PI3K is involved in PDGF-β receptor upregulation post-PDGF-BB treatment in mouse HSC

2006 ◽  
Vol 291 (6) ◽  
pp. G1051-G1061 ◽  
Author(s):  
Carmen G. Lechuga ◽  
Zamira H. Hernández-Nazara ◽  
Elizabeth Hernández ◽  
Marcia Bustamante ◽  
Gregory Desierto ◽  
...  
Keyword(s):  
Cell Activation ◽  
Molecular Mechanisms ◽  
Stellate Cell ◽  
Stellate Cells ◽  
Quiescent Cells ◽  
Protein Pool ◽  
Receptor Upregulation ◽  
Β Receptor ◽  
Dose Dependent ◽  
Dependent Mechanism

Increased expression of PDGF-β receptors is a landmark of hepatic stellate cell activation and transdifferentiation into myofibroblasts. However, the molecular mechanisms that regulate the fate of the receptor are lacking. Recent studies suggested that N-acetylcysteine enhances the extracellular degradation of PDGF-β receptor by cathepsin B, thus suggesting that the absence of PDGF-β receptors in quiescent cells is due to an active process of elimination and not to a lack of expression. In this communication we investigated further molecular mechanisms involved in PDGF-β receptor elimination and reappearance after incubation with PDGF-BB. We showed that in culture-activated hepatic stellate cells there is no internal protein pool of receptor, that the protein is maximally phosphorylated by 5 min and completely degraded after 1 h by a lysosomal-dependent mechanism. Inhibition of receptor autophosphorylation by tyrphostin 1296 prevented its degradation, but several proteasomal inhibitors had no effect. We also showed that receptor reappearance is time and dose dependent, being more delayed in cells treated with 50 ng/ml (48 h) compared with 10 ng/ml (24 h).

scholarly journals Zf9, a Kruppel-like transcription factor up-regulatedin vivoduring early hepatic fibrosis

1998 ◽  
Vol 95 (16) ◽  
pp. 9500-9505 ◽  
Author(s):  
Vlad Ratziu ◽  
Avraham Lalazar ◽  
Linda Wong ◽  
Qi Dang ◽  
Colin Collins ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Wound Repair ◽  
Cell Activation ◽  
Stellate Cell ◽  
Fetal Liver ◽  
Stellate Cells ◽  
Rat Tissues ◽  
Quiescent Cells ◽  
Terminal Domain

Wound repair in the liver induces altered gene expression in stellate cells (resident mesenchymal cells) in a process known as “activation.” A zinc finger transcription factor cDNA,zf9, was cloned from rat stellate cells activatedin vivo. Zf9 expression and biosynthesis are increased markedly in activated cellsin vivocompared with cells from normal rats (“quiescent” cells). The factor is localized to the nucleus and the perinuclear zone in activated but not quiescent cells. Zf9 mRNA also is expressed widely in nonhepatic adult rat tissues and the fetal liver. Thezf9nucleotide sequence predicts a member of the Kruppel-like family with a unique N-terminal domain rich in serine–proline clusters and leucines. The humanzf9gene maps to chromosome 10P near the telomere. Zf9 binds specifically to a DNA oligonucleotide containing a GC box motif. The N-terminal domain of Zf9 (amino acids 1–201) is transactivating in the chimeric GAL4 hybrid system. InDrosophila schneidercells, full length Zf9 transactivates a reporter construct driven by the SV40 promoter/enhancer, which contains several GC boxes. A physiologic role for Zf9 is suggested by its transactivation of a collagen α1(I) promoter reporter. Transactivation of collagen α1(I) by Zf9 is context-dependent, occurring strongly in stellate cells, modestly in Hep G2 cells, and not at all inD. schneidercells. Our results suggest that Zf9 may be an important signal in hepatic stellate cell activation after liver injury.

scholarly journals Characterization of a stellate cell activation-associated protein (STAP) with peroxidase activity found in rat hepatic stellate cells.

2001 ◽  
Vol 276 (50) ◽  
pp. 47744
Author(s):  
Norifumi Kawada ◽  
Dan Bach Kristensen ◽  
Kinji Asahina ◽  
Kazuki Nakatani ◽  
Yukiko Minamiyama ◽  
...  
Keyword(s):  
Peroxidase Activity ◽  
Hepatic Stellate Cells ◽  
Cell Activation ◽  
Stellate Cell ◽  
Stellate Cells

scholarly journals Dominant-negative soluble PDGF-β receptor inhibits hepatic stellate cell activation and attenuates liver fibrosis

2004 ◽  
Vol 84 (6) ◽  
pp. 766-777 ◽  
Author(s):  
Erawan Borkham-Kamphorst ◽  
Jens Herrmann ◽  
Doris Stoll ◽  
Jens Treptau ◽  
Axel M Gressner ◽  
...  
Keyword(s):  
Liver Fibrosis ◽  
Hepatic Stellate Cell ◽  
Cell Activation ◽  
Stellate Cell ◽  
Dominant Negative ◽  
Hepatic Stellate Cell Activation ◽  
Β Receptor

scholarly journals Nuclear Cathepsin F Regulates Activation Markers in Rat Hepatic Stellate Cells

2008 ◽  
Vol 19 (10) ◽  
pp. 4238-4248 ◽  
Author(s):  
Gunter Maubach ◽  
Michelle Chin Chia Lim ◽  
Lang Zhuo
Keyword(s):  
Hepatic Stellate Cells ◽  
Cell Activation ◽  
Stellate Cell ◽  
Stellate Cells ◽  
Activation Process ◽  
Type I ◽  
Activation Markers ◽  
Nuclear Activity ◽  
Cystatin B ◽  
Cathepsin F

Activation of hepatic stellate cells during liver fibrosis is a major event facilitating an increase in extracellular matrix deposition. The up-regulation of smooth muscle α-actin and collagen type I is indicative of the activation process. The involvement of cysteine cathepsins, a class of lysosomal cysteine proteases, has not been studied in conjunction with the activation process of hepatic stellate cells. Here we report a nuclear cysteine protease activity partially attributed to cathepsin F, which co-localizes with nuclear speckles. This activity can be regulated by treatment with retinol/palmitic acid, known to reduce the hepatic stellate cell activation. The treatment for 48 h leads to a decrease in activity, which is coupled to an increase in cystatin B and C transcripts. Cystatin B knockdown experiments during the same treatment confirm the regulation of the nuclear activity by cystatin B. We demonstrate further that the inhibition of the nuclear activity by E-64d, a cysteine protease inhibitor, results in a differential regulation of smooth muscle α-actin and collagen type I transcripts. On the other hand, cathepsin F small interfering RNA transfection leads to a decrease in nuclear activity and a transcriptional down-regulation of both activation markers. These findings indicate a possible link between nuclear cathepsin F activity and the transcriptional regulation of hepatic stellate cell activation markers.

Possible Therapeutic Uses of Extracellular Vesicles for Reversion of Activated Hepatic Stellate Cells: Context and Future Perspectives

2021 ◽  
Vol 21 ◽  
Author(s):  
Fahim Rejanur Tasin ◽  
Debasish Halder ◽  
Chanchal Mandal
Keyword(s):  
Liver Fibrosis ◽  
Extracellular Vesicles ◽  
Hepatic Stellate Cells ◽  
Cell Activation ◽  
Stellate Cell ◽  
Stellate Cells ◽  
Target Cells ◽  
Fibrotic Liver ◽  
Paracrine Effects ◽  
Cell Therapies

: Liver fibrosis is one of the leading causes for cirrhotic liver disease and the lack of therapies to treat fibrotic liver is a major concern. Liver fibrosis is mainly occurred by activation of hepatic stellate cells and some stem cell therapies had previously reported for treatment. However, due to some problems with cell-based treatment, a safe therapeutic agent is vehemently sought by the researchers. Extracellular vesicles are cell-derived nanoparticles that are employed in several therapeutic approaches, including fibrosis, for their ability to transfer specific molecules in the target cells. In this review the possibilities of extracellular vesicles to inactivate stellate cells are summarized and discussed. According to several studies, extracellular vesicles from different sources can either put beneficial or detrimental effects by regulating the activation of stellate cells. Therefore, targeting extracellular vesicles for maximizing or inhibiting their production is a potential approach for fibrotic liver treatment. Extracellular vesicles from different cells can also inactivate stellate cells by carrying out the paracrine effects of those cells, working as the agents. They are also implicated as smart carrier of anti-fibrotic molecules when their respective parent cells are engineered to produce specific stellate cell-regulating substances. A number of studies showed stellate cell activation can be regulated by up/downregulation of specific proteins, and extracellular vesicle-based therapies can be an effective move to exploit these mechanisms. In conclusion, EVs are advantageous nano-carriers with the potential to treat fibrotic liver by inactivating activated stellate cells by various mechanisms.

scholarly journals Identification of GDF15 as A Pro-Fibrotic Factor in Mouse Liver Fibrosis Progression

2021 ◽  
Author(s):  
Peng Qi ◽  
Ming-Ze Ma ◽  
Jing-Hua Kuai
Keyword(s):  
Carbon Tetrachloride ◽  
Liver Fibrosis ◽  
Hepatic Stellate Cell ◽  
Hepatic Stellate Cells ◽  
Liver Tissue ◽  
Cell Activation ◽  
Stellate Cell ◽  
Neutralizing Antibody ◽  
Stellate Cells ◽  
Fibrosis Progression

Abstract Aim:To elucidate the inhibitory role of growth differentiation factor 15 (GDF15) in liver fibrosis and its possible activation mechanism in hepatic stellate cells of mice.Methods:We generated a GDF15-neutralizing antibody that can inhibit TGF-β1-induced activation of the TGF-β/Smad2/3 pathway in LX-2 cells. All the mice in this study were induced by carbon tetrachloride and thioacetamide. In addition, primary hepatic stellate cells from mice were isolated from fresh livers using Nycodenz density gradient separation. The severity and extent of liver fibrosis in mice were evaluated by Sirius Red and Masson staining. The effect of GDF15 on the activation of the TGF-β pathway was detected using dual-luciferase reporter assays and Western blotting assays.Results:The expression of GDF15 in cirrhotic liver tissue was higher than that in normal liver tissue. Blocking GDF15 with a neutralizing antibody resulted in a delay in primary hepatic stellate cell activation and remission of liver fibrosis induced by carbon tetrachloride or thioacetamide. Meanwhile, TGF-β pathway activation was partly inhibited by a GDF15-neutralizing antibody in primary hepatic stellate cells. These results indicated that GDF15 plays an important role in regulating HSC activation and liver fibrosis progression.Conclusions:The inhibition of GDF15 attenuates chemical-inducible liver fibrosis and delays hepatic stellate cell activation, and this effect is probably mainly attributed to its regulatory role in TGF-β signalling.

scholarly journals Murine hepatic stellate cells veto CD8 T cell activation by a CD54-dependent mechanism

Hepatology ◽  
2011 ◽  
Vol 54 (1) ◽  
pp. 262-272 ◽  
Author(s):  
Frank A. Schildberg ◽  
Alexandra Wojtalla ◽  
Sören V. Siegmund ◽  
Elmar Endl ◽  
Linda Diehl ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Activation ◽  
Hepatic Stellate Cells ◽  
Cell Activation ◽  
Stellate Cells ◽  
Cd8 T Cell ◽  
Dependent Mechanism

scholarly journals RNA Binding Proteins Control Transdifferentiation of Hepatic Stellate Cells into Myofibroblasts

2018 ◽  
Vol 48 (3) ◽  
pp. 1215-1229 ◽  
Author(s):  
Sihyung Wang ◽  
Youngmi Jung ◽  
Jeongeun Hyun ◽  
Matthew Friedersdorf ◽  
Seh-Hoon Oh ◽  
...  
Keyword(s):  
Hepatic Stellate Cells ◽  
Binding Proteins ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Stellate Cells ◽  
Fibrous Matrix ◽  
Rna Immunoprecipitation ◽  
Physical Interactions ◽  
Β Receptor ◽  
Dependent Mechanism

Background/Aims: Myofibroblasts (MF) derived from quiescent nonfibrogenic hepatic stellate cells (HSC) are the major sources of fibrous matrix in cirrhosis. Because many factors interact to regulate expansion and regression of MF-HSC populations, efforts to prevent cirrhosis by targeting any one factor have had limited success, motivating research to identify mechanisms that integrate these diverse inputs. As key components of RNA regulons, RNA binding proteins (RBPs) may fulfill this function by orchestrating changes in the expression of multiple genes that must be coordinately regulated to affect the complex phenotypic modifications required for HSC transdifferentiation. Methods: We profiled the transcriptomes of quiescent and MF-HSC to identify RBPs that were differentially-expressed during HSC transdifferentiation, manipulated the expression of the most significantly induced RBP, insulin like growth factor 2 binding protein 3 (Igf2bp3), and evaluated transcriptomic and phenotypic effects. Results: Depleting Igf2bp3 changed the expression of thousands of HSC genes, including multiple targets of TGF-β signaling, and caused HSCs to reacquire a less proliferative, less myofibroblastic phenotype. RNA immunoprecipitation assays demonstrated that some of these effects were mediated by direct physical interactions between Igf2bp3 and mRNAs that control proliferative activity and mesenchymal traits. Inhibiting TGF-β receptor-1 signaling revealed a microRNA-dependent mechanism that induces Igf2bp3. Conclusions: The aggregate results indicate that HSC transdifferentiation is ultimately dictated by Igf2bp3-dependent RNA regulons and thus, can be controlled simply by manipulating Igf2bp3.

Modulating a modulator: biogenic amines at subthreshold levels potentiate peptide-mediated cardioexcitation of the heart of the tobacco hawkmoth Manduca sexta.

1994 ◽  
Vol 197 (1) ◽  
pp. 377-391 ◽  
Author(s):  
K R Prier ◽  
O H Beckman ◽  
N J Tublitz
Keyword(s):  
Cyclic Amp ◽  
Manduca Sexta ◽  
Biogenic Amine ◽  
Molecular Mechanisms ◽  
Adult Heart ◽  
The Central Nervous System ◽  
Messenger System ◽  
Dose Dependent Increase ◽  
Dose Dependent ◽  
Dependent Mechanism

The central nervous system of the moth Manduca sexta contains a group of myoregulatory neuropeptides, the CAPs (Cardioacceleratory Peptides), which cause a physiologically important, dose-dependent increase in heart rate during wing inflation and flight in adult moths. We report here that the response of the adult heart to a subset of the CAPs, the CAP2S, is potentiated nearly twofold in the chronic presence of subthreshold levels of the biogenic amine octopamine or near-threshold levels of the biogenic amine serotonin. Subthreshold levels of the CAP2S fail to alter the response of the heart to octopamine. We have begun to investigate the molecular mechanisms underlying this potentiation. Previous work on the adult heart has shown that the CAP2s act through an inositol-1,4,5-trisphosphate second-messenger system. Here, we demonstrate that the cardioexcitatory effects of the two amines, in contrast to those of the CAP2S, are both mediated by cyclic AMP. Application to the heart of either 10(-5) moll-1 octopamine or 10(-6)moll-1 serotonin elicits a threefold increase in intracellular cyclic AMP levels. The CAP2S have no effect on cyclic AMP levels in the heart. These results illustrate a mechanism by which the effectiveness of a neurohormone can be increased with minimal cost to the animal. In Manduca sexta, subthreshold levels of octopamine are found in the haemolymph during wing inflation and flight. Thus, it is possible that octopamine up-regulates the effects of CAP2 via a cyclic-AMP-dependent mechanism during these activities.

scholarly journals SAT-LB101 Loss of GLP-2R Signaling Activates Hepatic Stellate Cells and Exacerbates Diet-Induced Steatohepatitis in Mice

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Shai Z Fuchs ◽  
Bernardo Yusta ◽  
Laurie Baggio ◽  
Elodie Varin ◽  
Dianne Matthews ◽  
...  
Keyword(s):  
Hepatic Stellate Cells ◽  
Cell Activation ◽  
Ex Vivo ◽  
Stellate Cell ◽  
Intestinal Failure ◽  
Stellate Cells ◽  
Cell Fractionation ◽  
Hepatic Inflammation ◽  
Hepatic Lipid Accumulation ◽  
Gut Hormone

Abstract A GLP-2 analogue is used in individuals with intestinal failure at risk for liver disease, yet the hepatic actions of GLP-2 are not understood. Treatment of high fat diet (HFD)-fed mice with GLP-2 did not modify the development of hepatosteatosis or hepatic inflammation. In contrast, Glp2r-/- mice exhibited increased hepatic lipid accumulation, deterioration in glucose tolerance, and upregulation of biomarkers of hepatic inflammation. Both mouse and human liver expressed the canonical GLP-2R, and hepatic Glp2r expression was upregulated in mice with hepatosteatosis. Cell fractionation localized the Glp2r to hepatic stellate cells (HSC), and markers of HSC activation and fibrosis were increased in livers from Glp2r-/- mice. Moreover, GLP-2 directly modulated gene expression in isolated HSCs ex vivo. Taken together, these findings define an essential role for the GLP-2R in hepatic adaptation to nutrient excess and unveil a gut hormone-HSC axis, linking GLP-2R signaling to control of hepatic stellate cell activation.

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