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Hydrogen peroxide: a link between acetaldehyde-elicited alpha1(I) collagen gene up-regulation and oxidative stress in mouse hepatic stellate cells.
Hepatology. 2000 Jan; 31(1):109-16.Hep

Abstract

Ethanol induces liver fibrosis by several means that include, among others, the direct fibrogenic actions of acetaldehyde and the induction of an oxidative stress response. However, the mechanisms responsible for these activities, and the possible connections between oxidative stress and acetaldehyde-induced fibrosis are not well understood. In this communication we investigated the molecular mechanisms whereby acetaldehyde induces mouse alpha1(I) procollagen (col1a1) gene expression in cultured hepatic stellate cells. Transfection assays using reporter plasmids driven by different segments of the col1a1 promoter localized an acetaldehyde-responsive element (AcRE) between nucleotides -370 and -345. We also show that acetaldehyde enhances binding of a CCAAT/enhancer binding protein-beta (C/EBPbeta)-containing complex to this element, and that this effect is due, at least in part, to an increase in the concentration of nuclear p35C/EBPbeta protein. Although this element overlaps to a previously described transforming growth factor beta1 (TGF-beta1)-responsive element, the stimulatory effect of acetaldehyde is not mediated through this cytokine, because addition of neutralizing anti-TGF-beta1 antibodies does not prevent acetaldehyde-elicited col1a1 up-regulation. On the other hand, this effect is blocked by the addition of catalase, an H(2)O(2) scavenger. Moreover, this ethanol metabolite stimulates production of H(2)O(2) in stellate cells. Thus, these results suggest that acetaldehyde-induced col1a1 up-regulation is mediated, at least in part, through H(2)O(2). Altogether, these data suggest that the -370 to -344 region of the col1a1 gene is a point of convergence of the action of numerous extracellular stimuli that ultimately leads to col1a1 up-regulation. In addition, we have established a direct connection between oxidative stress and enhanced col1a1 expression induced by acetaldehyde.

Authors+Show Affiliations

Brookdale Center in the Department of Biochemistry and Molecular Biology, Mount Sinai School of Medicine, New York, NY, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

10613735

Citation

Greenwel, P, et al. "Hydrogen Peroxide: a Link Between Acetaldehyde-elicited alpha1(I) Collagen Gene Up-regulation and Oxidative Stress in Mouse Hepatic Stellate Cells." Hepatology (Baltimore, Md.), vol. 31, no. 1, 2000, pp. 109-16.
Greenwel P, Domínguez-Rosales JA, Mavi G, et al. Hydrogen peroxide: a link between acetaldehyde-elicited alpha1(I) collagen gene up-regulation and oxidative stress in mouse hepatic stellate cells. Hepatology. 2000;31(1):109-16.
Greenwel, P., Domínguez-Rosales, J. A., Mavi, G., Rivas-Estilla, A. M., & Rojkind, M. (2000). Hydrogen peroxide: a link between acetaldehyde-elicited alpha1(I) collagen gene up-regulation and oxidative stress in mouse hepatic stellate cells. Hepatology (Baltimore, Md.), 31(1), 109-16.
Greenwel P, et al. Hydrogen Peroxide: a Link Between Acetaldehyde-elicited alpha1(I) Collagen Gene Up-regulation and Oxidative Stress in Mouse Hepatic Stellate Cells. Hepatology. 2000;31(1):109-16. PubMed PMID: 10613735.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Hydrogen peroxide: a link between acetaldehyde-elicited alpha1(I) collagen gene up-regulation and oxidative stress in mouse hepatic stellate cells. AU - Greenwel,P, AU - Domínguez-Rosales,J A, AU - Mavi,G, AU - Rivas-Estilla,A M, AU - Rojkind,M, PY - 1999/12/29/pubmed PY - 1999/12/29/medline PY - 1999/12/29/entrez SP - 109 EP - 16 JF - Hepatology (Baltimore, Md.) JO - Hepatology VL - 31 IS - 1 N2 - Ethanol induces liver fibrosis by several means that include, among others, the direct fibrogenic actions of acetaldehyde and the induction of an oxidative stress response. However, the mechanisms responsible for these activities, and the possible connections between oxidative stress and acetaldehyde-induced fibrosis are not well understood. In this communication we investigated the molecular mechanisms whereby acetaldehyde induces mouse alpha1(I) procollagen (col1a1) gene expression in cultured hepatic stellate cells. Transfection assays using reporter plasmids driven by different segments of the col1a1 promoter localized an acetaldehyde-responsive element (AcRE) between nucleotides -370 and -345. We also show that acetaldehyde enhances binding of a CCAAT/enhancer binding protein-beta (C/EBPbeta)-containing complex to this element, and that this effect is due, at least in part, to an increase in the concentration of nuclear p35C/EBPbeta protein. Although this element overlaps to a previously described transforming growth factor beta1 (TGF-beta1)-responsive element, the stimulatory effect of acetaldehyde is not mediated through this cytokine, because addition of neutralizing anti-TGF-beta1 antibodies does not prevent acetaldehyde-elicited col1a1 up-regulation. On the other hand, this effect is blocked by the addition of catalase, an H(2)O(2) scavenger. Moreover, this ethanol metabolite stimulates production of H(2)O(2) in stellate cells. Thus, these results suggest that acetaldehyde-induced col1a1 up-regulation is mediated, at least in part, through H(2)O(2). Altogether, these data suggest that the -370 to -344 region of the col1a1 gene is a point of convergence of the action of numerous extracellular stimuli that ultimately leads to col1a1 up-regulation. In addition, we have established a direct connection between oxidative stress and enhanced col1a1 expression induced by acetaldehyde. SN - 0270-9139 UR - https://www.unboundmedicine.com/medline/citation/10613735/Hydrogen_peroxide:_a_link_between_acetaldehyde_elicited_alpha1_I__collagen_gene_up_regulation_and_oxidative_stress_in_mouse_hepatic_stellate_cells_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0270913900702187 DB - PRIME DP - Unbound Medicine ER -