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.

Regulation of peroxisome proliferator-activated receptor-γ in liver fibrosis

2006 ◽  
Vol 291 (5) ◽  
pp. G902-G911 ◽  
Author(s):  
Liu Yang ◽  
Che-Chang Chan ◽  
Oh-Sang Kwon ◽  
Songling Liu ◽  
Jason McGhee ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Liver Injury ◽  
Mrna Expression ◽  
Cell Activation ◽  
Stellate Cell ◽  
Stellate Cells ◽  
Collagen I ◽  
Peroxisome Proliferator ◽  
Actin Mrna

The peroxisome proliferator-activated receptors (PPARs) impart diverse cellular effects in biological systems. Because stellate cell activation during liver injury is associated with declining PPARγ expression, we hypothesized that its expression is critical in stellate cell-mediated fibrogenesis. We therefore modulated its expression during liver injury in vivo. PPARγ was depleted in rat livers by using an adenovirus-Cre recombinase system. PPARγ was overexpressed by using an additional adenoviral vector (AdPPARγ). Bile duct ligation was utilized to induce stellate cell activation and liver fibrosis in vivo; phenotypic effects (collagen I, smooth muscle α-actin, hydroxyproline content, etc.) were measured. PPARγ mRNA levels decreased fivefold and PPARγ protein was undetectable in stellate cells after culture-induced activation. During activation in vivo, collagen accumulation, assessed histomorphometrically and by hydroxyproline content, was significantly increased after PPARγ depletion compared with controls (1.28 ± 0.14 vs. 1.89 ± 0.21 mg/g liver tissue, P < 0.03). In isolated stellate cells, AdPPARγ overexpression resulted in significantly increased adiponectin mRNA expression and decreased collagen I and smooth muscle α-actin mRNA expression compared with controls. During in vivo fibrogenesis, rat livers exposed to AdPPARγ had significantly less fibrosis than controls. Collagen I and smooth muscle α-actin mRNA expression were significantly reduced in AdPPARγ-infected rats compared with controls ( P < 0.05, n = 10). PPARγ-deficient mice exhibited enhanced fibrogenesis after liver injury, whereas PPARγ receptor overexpression in vivo attenuated stellate cell activation and fibrosis. The data highlight a critical role for PPARγ during in vivo fibrogenesis and emphasize the importance of the PPARγ pathway in stellate cells during liver injury.

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 Preproendothelin-1 expression is negatively regulated by IFNγ during hepatic stellate cell activation

2012 ◽  
Vol 302 (9) ◽  
pp. G948-G957 ◽  
Author(s):  
Tianxia Li ◽  
Zengdun Shi ◽  
Don C. Rockey
Keyword(s):  
Cell Proliferation ◽  
Mrna Expression ◽  
Signaling Pathways ◽  
Cell Activation ◽  
Stellate Cell ◽  
Intraperitoneal Administration ◽  
Stellate Cells ◽  
In Vivo Model ◽  
Specific Gene

Endothelin-1 (ET-1), a powerful vasoconstrictor peptide, is produced by activated hepatic stellate cells (HSC) and promotes cell proliferation, fibrogenesis, and contraction, the latter of which has been thought to be mechanistically linked to portal hypertension in cirrhosis. Interferon-γ (IFNγ), a Th1 cytokine produced by T cells, inhibits stellate cell proliferation, fibrogenesis, and muscle-specific gene expression. Whether IFNγ-induced inhibitory effects are linked to regulation of ET-1 expression in activated stellate cells remains unknown. Here we examined IFNγ's effects on preproET-1 mRNA expression and the signaling pathways underlying this process. We demonstrated that preproET-1 mRNA expression in HSCs was prominently increased during cell culture-induced activation; IFNγ significantly inhibited both preproET-1 mRNA expression and ET-1 peptide production. Similar results were found in an in vivo model of liver injury and intraperitoneal administration of IFNγ. PreproET-1 promoter analysis revealed that IFNγ-induced inhibition of preproET-1 mRNA expression was closely linked to the AP-1 and Smad3 signaling pathways. Furthermore, IFNγ reduced JNK phosphorylation, which tightly was associated with decreased phosphorylation of downstream factors c-Jun and Smad3 and decreased binding activity of c-Jun and Smad3 in the preprpET-1 promoter. Importantly, IFNγ reduced both c-Jun mRNA and protein levels. Given the important role of ET-1 in wound healing, our results suggest a novel negative signaling network by which IFNγ inhibits preproET-1 expression, highlighting one potential molecular mechanism for IFNγ-induced host immunomodulation of liver fibrogenesis.

Rat hepatic stellate cells produce cytokine-induced neutrophil chemoattractant in culture and in vivo

1998 ◽  
Vol 275 (4) ◽  
pp. G847-G853 ◽  
Author(s):  
Jacquelyn J. Maher ◽  
John S. Lozier ◽  
Myron K. Scott
Keyword(s):  
Hepatic Stellate Cells ◽  
Cell Activation ◽  
Stellate Cell ◽  
Stellate Cells ◽  
Biologically Active ◽  
Hepatic Inflammation ◽  
Protein 4.1 ◽  
Potential Sources ◽  
Normal Rat

Hepatic stellate cells are widely recognized for their contribution to liver fibrosis. This study investigated whether these cells also promote hepatic inflammation by producing neutrophil chemoattractants. Specifically, stellate cells were examined as potential sources of cytokine-induced neutrophil chemoattractant (CINC), a rat chemokine resembling human interleukin-8. Stellate cells from normal rat liver expressed little or no CINC. In culture, CINC mRNA was induced rapidly, coinciding with the phenomenon of culture activation. CINC mRNA rose 4.6-fold within 3 days and was accompanied by secretion of immunoreactive and biologically active CINC protein (4.1 ng ⋅ μg DNA−1⋅ day−1). Studies in vivo demonstrated that CINC could be induced in stellate cells during liver injury. CINC mRNA rose significantly (4- to 6-fold) in two models of liver disease, both of which cause stellate cell activation. In summary, the data indicate that CINC is induced during stellate cell activation in culture and in vivo. They suggest that stellate cell-derived CINC can promote hepatic inflammation in vivo.

scholarly journals Epiregulin (EREG) and Myocardin Related Transcription Factor A (MRTF-A) Form a Feedforward Loop to Drive Hepatic Stellate Cell Activation

2021 ◽  
Vol 8 ◽  
Author(s):  
Xiaoyan Wu ◽  
Wenhui Dong ◽  
Tianyi Zhang ◽  
Haozhen Ren ◽  
Jinglin Wang ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Liver Fibrosis ◽  
Cell Activation ◽  
Serum Response Factor ◽  
Stellate Cell ◽  
Feedforward Loop ◽  
Related Transcription Factor ◽  
Egf Family

Trans-differentiation of quiescent hepatic stellate cells (HSC) into myofibroblast cells is considered the linchpin of liver fibrosis. A myriad of signaling pathways contribute to HSC activation and consequently liver fibrosis. Epidermal growth factor (EGF) family of cytokines signal through the cognate receptor EGFR to promote HSC activation. In the present study we investigated the transcription regulation of epiregulin (EREG), an EGFR ligand, during HSC activation. We report that EREG expression was significantly up-regulated in activated HSCs compared to quiescent HSCs isolated from mice. In addition, there was an elevation of EREG expression in HSCs undergoing activation in vitro. Of interest, deficiency of myocardin-related transcription factor A (MRTF-A), a well-documented regulator of HSC trans-differentiation, attenuated up-regulation of EREG expression both in vivo and in vitro. Further analysis revealed that MRTF-A interacted with serum response factor (SRF) to bind directly to the EREG promoter and activate EREG transcription. EREG treatment promoted HSC activation in vitro, which was blocked by MRTF-A depletion or inhibition. Mechanistically, EREG stimulated nuclear trans-location of MRTF-A in HSCs. Together, our data portray an EREG-MRTF-A feedforward loop that contributes to HSC activation and suggest that targeting the EREG-MRTF-A axis may yield therapeutic solutions against liver fibrosis.

scholarly journals Pentoxifylline blocks hepatic stellate cell activation independently of phosphodiesterase inhibitory activity

1997 ◽  
Vol 273 (5) ◽  
pp. G1094-G1100 ◽  
Author(s):  
Kwan S. Lee ◽  
Howard B. Cottam ◽  
Karl Houglum ◽  
D. Bruce Wasson ◽  
Dennis Carson ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Inhibitory Activity ◽  
Cell Activation ◽  
Stellate Cell ◽  
Smooth Muscle Actin ◽  
Stellate Cells ◽  
Collagen Type I ◽  
Type I ◽  
Molecular Abnormalities

Activated, but not quiescent, hepatic stellate cells (lipocytes) have a high level of collagen type I and smooth muscle actin (SMA) gene expression. Therefore, stellate cell activation is a critical step in hepatic fibrosis. The mechanisms leading to stellate cell activation in vivo are unknown. The characteristic hepatic oxidative stress cascade induced in rats by CCl4markedly stimulated stellate cell entry into S phase, nuclear factor (NF)-κB activity, and c- myb expression. These changes were prevented by pentoxifylline, which also decreased CCl4-induced hepatic injury. As expected, cAMP-mediated phosphorylation of CREB-Ser133was induced in vivo in stellate cells by pentoxifylline but not by its metabolite 5, an N-1 carboxypropyl derivative, which lacks phosphodiesterase inhibitory activity. Stellate cell nuclear extracts from CCl4-treated, but not from control, animals formed a complex with the critical promoter E box of the α-SMA gene, which was disrupted by c- myb antibodies and competed with by c- myb cognate DNA. Treatment with pentoxifylline or metabolite 5 prevented the molecular abnormalities characteristic of stellate cell activation induced by CCl4. These results suggest that induction of c- myb plays an important role in the in vivo activation of stellate cells. Pentoxifylline blocks stellate cell activation in vivo independently of its inhibitory effects on phosphodiesterases by interfering with the oxidative stress cascade and the activation of NF-κB and c- myb.

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

Regulation of hepatic stellate cell activation and growth by transcription factor myocyte enhancer factor 2

2004 ◽  
Vol 127 (4) ◽  
pp. 1174-1188 ◽  
Author(s):  
Xuemin Wang ◽  
Xiaoli Tang ◽  
Xiaoming Gong ◽  
Efsevia Albanis ◽  
Scott L. Friedman ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Hepatic Stellate Cell ◽  
Cell Activation ◽  
Stellate Cell ◽  
Myocyte Enhancer Factor 2 ◽  
Hepatic Stellate Cell Activation ◽  
Myocyte Enhancer Factor ◽  
Enhancer Factor

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.

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