scholarly journals Prostaglandin D2 mediates the stimulation of glycogenolysis in the liver by phorbol ester

1988 ◽  
Vol 250 (1) ◽  
pp. 77-80 ◽  
Author(s):  
E Casteleijn ◽  
J Kuiper ◽  
H C J Van Rooij ◽  
J A A M Kamps ◽  
J F Koster ◽  
...  
Keyword(s):  
Phorbol Ester ◽  
Cell Types ◽  
Liver Cells ◽  
Prostaglandin D2 ◽  
Perfused Liver ◽  
Glucose Homoeostasis ◽  
Parenchymal Liver Cell ◽  
Parenchymal Liver ◽  
Complex Regulation ◽  
Stimulation Of

The tumour-promoting phorbol ester, phorbol 12-myristate 13-acetate (PMA), when added to the perfused liver, stimulates glycogenolysis 2-fold. This stimulation is not seen when aspirin is present in the perfusion medium. In isolated parenchymal liver cells. PMA is not able to stimulate glycogenolysis, suggesting that its effect on glycogenolysis might be indirect and depends on the presence of the non-parenchymal liver cell types. To test the possible operation of an indirect mechanism, we measured the amount of prostaglandin (PG) D2 in liver perfusates. After addition of PMA, the amount of PGD2 is doubled, in parallel with the increase in glycogenolysis. Glycogenolysis in both isolated parenchymal liver cells and perfused liver could be stimulated by the addition of PGD2. Our data indicate that stimulation of glycogenolysis in the liver by PMA may be mediated by non-parenchymal liver cells, which produce PGD2 in response to PMA. Subsequently PGD2 activates glycogenolysis in the parenchymal liver cells. The intercellular communication inside the liver in response to PMA adds a new mechanism to the complex regulation of glucose homoeostasis by the liver.

scholarly journals Conditioned media of Kupffer and endothelial liver cells influence protein phosphorylation in parenchymal liver cells. Involvement of prostaglandins

1988 ◽  
Vol 252 (2) ◽  
pp. 601-605 ◽  
Author(s):  
E Casteleijn ◽  
J Kuiper ◽  
H C Van Rooij ◽  
J F Koster ◽  
T J Van Berkel
Keyword(s):  
Protein Phosphorylation ◽  
Liver Cell ◽  
Cell Function ◽  
Liver Cells ◽  
Conditioned Media ◽  
Prostaglandin D2 ◽  
Phosphorylation State ◽  
Glucose Homoeostasis ◽  
Parenchymal Liver ◽  
Parenchymal Cells

The possible role of Kupffer and endothelial liver cells in the regulation of parenchymal-liver-cell function was assessed by studying the influence of conditioned media of isolated Kupffer and endothelial cells on protein phosphorylation in isolated parenchymal cells. The phosphorylation state of three proteins was selectively influenced by the conditioned media. The phosphorylation state of an Mr-63,000 protein was decreased and the phosphorylation state of an Mr-47,000 and an Mr-97,000 protein was enhanced by these media. These effects could be mimicked by adding either prostaglandin E1, E2 or D2. Both conditioned media and prostaglandins stimulated the phosphorylase activity in parenchymal liver cells, suggesting that the Mr-97,000 phosphoprotein might be phosphorylase. Parenchymal liver cells secrete a phosphoprotein of Mr-63,000 and pI 5.0-5.5. The phosphorylation of this protein is inhibited by Kupffer- and endothelial-liver-cell media, and prostaglandins E1, E2 and D2 had a similar effect. The data indicate that Kupffer and endothelial liver cells secrete factors which influence the protein phosphorylation in parenchymal liver cells. This forms further evidence that products from non-parenchymal liver cells, in particular prostaglandin D2, might regulate glucose homoeostasis and/or other specific metabolic processes inside parenchymal cells. This stresses the concept of cellular communication inside the liver as a way by which the liver can rapidly respond to extrahepatic signals.

scholarly journals Cellular communication inside the liver. Binding, conversion and metabolic effect of prostaglandin D2 on parenchymal liver cells

1989 ◽  
Vol 262 (1) ◽  
pp. 195-201 ◽  
Author(s):  
J Kuiper ◽  
F J Zijlstra ◽  
J A A M Kamps ◽  
T J C Van Berkel
Keyword(s):  
Parenchymal Cell ◽  
Cell Types ◽  
Liver Cells ◽  
Metabolic Effect ◽  
Cell Protein ◽  
Prostaglandin D2 ◽  
Affinity Binding ◽  
High Affinity Binding ◽  
High Affinity ◽  
Parenchymal Liver

The major eicosanoid produced within the rat liver, prostaglandin (PG) D2, wa studied for its ability to interact with the various liver cell types. It appeared that PGD2 bound specifically to parenchymal liver cells, whereas the binding of PGD2 to Kupffer and endothelial liver cells was quantitatively unimportant. Maximally 700 pg of PGD2/mg of parenchymal-cell protein could be bound by a high-affinity site (1 x 10(6) PGD2-binding sites/cell). The recognition site for PGD2 is probably a protein because trypsin treatment of the cells virtually abolished the high-affinity binding. High-affinity binding of PGD2 was a prerequisite for the induction of a metabolic effect in isolated parenchymal liver cells, i.e. the induction of glycogenolysis. High-affinity binding of PGD2 by parenchymal cells was coupled to the conversion of PGD2 into three metabolites, whereas no conversion of PGD2 by Kupffer and endothelial liver cells was noticed. The temperature-sensitivity of the conversion of PGD2 was consistent with a conversion of PGD2 on or in the vicinity of the cell membrane. One of the PGD2 metabolites could be identified as 9 alpha, 11 beta-PGF2. It can be calculated that the conversion rate of PGD2 by parenchymal liver cells exceeds the production rate of PGD2 by Kupffer plus endothelial liver cells, indicating that PGD2 is meant to exert its activity within the liver. The present finding that PGD2 formed by the non-parenchymal liver cells is recognized by a specific receptor on parenchymal liver cells and that binding, conversion and metabolic effect of PGD2 are interlinked by this receptor provides further support for the specific role of PGD2 in the intercellular communication in the liver.

scholarly journals Regulation of H2O2 generation in thyroid cells does not involve Rac1 activation

2005 ◽  
Vol 152 (1) ◽  
pp. 127-133 ◽  
Author(s):  
N Fortemaison ◽  
F Miot ◽  
J E Dumont ◽  
S Dremier
Keyword(s):  
Phorbol Ester ◽  
Cell Types ◽  
Glutathione S Transferase ◽  
Thyroid Cells ◽  
Toxin B ◽  
Regulatory Cascade ◽  
Nox Family ◽  
Design And Methods ◽  
Generating System ◽  
Stimulation Of

Objectives: The H2O2 generating system of the thyrocyte and the O2− generating system of macrophages and leukocytes present numerous functional analogies. The main constituent enzymes belong to the NADPH oxidase (NOX) family (Duox/ThOX for the thyroid and NOX2/gp91phox for the leukocytes and macrophages), and in both cell types, H2O2 generation is activated by the intra-cellular generation of Ca2+ and diacylglycerol signals. Nevertheless, although the controls involved in these two systems are similar, their mechanisms are different. The main factors controlling O2− production by NOX2 are the cytosolic proteins p67phox and p47phox, and Rac, a small GTP-binding protein. We have previously reported that there is no expression of p67phox and p47phox in thyrocytes. Here, we investigated whether Rac1 is an actor in the thyroid H2O2-generating system. Design and methods: Ionomycin- and carbamylcholine-stimulated H2O2 generation was measured in dog thyroid cells pretreated with the Clostridium difficile toxin B, which inhibits Rac proteins. Activation of Rac1 was measured in response to agents stimulating H2O2 production, using the CRIB domain of PAK1 as a probe in a glutathione S-transferase (GST) pull-down assay. Results: Among the various agents inducing H2O2 generation in dog thyrocytes, carbamylcholine is the only one which activates Rac1, whereas phorbol ester and calcium increase alone have no effect, and cAMP inactivates it. Moreover, whereas toxin B inhibits the stimulation of O2 generation by phorbol ester in leukocytes, it does not inhibit H2O2 generation induced by carbamylcholine and ionomycin in dog thyrocytes. Conclusions: Unlike in leukocytes, Rac proteins do not play a role in H2O2 generation in thyroid cells. A different regulatory cascade for the control of H2O2 generation remains to be defined.

scholarly journals The effects of added purines on urate and purine synthesis de novo by isolated chick liver, kidney and lymphoid cells

1976 ◽  
Vol 158 (3) ◽  
pp. 549-556 ◽  
Author(s):  
P Badenoch-Jones ◽  
P J Buttery
Keyword(s):  
De Novo ◽  
Cell Types ◽  
Liver Cells ◽  
Lymphoid Cells ◽  
Kidney Cells ◽  
Purine Synthesis ◽  
Liver And Kidney ◽  
Stimulation Of

1. Isolated chick lymphoid cells, together with isolated chick liver and kidney cells, incorporate [1-14C]glycine or [14C]formate into urate. 2. Of the cell types used, bursal cells incorporate 14C into urate at the fastest rate, although the output of total urate by bursal cells is only 10% that of liver cells. 3. When suspended in Eagle's medium the incorporation of 14C into urate is inhibited by adenine and guanine up to 1 mM. In contrast, the addition of 1 mM-AMP or -GMP results in a relatively large stimulation of this incorporation. 4. Added adenine is rapidly taken up by liver cells and then released in an unmetabolized form; AMP is taken up more slowly and is rapidly metabolized. The metabolites (possibly including adenine) are then released. 5. Intracellular liver 5-phosphoribosyl 1-pyrophosphate is approx. 0.7mM and remains constant or falls slightly during a 3 h incubation of the cells. 6. The addition of adenine or guanine, AMP or GMP, does not alter liver intracellular 5-phosphoribosyl 1-pyrophosphate concentrations. Added 5-phosphoribosyl 1-pyrophosphate is not taken up by liver cells. 7. The results are discussed in the context of the control of urate and purine synthesis de novo in the chick.

scholarly journals Quantitative role of parenchymal and non-parenchymal liver cells in the uptake of [14C]sucrose-labelled low-density lipoprotein in vivo

1984 ◽  
Vol 224 (1) ◽  
pp. 21-27 ◽  
Author(s):  
L Harkes ◽  
J C Van Berkel
Keyword(s):  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Cell Types ◽  
Liver Cells ◽  
Low Density ◽  
Apo B ◽  
Parenchymal Liver ◽  
Ldl Uptake ◽  
Parenchymal Cells

In order to assess the relative importance of the receptor for low-density lipoprotein (LDL) (apo-B,E receptor) in the various liver cell types for the catabolism of lipoproteins in vivo, human LDL was labelled with [14C]sucrose. Up to 4.5h after intravenous injection, [14C]sucrose becomes associated with liver almost linearly with time. During this time the liver is responsible for 70-80% of the removal of LDL from blood. A comparison of the uptake of [14C]sucrose-labelled LDL and reductive-methylated [14C]sucrose-labelled LDL ([14C]sucrose-labelled Me-LDL) by the liver shows that methylation leads to a 65% decrease of the LDL uptake. This indicated that 65% of the LDL uptake by liver is mediated by a specific apo-B,E receptor. Parenchymal and non-parenchymal liver cells were isolated at various times after intravenous injection of [14C]sucrose-labelled LDL and [14C]sucrose-labelled Me-LDL. Non-parenchymal liver cells accumulate at least 60 times as much [14C]sucrose-labelled LDL than do parenchymal cells accumulate at least 60 times as much [14C]sucrose-labelled LDL than do parenchymal cells when expressed per mg of cell protein. This factor is independent of the time after injection of LDL. Taking into account the relative protein contribution of the various liver cell types to the total liver, it can be calculated that non-parenchymal cells are responsible for 71% of the total liver uptake of [14C]sucrose-labelled LDL. A comparison of the cellular uptake of [14C]sucrose-labelled LDL and [14C]sucrose-labelled Me-LDL after 4.5h circulation indicates that 79% of the uptake of LDL by non-parenchymal cells is receptor-dependent. With parenchymal cells no significant difference in uptake between [14C]sucrose-labelled LDL and [14C]sucrose-labelled Me-LDL was found. A further separation of the nonparenchymal cells into Kupffer and endothelial cells by centrifugal elutriation shows that within the non-parenchymal-cell preparation solely the Kupffer cells are responsible for the receptor-dependent uptake of LDL. It is concluded that in rats the Kupffer cell is the main cell type responsible for the receptor-dependent catabolism of lipoproteins containing only apolipoprotein B.

scholarly journals Uptake and degradation of human low-density lipoprotein by human liver parenchymal and Kupffer cells in culture

1991 ◽  
Vol 276 (1) ◽  
pp. 135-140 ◽  
Author(s):  
J A A M Kamps ◽  
J K Kruijt ◽  
J Kuiper ◽  
T J C Van Berkel
Keyword(s):  
Kupffer Cells ◽  
Human Liver ◽  
Low Density Lipoprotein ◽  
Ldl Receptor ◽  
Density Lipoprotein ◽  
Cell Types ◽  
Liver Cells ◽  
Cell Protein ◽  
Parenchymal Liver ◽  
Parenchymal Cells

The association with and degradation by cultured human parenchymal liver cells and human Kupffer cells of human low-density lipoprotein (LDL) was investigated in order to define, for the human situation, the relative abilities of the various liver cell types to interact with LDL. With both human parenchymal liver cells and Kupffer cells the association of LDL with the cells followed saturation kinetics which were coupled to LDL degradation. The association of LDL (per mg of cell protein) to both cell types was comparable, but the association with human Kupffer cells was much more efficiently coupled to degradation than was the case in parenchymal cells. The capacity of human Kupffer cells to degrade LDL was consequently 18-fold higher (per mg of cell protein) than that of the human parenchymal liver cells. Competition studies showed that unlabelled LDL competed efficiently with the cell association and degradation of 125I-labelled LDL with both parenchymal and Kupffer cells, while unlabelled acetyl-LDL was ineffective. The degradation of LDL by parenchymal and Kupffer cells was blocked by chloroquine and NH4Cl, indicating that it occurs in the lysosomes. Binding and degradation of LDL by human liver parenchymal cells and human Kupffer cells appeared to be completely calcium-dependent. It is concluded that the association and degradation of LDL by human Kupffer and parenchymal liver cells proceeds through the specific LDL receptor, whereas the association of LDL to Kupffer cells is more efficiently coupled to degradation. The presence of the highly active LDL receptor on human Kupffer cells might contribute significantly to LDL catabolism by human liver, especially under conditions whereby the LDL receptor on parenchymal cells is down-regulated.

scholarly journals Disposition of the Acyclic Nucleoside Phosphonate (S)-9(3-Hydroxy-2-Phosphonylmethoxypropyl)Adenine

1998 ◽  
Vol 42 (5) ◽  
pp. 1146-1150 ◽  
Author(s):  
Martin K. Bijsterbosch ◽  
Louis J. J. W. Smeijsters ◽  
Theo J. C. van Berkel
Keyword(s):  
Cell Types ◽  
Hepatic Uptake ◽  
Liver Cells ◽  
The Body ◽  
Total Uptake ◽  
Parenchymal Liver ◽  
Acyclic Nucleoside ◽  
Parenchymal Cells ◽  
Acyclic Nucleoside Phosphonate

ABSTRACT The acyclic nucleoside phosphonate (S)-9-(3-hydroxy-2-phosphonylmethoxypropyl)adenine [(S)-HPMPA] has been shown to be active against pathogens, like hepatitis B viruses and Plasmodiumparasites, that infect parenchymal liver cells. (S)-HPMPA is therefore an interesting candidate drug for the treatment of these infections. To establish effective therapeutic protocols for (S)-HPMPA, it is essential that the kinetics of its hepatic uptake be evaluated and that the role of the various liver cell types be examined. In the present study, we investigated the disposition of (S)-HPMPA and assessed its hepatic uptake. Rats were intravenously injected with [3H](S)-HPMPA, and after an initial rapid distribution phase (360 ± 53 ml/kg of body weight), the radioactivity was cleared from the circulation with a half-life of 11.7 ± 1.4 min. The tissue distribution of [3H](S)-HPMPA was determined at 90 min after injection (when >99% of the dose cleared). Most (57.0% ± 1.1%) of the injected [3H](S)-HPMPA was excreted unchanged in the urine. The radioactivity that was retained in the body was almost completely recovered in the kidneys and the liver (68.4% ± 2.5% and 16.1% ± 0.4% of the radioactivity in the body, respectively). The uptake of [3H](S)-HPMPA by the liver occurred mainly by parenchymal cells (92.1% ± 3.4% of total uptake by the liver). Kupffer cells and endothelial cells accounted for only 6.1% ± 3.5% and 1.8% ± 0.8% of the total uptake by the liver, respectively. Preinjection with probenecid reduced the hepatic and renal uptake of [3H](S)-HPMPA by approximately 75%, which points to a major role of a probenecid-sensitive transporter in the uptake of (S)-HPMPA by both tissues. In conclusion, we show that inside the liver, (S)-HPMPA is mainly taken up by parenchymal liver cells. However, the level of uptake by the kidneys is much higher, which leads to nephrotoxicity. An approach in which (S)-HPMPA is coupled to carriers that are specifically taken up by parenchymal cells may increase the effectiveness of the drug in the liver and reduce its renal toxicity.

scholarly journals Targeted delivery of oligodeoxynucleotides to parenchymal liver cells in vivo

1999 ◽  
Vol 340 (3) ◽  
pp. 783-792 ◽  
Author(s):  
Erik A. L. BIESSEN ◽  
Helene VIETSCH ◽  
Erik T. RUMP ◽  
Kees FLUITER ◽  
Johan KUIPER ◽  
...  
Keyword(s):  
Liver Cell ◽  
Targeted Delivery ◽  
Liver Cells ◽  
Asialoglycoprotein Receptor ◽  
Confocal Laser ◽  
Great Promise ◽  
Target Tissue ◽  
Parenchymal Liver Cell ◽  
Parenchymal Liver

Anti-sense oligodeoxynucleotides (ODNs) hold great promise for correcting the biosynthesis of clinically relevant proteins. The potential of ODNs for modulating liver-specific genes might be increased by preventing untimely elimination and by improving the local bioavailability of ODNs in the target tissue. In the present study we have assessed whether the local ODN concentration can be enhanced by the targeted delivery of ODNs through conjugation to a ligand for the parenchymal liver cell-specific asialoglycoprotein receptor. A capped ODN (miscellaneous 20-mer sequence) was derivatized with a ligand with high affinity for this receptor, N2-[N2-(N2,N6-bis{N-[p-(β-D-galactopyranosyloxy) anilino] thiocarbamyl} - L - lysyl) - N6 - (N - {p - [β-D -galactopyranosyloxy] anilino} thiocarbamyl) - L - lysyl] - N6 - [N - (p -{β-ᴅ-galactopyranosyloxy}anilino)thiocarbamyl]-ʟ-lysine (L3G4) (Kd 6.5±0.2 nM, mean±S.D.). Both the uptake studies in vitro and the confocal laser scan microscopy studies demonstrated that L3G4-ODN was far more efficiently bound to and taken up by parenchymal liver cells than underivatized ODN. Studies in vivo in rats showed that hepatic uptake could be greatly enhanced from 19±1% to 77±6% of the injected dose after glycoconjugation. Importantly, specific ODN accumulation of ODN into parenchymal liver cells was improved almost 60-fold after derivatization with L3G4, and could be attributed to the asialoglycoprotein receptor. In conclusion, the scavenger receptor-mediated elimination pathway for miscellaneous ODN sequences can be circumvented by direct conjugation to a synthetic tag for the asialoglycoprotein receptor. In this manner a crucial requisite is met towards the application of ODNs in vivo to modulate the biosynthesis of parenchymal liver cell-specific genes such as those for apolipoprotein (a), cholesterol ester transfer protein and viral proteins.

scholarly journals 3,5,3′-Tri-iodo-l-thyronine acutely regulates a protein kinase C-sensitive, Ca2+-independent, branch of the hepatic α1-adrenoreceptor signalling pathway

1998 ◽  
Vol 331 (1) ◽  
pp. 89-97 ◽  
Author(s):  
Francisco J. DAZA ◽  
Roberto PARRILLA ◽  
Angeles MARTÍN-REQUERO
Keyword(s):  
Protein Kinase C ◽  
Protein Kinase ◽  
Hepatic Metabolism ◽  
Liver Cells ◽  
Signalling Pathway ◽  
Perfused Liver ◽  
Kinase C ◽  
Isolated Liver Cells ◽  
Isolated Liver ◽  
Stimulation Of

This work aimed to investigate the acute effect of the thyroid hormone 3,5,3´-tri-iodo-l-thyronine (T3) in regulating the hepatic metabolism either directly or by controlling the responsiveness to Ca2+-mobilizing agonists. We did not detect any acute metabolic effect of T3 either in perfused liver or in isolated liver cells. However, T3 exerted a powerful inhibitory effect on the α1-adrenoreceptor-mediated responses. The promptness of this T3 effect rules out that it was the result of rate changes in gene(s) transcription. T3 inhibited the α1-adrenoreceptor-mediated sustained stimulation of respiration and release of Ca2+ and H+, but not the glycogenolytic or gluconeogenic responses, in perfused liver. In isolated liver cells, T3 enhanced the α1-agonist-induced increase in cytosolic free Ca2+ and impeded the intracellular alkalinization. Since T3 also prevented the α1-adrenoreceptor-mediated activation of protein kinase C, its effects on pH seem to be the result of a lack of activation of the Na+/H+ exchanger. The failure of T3 to prevent the α1-adrenergic stimulation of gluconeogenesis despite the inhibition of protein kinase C activation indicates that the elevation of cytosolic free Ca2+ is a sufficient signal to elicit that response. T3 also impaired some of the angiotensin-II-mediated responses, but did not alter the effects of PMA on hepatic metabolism, indicating, therefore, that some postreceptor event is the target for T3 actions. The differential effect of T3 in enhancing the α1-adrenoreceptor-mediated increase in cytosolic free Ca2+ and preventing the activation of protein kinase C, provides a unique tool for further investigating the role of each branch of the signalling pathway in controlling the hepatic functions. Moreover, the low effective concentrations of T3 (⩽ 10 nM) in perturbing the α1-adrenoreceptor-mediated response suggests its physiological significance.

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