title: Acetaldehyde stimulates the activation of latent transforming growth factor-beta1 and induces expression of the type II receptor of the cytokine in rat cultured hepatic stellate cells.
abstract: Acetaldehyde, the major active metabolite of alcohol, induces the activation of hepatic stellate cells (HSC), leading to over-production of alpha1(I) collagen and ultimately causing hepatic fibrosis. The underlying mechanisms of this process remain largely unknown. Transforming growth factor-beta1 (TGF-beta1) is a potent inducer of alpha1(I) collagen production. Accumulating evidence has shown a potential role for TGF-beta1 in alcohol-induced hepatic fibrogenesis. The aims of this study were to determine the effect of acetaldehyde on TGF-beta signalling, to elucidate the underlying mechanisms as well as to evaluate its role in expression of alpha1(I) collagen gene in cultured HSC. It was hypothesized that acetaldehyde activated TGF-beta signalling by inducing the expression of elements in the TGF-beta signal transduction pathway, which might contribute to alpha1(I) collagen gene expression in cultured HSC. Initial results revealed that acetaldehyde activated TGF-beta signalling in cultured HSC. Additional studies demonstrated that acetaldehyde stimulated the secretion and activation of latent TGF-beta1, and induced the expression of the type II TGF-beta receptor (Tbeta-RII). Further experiments found cis - and trans -activating elements responsible for Tbeta-RII gene expression induced by acetaldehyde. Activation of TGF-beta signalling by acetaldehyde contributed to alpha1(I) collagen gene expression in cultured HSC. In summary, this report demonstrated that acetaldehyde stimulated TGF-beta signalling by increasing the secretion and activation of latent TGF-beta1 as well as by inducing the expression of Tbeta-RII in cultured HSC. Results from this report provided a novel insight into mechanisms by which acetaldehyde stimulated the expression of alpha1(I) collagen in HSC and a better understanding of effects of alcohol (or acetaldehyde) on hepatic fibrogenesis.
authors.affiliation: Department of Pathology, Louisiana State University Health Sciences Center in Shreveport, 1501 Kings Hwy., Shreveport, LA 71130, USA. achen@lsuhsc.edu
authors.forename: Anping
authors.initials: A
authors.lastname: Chen
mesh_terms: D000079:Acetaldehyde / Q000378:metabolism / Q000494:pharmacology*; D000438:Alcohols / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western; D002460:Cell Line; D003094:Collagen / Q000378:metabolism; D016895:Culture Media, Serum-Free / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004797:Enzyme-Linked Immunosorbent Assay; D005786:Gene Expression Regulation; D008099:Liver / Q000166:cytology / Q000378:metabolism; D008297:Male; D008954:Models, Biological; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D010957:Plasmids / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases; D012313:RNA / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism*; D012260:Ribonucleases / Q000378:metabolism; D015398:Signal Transduction; D013997:Time Factors; D015533:Transcriptional Activation; D014162:Transfection; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D053773:Transforming Growth Factor beta1; D015854:Up-Regulation
chemical_list: D000438:Alcohols; D016895:Culture Media, Serum-Free; D016376:Oligonucleotides, Antisense; D018125:Receptors, Transforming Growth Factor beta; C508962:Tgfb1 protein, rat; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D012313:RNA; D003094:Collagen; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II; D012260:Ribonucleases; D000079:Acetaldehyde