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Intracellular signaling pathways involved in acetaldehyde-induced collagen and fibronectin gene expression in human hepatic stellate cells.
Hepatology. 2001 May; 33(5):1130-40.Hep

Abstract

Ethanol induces liver fibrosis by several means that include, among others, the direct fibrogenic action of acetaldehyde on hepatic stellate cells (HSC). However the mechanisms responsible for this effect are not well understood. In this communication we investigated signal transduction pathways triggered by acetaldehyde leading to upregulation of alpha2(I) collagen and fibronectin gene expression in human HSC. Run-on assays showed that acetaldehyde-enhanced transcription of these 2 genes as early as 2 hours, via de novo protein synthesis-independent and -dependent mechanisms. It also stimulated a time-dependent induction in phosphorylation of pp70(S6K) and extracellular-regulated kinase (1/2) (ERK1/2). These effects were completely prevented by calphostin C, a protein kinase C inhibitor. As expected, acetaldehyde-elicited ERK1/2 phosphorylation was inhibited by PD98059, a MEK inhibitor, but not by wortmannin, a PI3K inhibitor. On the other hand, both of these inhibitors partially inhibited phosphorylation of pp70(S6K) induced by acetaldehyde suggesting that its activation is ERK1/2- and PI3K-dependent. Acetaldehyde-elicited fibronectin and alpha2(I) collagen upregulation was inhibited by calphostin C. However, while PD98059, wortmannin and rapamycin (a pp70(S6K) inhibitor) completely abrogated alpha2(I) collagen upregulation, they had no effect on fibronectin expression. Overall, these data suggest that protein kinase C is an upstream component from which acetaldehyde signals are transduced to other pathways such as PI3K and ERK1/2. In addition, differential activation of these pathways is needed for the increase in fibronectin and alpha2(I) collagen gene expression induced by acetaldehyde in human HSC.

Authors+Show Affiliations

Department of Gastroenterology, University of Ancona, Italy. g.svegliati@unian.itNo affiliation info availableNo affiliation info availableNo 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

11343241

Citation

Svegliati-Baroni, G, et al. "Intracellular Signaling Pathways Involved in Acetaldehyde-induced Collagen and Fibronectin Gene Expression in Human Hepatic Stellate Cells." Hepatology (Baltimore, Md.), vol. 33, no. 5, 2001, pp. 1130-40.
Svegliati-Baroni G, Ridolfi F, Di Sario A, et al. Intracellular signaling pathways involved in acetaldehyde-induced collagen and fibronectin gene expression in human hepatic stellate cells. Hepatology. 2001;33(5):1130-40.
Svegliati-Baroni, G., Ridolfi, F., Di Sario, A., Saccomanno, S., Bendia, E., Benedetti, A., & Greenwel, P. (2001). Intracellular signaling pathways involved in acetaldehyde-induced collagen and fibronectin gene expression in human hepatic stellate cells. Hepatology (Baltimore, Md.), 33(5), 1130-40.
Svegliati-Baroni G, et al. Intracellular Signaling Pathways Involved in Acetaldehyde-induced Collagen and Fibronectin Gene Expression in Human Hepatic Stellate Cells. Hepatology. 2001;33(5):1130-40. PubMed PMID: 11343241.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Intracellular signaling pathways involved in acetaldehyde-induced collagen and fibronectin gene expression in human hepatic stellate cells. AU - Svegliati-Baroni,G, AU - Ridolfi,F, AU - Di Sario,A, AU - Saccomanno,S, AU - Bendia,E, AU - Benedetti,A, AU - Greenwel,P, PY - 2001/5/9/pubmed PY - 2001/6/2/medline PY - 2001/5/9/entrez SP - 1130 EP - 40 JF - Hepatology (Baltimore, Md.) JO - Hepatology VL - 33 IS - 5 N2 - Ethanol induces liver fibrosis by several means that include, among others, the direct fibrogenic action of acetaldehyde on hepatic stellate cells (HSC). However the mechanisms responsible for this effect are not well understood. In this communication we investigated signal transduction pathways triggered by acetaldehyde leading to upregulation of alpha2(I) collagen and fibronectin gene expression in human HSC. Run-on assays showed that acetaldehyde-enhanced transcription of these 2 genes as early as 2 hours, via de novo protein synthesis-independent and -dependent mechanisms. It also stimulated a time-dependent induction in phosphorylation of pp70(S6K) and extracellular-regulated kinase (1/2) (ERK1/2). These effects were completely prevented by calphostin C, a protein kinase C inhibitor. As expected, acetaldehyde-elicited ERK1/2 phosphorylation was inhibited by PD98059, a MEK inhibitor, but not by wortmannin, a PI3K inhibitor. On the other hand, both of these inhibitors partially inhibited phosphorylation of pp70(S6K) induced by acetaldehyde suggesting that its activation is ERK1/2- and PI3K-dependent. Acetaldehyde-elicited fibronectin and alpha2(I) collagen upregulation was inhibited by calphostin C. However, while PD98059, wortmannin and rapamycin (a pp70(S6K) inhibitor) completely abrogated alpha2(I) collagen upregulation, they had no effect on fibronectin expression. Overall, these data suggest that protein kinase C is an upstream component from which acetaldehyde signals are transduced to other pathways such as PI3K and ERK1/2. In addition, differential activation of these pathways is needed for the increase in fibronectin and alpha2(I) collagen gene expression induced by acetaldehyde in human HSC. SN - 0270-9139 UR - https://www.unboundmedicine.com/medline/citation/11343241/Intracellular_signaling_pathways_involved_in_acetaldehyde_induced_collagen_and_fibronectin_gene_expression_in_human_hepatic_stellate_cells_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0270-9139(01)53505-3 DB - PRIME DP - Unbound Medicine ER -