E-box-binding Repressor Is Down-regulated in Hepatic Stellate Cells during Up-regulation of Mannose 6-Phosphate/Insulin-like Growth Factor-II Receptor Expression in Early Hepatic Fibrogenesis

Weiner, Joel A.; Chen, Anping; Davis, Bernard H.

doi:10.1074/jbc.273.26.15913

Cited by 31 publications

(38 citation statements)

References 34 publications

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“…M6P is a ligand for M6P/IGF II receptor, which is upregulated in fibroblast-like cells such as activated HSCs during liver fibrosis (18,19). Coupling of M6P to albumin increased selective uptake of this modified albumin by HSCs during liver fibrosis (30).…”

Section: Discussionmentioning

confidence: 99%

Receptor-Mediated Hepatic Uptake of M6P−BSA-Conjugated Triplex-Forming Oligonucleotides in Rats

Cheng

Guntaka

et al. 2006

Bioconjugate Chem.

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Excessive production of extracellular matrix, predominantly type I collagen results in liver fibrosis. Earlier we synthesized mannose 6-phosphate-bovine serum albumin (M6P-BSA) and conjugated to the type I collagen specific triplex forming oligonucleotide (TFO) for its enhanced delivery to hepatic stellate cells (HSCs), which is the principle liver fibrogenic cell. In this report, we demonstrate a time-dependent cellular uptake of M6P-BSA-33 P-TFO by HSC-T6 cells. Both cellular uptake and nuclear deposition of M6P-BSA-33 P-TFO were significantly higher than those of 33 P-TFO, leading to enhanced inhibition of type I collagen transcription. Following systemic administration into rats, hepatic accumulation of M6P-BSA-33 P-TFO increased from 55% to 68% with the number of M6P per BSA from 14 to 27. Unlike 33 P-TFO, there was no significant decrease in the hepatic uptake of (M6P) 20 -BSA-33 P-TFO in fibrotic rats. Prior administration of excess M6P-BSA decreased the hepatic uptake of (M6P) 20 -BSA-33 P-TFO from 66% to 40% in normal rats, and from 60% to 15% in fibrotic rats, suggesting M6P/insulin-like growth factor II (M6P/IGF-II) receptor-mediated endocytosis of M6P-BSA-33 P-TFO by HSCs. Almost 82% of the total liver uptake in fibrotic rats was contributed by HSCs. In conclusion, by conjugation with M6P-BSA, the TFO could be potentially used for the treatment of liver fibrosis.

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Section: Discussionmentioning

confidence: 99%

Receptor-Mediated Hepatic Uptake of M6P−BSA-Conjugated Triplex-Forming Oligonucleotides in Rats

Cheng

Guntaka

et al. 2006

Bioconjugate Chem.

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“…The dried gel was exposed to a phosphor imaging system (Phosphor Image SI, Molecular Dynamics, Sunnyvale, CA). The radioactivity in each band was measured by computer-aided densitometry of the phosphorimage using IPLab Gel (Signal Analytics Corp.) as described previously (20).…”

Section: Methodsmentioning

confidence: 99%

UV Irradiation Activates JNK and Increases αI(I) Collagen Gene Expression in Rat Hepatic Stellate Cells

Chen

Davis

1999

Journal of Biological Chemistry

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“…Treatment of rats with CCl 4 for 1-3 days results in acute liver injury that is accompanied by HSC activation (26,27). Nuclear extracts were prepared from HSCs isolated from rats injured for 48 h by intraperitoneal injection of CCl 4 or olive oil carrier as a control.…”

Section: Jund Is a Major Constituent Of Ap-1 Dna-binding Complexes Inmentioning

confidence: 99%

JunD Regulates Transcription of the Tissue Inhibitor of Metalloproteinases-1 and Interleukin-6 Genes in Activated Hepatic Stellate Cells

Smart

Vincent

Arthur

et al. 2001

Journal of Biological Chemistry

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Hepatic stellate cells (HSCs)1 represent up to 15% of the resident cells of the liver and play a pivotal role in the cellular pathology underlying hepatic fibrosis (1). In response to liver injury of any etiology, the normally quiescent HSC undergoes a progressive process of trans-differentiation into a proliferating myofibroblast-like activated HSC (1). Through increased secretion of extracellular matrix proteins and the tissue inhibitor of metalloproteinases (TIMP)-1 and TIMP-2, activated HSCs are responsible for deposition and accumulation of the majority of the excess extracellular matrix in the fibrotic liver (2). Furthermore, activated HSCs can contribute to the fibrogenic process through their ability to secrete and respond to a wide range of cytokines and growth factors (3).Details of the molecular events that regulate HSC activation are beginning to be unraveled, as is the potential for specific members of the AP-1, NF-B, and Kruppel-like transcription factor families to control key profibrogenic features of the activated HSCs (1, 4 -6). Putative AP-1 and NF-B sites are found in the promoters of many genes that are induced upon HSC activation and contribute to the fibrotic process, including TIMP-1 (AP-1), IL-6 (AP-1 and NF-B), and ICAM-1 (NF-B) (4, 5, 7). Since in vivo activation of HSCs can be closely mimicked by culturing HSCs isolated from normal rat liver on plastic and in the presence of serum, it has been possible to investigate the transcriptional control of potential profibrotic genes during HSC activation (1). Investigators including ourselves have previously demonstrated that basal and cytokine/ growth factor-inducible transcription of these genes is dependent on interaction of specific AP-1 and NF-B (Rel) protein dimers with their putative promoter-binding sites (4 -6). These observations indicate that these inducible transcription factors are likely to play a key role in the activation and/or persistence of myofibroblast-like HSCs. Recent studies have identified target genes of NF-B (IL-6 and ICAM-1) and have also indicated that NF-B may protect activated HSCs against apoptosis (5,6,8). Less attention has been directed at studying the role played by AP-1 in HSC activation. Although in vitro studies have shown that activated HSCs express inducible AP-1 DNA-binding activity (4, 9, 10), there is little direct evidence that AP-1 plays a key role in the transcriptional regulation of the activated HSC phenotype. Chen and Davis (11, 12) recently re-

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E-box-binding Repressor Is Down-regulated in Hepatic Stellate Cells during Up-regulation of Mannose 6-Phosphate/Insulin-like Growth Factor-II Receptor Expression in Early Hepatic Fibrogenesis

Cited by 31 publications

References 34 publications

Receptor-Mediated Hepatic Uptake of M6P−BSA-Conjugated Triplex-Forming Oligonucleotides in Rats

Receptor-Mediated Hepatic Uptake of M6P−BSA-Conjugated Triplex-Forming Oligonucleotides in Rats

UV Irradiation Activates JNK and Increases αI(I) Collagen Gene Expression in Rat Hepatic Stellate Cells

JunD Regulates Transcription of the Tissue Inhibitor of Metalloproteinases-1 and Interleukin-6 Genes in Activated Hepatic Stellate Cells

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