolated (6,7,11,12) or cultured hepatocytes (13)(14)(15) have identified amino acids and the hormones insulin and glucagon as major determinants of hepatic lysosomal proteolysis and protein synthesis. High ambient concentrations of amino acids and insulin suppress intrahepatic proteolysis (1,6,7) and stimulate protein synthesis (16)(17)(18)(19), whereas glucagon exerts the opposite effect (1,13,14,20).…”

mentioning

confidence: 99%

Changes in Hepatic Nitrogen Balance in Plasma Concentrations of Amino Acids and Hormones and in Cell Volume after Overnight Fasting in Perinatal and Adult Rat

et al. 1995

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ARSTRImportant regulatory factors of intrahepatic protein synthesis and proteolysis are amino acids, glucagon, insulin, and cell volume. We have investigated the changes in these factors with development and after an overnight fast and evaluated their contribution to changes in the hepatic nitrogen balance in vivo. In the fed state, glucagon levels were highest in suckling animals and gradually declined in older rats, whereas the concentration of insulin increased during development. The amino acid concentrations in liver and plasma declined during the suckling period to levels that in vitro are highly permissive for induction of autophagic proteolysis. In all age groups investigated, fasting was associated with a drop in hepatic protein content, together with a marked decrease in hepatocellular volume and insulin concentrations. On the other hand, glucagon concentrations and the concentration of many amino acids in plasma and liver responded to fasting with a pronounced decrease in perinatal and suckling animals, but this response had become blunted at weaning and had disappeared in adult animals. These findings suggest that insulin and/or hepatocellular volume are more likely candidates as short-term physiologic regulators of the hepatic nitrogen balance than are glucagon or amino acids. In glucosesupplemented fetuses, high levels of insulin could not compensate for a decreased hepatocellular volume in averting a catabolic state, suggesting that cell volume is the more important factor. Although our study cannot discriminate between the effects of fasting on protein synthesis and degradation, our findings show unequivocally that, for a rapid growth of the liver, suckling animals have to be fed around-the-clock. (Pediatr Res 38: 1018-1025, 1995)The cellular protein content is regulated by modulation of the rates of synthesis and/or degradation. The nutritional and hormonal status have been shown to be of paramount importance as modulators of the rate of synthesis and degradation of proteins in the liver (1-7). In vivo studies in which the effect of refeeding after prolonged periods of starvation (2-5 d) was studied (8-10) and in vitro studies with perfused livers (cf. Ref. I), freshly isolated (6,7,11,12) or cultured hepatocytes (13-15) have identified amino acids and the hormones insulin and glucagon as major determinants of hepatic lysosomal proteolysis and protein synthesis. High ambient concentrations of amino acids and insulin suppress intrahepatic proteolysis (1, 6, 7) and stimulate protein synthesis (16-19), whereas glucagon exerts the opposite effect (1,13,14,20). More recently, it was proposed that lysosomal proteolysis in rat liver is also regulated by changes in the volume of the hepatocyte, an increase in cell volume being inhibitory (21, 22). As indicated, most of these findings were obtained from in vitro studies, involving strong manipulation of the nutritional and hormonal environment of the hepatocytes. In this respect, we had previously observed in cultured hepatocytes that intrahepatic lysoso...

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Stimulation by glucocorticoids of protein degradation in hepatocyte monolayers

Cited by 46 publications

References 56 publications

Down-regulation of liver RNA breakdown by turpentine administration in the starved rat: Autophagy and relevant factors

Down-regulation of liver RNA breakdown by turpentine administration in the starved rat: Autophagy and relevant factors

Roles of mitophagy and the mitochondrial permeability transition in remodeling of cultured rat hepatocytes

Changes in Hepatic Nitrogen Balance in Plasma Concentrations of Amino Acids and Hormones and in Cell Volume after Overnight Fasting in Perinatal and Adult Rat

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