Tumor necrosis factorα down-regulates expression of theα1(I) collagen gene in rat hepatic stellate cells through a p20C/EBPβ- and C/EBPδ-dependent mechanism

Iraburu, María J.; Domı́nguez-Rosales, José Alfredo; Fontana, Luis; Auster, Anitra S.; Garcı́a-Trevijano, Elena R.; Covarrubias‐Pinedo, Amador; Rivas-Estilla, Ana María; Greenwel, Patricia; Rojkind, Marcos

doi:10.1053/he.2000.5981

Cited by 71 publications

(51 citation statements)

References 40 publications

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“…17 Previous studies from our laboratory have localized an acetaldehyde-responsive element in the Ϫ370 to Ϫ344 of the col1a1 promoter and that this element co-localized with TGF-␤1-and TNF-␣-responsive elements. 18,32,33 Furthermore, we established that acetaldehyde upregulates col1a1 gene expression by a mechanism dependent on the generation of H 2 O 2 and involving nuclear translocation and binding of members of the C/EBP␤ family of transcription factors. Type I collagen is a trimeric molecule product of 2 distinct genes that are coordinately expressed through apparently distinct transcriptional mechanisms.…”

Section: Discussionmentioning

confidence: 95%

“…Stable transfectants were selected by culturing the cells for approximately 3 weeks in the presence of 400 g/mL G418. 33 For some experiments, HHSCs were cotransfected with 7.0 g of the Ϫ378 COL1A2LUC reporter construct and 2.5 g of either one of the dominant negative Smad2, Smad3, or Sp1 vectors followed by treatment with acetaldehyde using the conditions described above.…”

Section: Methodsmentioning

confidence: 99%

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Early response of α2(I) collagen to acetaldehyde in human hepatic stellate cells is TGF-β independent

et al. 2005

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Acetaldehyde is fibrogenic and induces the expression of type I collagen genes in hepatic stellate cells. Some of these acetaldehyde-dependent events are mediated by H 2 O 2 and thus establish a direct connection between oxidative stress and collagen upregulation. We localized to the ؊378 to ؊183 region of the ␣2(I) collagen (COL1A2) promoter an acetaldehyde-responsive element (AcRE) functional in human hepatic stellate cells (HHSCs) and investigated molecular mechanisms whereby acetaldehyde stimulates and modulates its transcriptional activity. Because the AcRE co-localized with a previously described transforming growth factor ␤ (TGF-␤)1-responsive element, and both acetaldehyde and this cytokine induce their effects through H 2 O 2 , we investigated whether all fibrogenic actions of acetaldehyde were mediated by this cytokine. Here we show that acetaldehyde-induced COL1A2 upregulation in HHSCs recognizes two distinct but overlapping early and late stages that last from 1 to 6 hours and from 6 to 24 hours, respectively. We present several lines of evidence to show that early acetaldehyde-mediated events are independent of TGF-␤1. These include significant timecourse differences in the expression of COL1A2 and TGF-␤1 mRNAs and inability of neutralizing antibodies to TGF-␤1 to inhibit acetaldehyde-dependent collagen gene transcription and Smad 3 phosphorylation. We also show that although acetaldehyde-dependent upregulation of collagen was PI3K dependent, that of TGF-␤1 was PI3K independent. In conclusion, acetaldehyde-dependent mechanisms involved in COL1A2 upregulation are similar, but not identical, to those of TGF-␤1. We suggest that early acetaldehyde-dependent events induce the late expression of TGF-␤1 and create an H 2 O 2 -dependent autocrine loop that may sustain and amplify the fibrogenic response of this alcohol metabolite. (HEPATOLOGY 2005;42:343-352.)

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Section: Discussionmentioning

confidence: 95%

Section: Methodsmentioning

confidence: 99%

Early response of α2(I) collagen to acetaldehyde in human hepatic stellate cells is TGF-β independent

et al. 2005

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“…Amino acid deficiency typically activates ATF-4 and other members of the leucine-zipper family such as CHOP and C/EBP-b via GCN2. 3,4 Some members of this family of transcription factors have been shown to participate either in the upregulation 15,29 or in the downregulation 30,31 of the col1a1 and col1a2 genes in rat HSC, and other cells. 32 Therefore, downregulation of col1a1 and col1a2 genes could be part of the modification of gene expression mediated by GCN2 to cope with stress situations.…”

Section: Discussionmentioning

confidence: 99%

GCN2 kinase is a key regulator of fibrogenesis and acute and chronic liver injury induced by carbon tetrachloride in mice

Arriazu

López-Zabalza

Leung

et al. 2013

Laboratory Investigation

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General control nonderepresible 2 (GCN2) is a highly conserved cytosolic kinase that modulates a complex response for coping with the stress owing to lack of amino acids. GCN2 has been recently shown to be involved in the regulation of metabolic balance and lipid degradation rate in the liver. We hypothesized that GCN2 could have a role in in hepatic fibrogenesis and in the response to acute or chronic liver injury. Activation of GCN2 in primary or immortalized human hepatic stellate cells by incubation with medium lacking the essential amino acid histidine correlated with decreased levels of collagen type I protein and mRNA, suggesting an antifibrogenic effect of GCN2. In vivo studies with Gcn2 knockout mice (Gcn2 À / À ) showed increased susceptibility to both acute or chronic liver damage induced by CCl 4 , as shown by higher alanine aminotransferase and aspartate aminotransferase activities, increased necrosis and higher inflammatory infiltrates compared with wild-type mice (WT). Chronic CCl 4 treatment increased deposition of interstitial collagen type I more in Gcn2 À / À mice than in WT mice. Col1a1 and col1a2 mRNA levels also increased in CCl 4 -treated Gcn2 À / À mice compared with WT mice. These results suggest that GCN2 is a key regulator of the fibrogenic response to liver injury.

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“…(2). In addition, the p20 isoform has been shown to decrease type I collagen gene transcription in HSC in response to TNF-␣ treatment (15). Binding sites for C/EBP proteins exist throughout the type I collagen gene(s) promoter sequence.…”

Section: Discussionmentioning

confidence: 99%

Differences in regulation of type I collagen synthesis in primary and passaged hepatic stellate cell cultures: the role of α₅β₁-integrin

Dodig¹,

Ogunwale²,

Dasarathy³

et al. 2007

American Journal of Physiology-Gastrointestinal and Liver Physi

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Hepatic stellate cells (HSC) differ in their phenotype depending on the initiation and progression of their activation. Our hypothesis was that different mechanisms govern type I collagen synthesis depending on stage of HSC activation. We investigated the role of ␣5␤1-integrin as a regulator of type I collagen gene COL1A1 expression in primary and passaged HSC cultures using transgenic mouse containing type I collagen gene COL1A1 promoter linked to the chloramphenicol acetyltransferase (CAT) reporter gene. The ␣5␤1 protein levels increased during the activation and were highest in day 6 primary cultures but decreased in passaged HSC. CAT activity, reflecting COL1A1 expression, was upregulated by ␣5␤1-integrin. Inhibition of ␣5␤1-integrin by echistatin and blocking antibody resulted in reduced transgene activity only in early primary cultures (compared with the control, 53.3 Ϯ 12% echistatin and 58.8 Ϯ 7% blocking antibody, respectively, P Ͻ 0.05). Treatment of passaged HSC with either echistatin or blocking antibody had no effect. Fibronectin, an ␣5␤1-integrin ligand, increased transgene activity in primary (210 Ϯ 33%, P Ͻ 0.05) but not in passaged HSC cultures (119 Ϯ 8%). This ␣5␤1-integrin effect appears to be at least in part mediated by CCAAT enhancer binding protein-␤ (C/EBP␤), because fibronectin increased and ␣5-gene silencing by small interfering RNA decreased C/EBP␤ levels. In addition, C/EBP␤ knockout mice showed reduced type I collagen synthesis compared with wild-type littermates. Therefore ␣5␤1-integrin is an important regulator of type I collagen production in early primary HSC cultures but appears to have no direct role once the HSC are fully activated.

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Tumor necrosis factorα down-regulates expression of theα1(I) collagen gene in rat hepatic stellate cells through a p20C/EBPβ- and C/EBPδ-dependent mechanism

Cited by 71 publications

References 40 publications

Early response of α2(I) collagen to acetaldehyde in human hepatic stellate cells is TGF-β independent

Early response of α2(I) collagen to acetaldehyde in human hepatic stellate cells is TGF-β independent

GCN2 kinase is a key regulator of fibrogenesis and acute and chronic liver injury induced by carbon tetrachloride in mice

Differences in regulation of type I collagen synthesis in primary and passaged hepatic stellate cell cultures: the role of α₅β₁-integrin

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Tumor necrosis factorα down-regulates expression of theα1(I) collagen gene in rat hepatic stellate cells through a p20C/EBPβ- and C/EBPδ-dependent mechanism

Cited by 71 publications

References 40 publications

Early response of α2(I) collagen to acetaldehyde in human hepatic stellate cells is TGF-β independent

Early response of α2(I) collagen to acetaldehyde in human hepatic stellate cells is TGF-β independent

GCN2 kinase is a key regulator of fibrogenesis and acute and chronic liver injury induced by carbon tetrachloride in mice

Differences in regulation of type I collagen synthesis in primary and passaged hepatic stellate cell cultures: the role of α5β1-integrin

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Differences in regulation of type I collagen synthesis in primary and passaged hepatic stellate cell cultures: the role of α₅β₁-integrin