MRTF-A/SRF Inhibition Ameliorates Liver Fibrosis via Inhibition of Type I Collagen Expression in Hepatic Stellate Cells

2017 ◽  
Vol 152 (5) ◽  
pp. S1104 ◽  
Author(s):  
Zengdun Shi ◽  
Don C. Rockey
Keyword(s):  
Liver Fibrosis ◽  
Hepatic Stellate Cells ◽  
Type I Collagen ◽  
Stellate Cells ◽  
Type I ◽  
Collagen Expression

scholarly journals LincRNA-p21 Inhibits the Wnt/β-Catenin Pathway in Activated Hepatic Stellate Cells via Sponging MicroRNA-17-5p

2017 ◽  
Vol 41 (5) ◽  
pp. 1970-1980 ◽  
Author(s):  
Fujun Yu ◽  
Yong Guo ◽  
Bicheng Chen ◽  
Liang Shi ◽  
Peihong Dong ◽  
...  
Keyword(s):  
Liver Fibrosis ◽  
Hepatic Stellate Cells ◽  
Noncoding Rna ◽  
Type I Collagen ◽  
Smooth Muscle Actin ◽  
Stellate Cells ◽  
Type I ◽  
Muscle Actin ◽  
Pathway Activity ◽  
Long Intergenic Noncoding Rna

Background/Aims: It is known that the activation of hepatic stellate cells (HSCs) is a pivotal step in the initiation and progression of liver fibrosis. Aberrant activated Wnt/β-catenin pathway is known to accelerate the development of liver fibrosis. microRNAs (miRNAs)-mediated Wnt/β-catenin pathway has been reported to be involved in HSC activation during liver fibrosis. However, whether long noncoding RNAs (lncRNAs) regulate Wnt/β-catenin pathway during HSC activation still remains unclear. Methods: Long intergenic noncoding RNA-p21 (lincRNA-p21) expression was detected in Salvianolic acid B (Sal B)-treated cells. Effects of lincRNA-p21 knockdown on HSC activation and Wnt/β-catenin pathway activity were analyzed in Sal B-treated cells. In lincRNA-p21-overexpressing cells, effects of miR-17-5p on HSC activation and Wnt/β-catenin pathway activity were examined. Results: LincRNA-p21 expression was up-regulated in HSCs after Sal B treatment. In primary HSCs, lincRNA-p21 expression was down-regulated at Day 5 relative to Day 2. Sal B-inhibited HSC activation including the reduction of cell proliferation, α-smooth muscle actin (α-SMA) and type I collagen was inhibited by lincRNA-p21 knockdown. Sal B-induced Wnt/β-catenin pathway inactivation was blocked down by loss of lincRNA-p21. Notably, lincRNA-p21, confirmed as a target of miR-17-5p, suppresses miR-17-5p level. Lack of the miR-17-5p binding site in lincRNA-p21 prevents the suppression of miR-17-5p expression. In addition, the suppression of HSC activation and Wnt/β-catenin pathway induced by lincRNA-p21 overexpression was almost inhibited by miR-17-5p. Conclusion: We demonstrate that lincRNA-p21-inhibited Wnt/β-catenin pathway is involved in the effects of Sal B on HSC activation and lincRNA-p21 suppresses HSC activation, at least in part, via miR-17-5p-mediated-Wnt/β-catenin pathway.

scholarly journals EFFECT OF COLLAGEN I GEL ON APOPTOSIS OF RAT HEPATIC STELLATE CELLS

2013 ◽  
Vol 56 (2) ◽  
pp. 73-79
Author(s):  
Lenka Bittnerová ◽  
Alena Jiroutová ◽  
Emil Rudolf ◽  
Martina Řezáčová ◽  
Jiří Kanta
Keyword(s):  
Hepatic Stellate Cells ◽  
Type I Collagen ◽  
Collagen Gel ◽  
Stellate Cells ◽  
Type I ◽  
Function Type ◽  
Fibrotic Liver ◽  
Normal Rat ◽  
And Function

Activated hepatic stellate cells (HSC) are a major source of fibrous proteins in cirrhotic liver. Inducing or accelerating their apoptosis is a potential way of liver fibrosis treatment. Extracellular matrix (ECM) surrounding cells in tissue affects their differentiation, migration, proliferation and function. Type I collagen is the main ECM component in fibrotic liver. We have examined how this protein modifies apoptosis of normal rat HSC induced by gliotoxin, cycloheximide and cytochalasin D in vitro and spontaneous apoptosis of HSC isolated from CCl4-damaged liver. We have found that type I collagen gel enhances HSC apoptosis regardless of the agent triggering this process.

scholarly journals Reciprocal Modulation of Matrix Metalloproteinase-13 and Type I Collagen Genes in Rat Hepatic Stellate Cells

2003 ◽  
Vol 162 (6) ◽  
pp. 1771-1780 ◽  
Author(s):  
Benjamin Schaefer ◽  
Ana María Rivas-Estilla ◽  
Noemí Meraz-Cruz ◽  
Miguel Arturo Reyes-Romero ◽  
Zamira H. Hernández-Nazara ◽  
...  
Keyword(s):  
Matrix Metalloproteinase ◽  
Hepatic Stellate Cells ◽  
Type I Collagen ◽  
Stellate Cells ◽  
Type I ◽  
Matrix Metalloproteinase 13 ◽  
Collagen Genes

Molecular basis for calcium signaling in hepatic stellate cells

2007 ◽  
Vol 292 (4) ◽  
pp. G975-G982 ◽  
Author(s):  
Emma A. Kruglov ◽  
Paulo R. A. V. Correa ◽  
Gaurav Arora ◽  
Jin Yu ◽  
Michael H. Nathanson ◽  
...  
Keyword(s):  
Liver Fibrosis ◽  
Hepatic Stellate Cells ◽  
Stellate Cells ◽  
P2y Receptors ◽  
Type I ◽  
Inositol 1,4,5 Trisphosphate ◽  
Trisphosphate Receptor ◽  
Healthy Liver ◽  
Organ Fibrosis ◽  
Injured Liver

Progressive liver fibrosis (with the resultant cirrhosis) is the primary cause of chronic liver failure. Hepatic stellate cells (HSCs) are critically important mediators of liver fibrosis. In the healthy liver, HSCs are quiescent lipid-storing cells limited to the perisinusoidal endothelium. However, in the injured liver, HSCs undergo myofibroblastic transdifferentiation (activation), which is a critical step in the development of organ fibrosis. HSCs express P2Y receptors linking extracellular ATP to inositol (1,4,5)-trisphosphate-mediated cytosolic Ca2+ signals. Here, we report that HSCs express only the type I inositol (1,4,5)-trisphosphate receptor and that the receptor shifts into the nucleus and cell extensions upon activation. These cell extensions, furthermore, express sufficient machinery to enable local application of ATP to evoke highly localized Ca2+ signals that induce localized contractions. These autonomous units of subcellular signaling and response reveal a new level of subcellular organization, which, in turn, establishes a novel paradigm for the local control of fibrogenesis in the liver.

scholarly journals Suberoylanilide hydroxamic acid suppresses hepatic stellate cells activation by HMGB1 dependent reduction of NF-κB1

PeerJ ◽  
2015 ◽  
Vol 3 ◽  
pp. e1362 ◽  
Author(s):  
Wenwen Wang ◽  
Min Yan ◽  
Qiuhong Ji ◽  
Jinbiao Lu ◽  
Yuhua Ji ◽  
...  
Keyword(s):  
Liver Fibrosis ◽  
Hepatic Stellate Cells ◽  
Hydroxamic Acid ◽  
Molecular Mechanisms ◽  
Stellate Cell ◽  
Smooth Muscle Actin ◽  
Cdna Array ◽  
Stellate Cells ◽  
Type I ◽  
Suberoylanilide Hydroxamic Acid

Hepatic stellate cells (HSCs) activation is essential to the pathogenesis of liver fibrosis. Exploring drugs targeting HSC activation is a promising anti-fibrotic strategy. In the present study, we found suberoylanilide hydroxamic acid (SAHA), a histone deacetylase inhibitor, prominently suppressed the activation phenotype of a human hepatic stellate cell line—LX2. The production of collagen type I andα-smooth muscle actin (α-SMA) as well as the proliferation and migration of LX2 cells were significantly reduced by SAHA treatment. To determine the molecular mechanisms underlying this suppression, genome wild gene regulation by SAHA was determined by Affymetrix 1.0 human cDNA array. Upon SAHA treatment, the abundance of 331 genes was up-regulated and 173 genes was down-regulated in LX2 cells. Bioinformatic analyses of these altered genes highlighted the high mobility group box 1 (HMGB1) pathway was one of the most relevant pathways that contributed to SAHA induced suppression of HSCs activation. Further studies demonstrated the increased acetylation of intracellular HMGB1 in SAHA treated HSCs, and this increasing is most likely to be responsible for SAHA induced down-regulation of nuclear factor kappa B1 (NF-κB1) and is one of the main underlying mechanisms for the therapeutic effect of SAHA for liver fibrosis.

Hematopoietic Origin of Hepatic Stellate Cell.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 1679-1679
Author(s):  
Eri Miyata ◽  
Masahiro Masuya ◽  
Fumihiko Ishikawa ◽  
Shuro Yoshida ◽  
Keizo Kato ◽  
...  
Keyword(s):  
Stem Cells ◽  
Liver Injury ◽  
Hematopoietic Stem Cells ◽  
Hepatic Stellate Cells ◽  
Type I Collagen ◽  
Stellate Cells ◽  
Gradual Transition ◽  
Type I ◽  
Chimeric Mice ◽  
Hematopoietic Stem

Abstract Hepatic stellate cells are believed to play a key role in the development of liver fibrosis. They undergo a gradual transition from a quiescent, fat-storing phenotype to an activated myofibroblast-like phenotype and then produce high amount of extracellular matrix such as collagen by liver injury. They express mesenchymal markers such as vimentin and desmin, or neural/neuroectodermal markers such as glial fibrillary acidic protein (GFAP). Based on the characteristic phenotype, the embryonic origin of stellate cells is thought to be the septum transversum mesenchyme or neural crest. However, their origin in the adult liver is still unknown. Recently, several studies have reported that crude bone marrow (BM) cells can give rise to hepatic stellate cells. However, since adult BM cells are thought to contain hematopoietic stem cells and mesenchymal stem cells, it is important to clarify which type of stem cells is the true source of hepatic stellate cells. We hypothesized that hepatic stellate cells are derived from hematopoietic stem cells. To test this hypothesis, we generated chimeric mice by transplantation of singe enhanced green fluorescent protein (EGFP)-marked hematopoietic stem cells (Lin− Sca-1+ c-kit+ CD34− cells) into lethally irradiated nontransgenic mice and examined the histology of liver tissues obtained from chimeric mice with carbon tetrahydrochloride (CCl4)-induced injury. Following 12 weeks treatment of CCl4, hepatic nodules and bridging fibrosis developed in all livers. We detected EGFP+ cells in the liver and some of them contained intracytoplasmic lipid droplets, which were proved by oil red O staining. Immunohistochemical analysis demonstrated that 60% of EGFP+ cells were negative for leukocyte common antigen (CD45); however, they expressed vimentin, GFAP and ADAMTS-13, which is a circulating zinc metalloproteinase synthesized in hepatic stellate cells. Moreover, nonparenchymal cell populations were isolated from the livers of chimeric mice with CCl4 treatment and were incubated on noncoated glass slides for 3 days. EGFP+ cells were also positive for type I collagen. These phenotypes are consistent with those of hepatic stellate cells. Our findings suggest that hematopoietic stem cells contribute to the generation of hepatic stellate cells upon liver injury.

Direct Hepatotoxic Effect of KC Chemokine in the Liver Without Infiltration of Neutrophils

2005 ◽  
Vol 230 (8) ◽  
pp. 573-586 ◽  
Author(s):  
Lela Stefanovic ◽  
David A. Brenner ◽  
Branko Stefanovic
Keyword(s):  
Hepatic Stellate Cells ◽  
Type I Collagen ◽  
Feedback Regulation ◽  
Fold Increase ◽  
Stellate Cells ◽  
Polymerase Chain Reaction Analysis ◽  
Type I ◽  
Hepatotoxic Effect ◽  
Polymerase Chain

KC is a mouse homolog of human chemokine gro-α (CXCL1), expression of which is increased in liver diseases. We show that activated, but not quiescent, hepatic stellate cells (HSCs) express KC. Hepatic stellate cells constitutively express the KC receptor, CXCR2. Addition of recombinant KC to HSCs undergoing activation in culture Increases secretion and processing of Type I collagen. Overexpression of endogenous KC in the mouse liver could be achieved by an intraperitoneal injection CCl4 followed after 24 hrs by an injection of recombinant KC into circulation. This protocol resulted in about a 14-fold increase in concentration of KC protein in the liver. Overexpression of KC was associated with upregulation of the mRNA for CXCR2 and MIP-2 and with necrosis and increased synthesis of Type I collagen. This suggests that KC has a direct hepatotoxic effect, which led to a massive liver necrosis after 48 hrs. No accumulation of neutrophils was seen in the livers as judged by histology and reverse transcriptase-polymerase chain reaction analysis of myeloperoxidase mRNA. Autostimulation of KC and CXCR2 expression by recombinant KC protein in the mice with preexisting liver injury indicates a positive feedback regulation. Such regulation and direct hepatotoxicity of KC with increased collagen synthesis represent novel findings about the role of KC/gro-α in liver pathology.

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