Acetaldehyde stimulates the activation of latent transforming growth factor-β1 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 α1(I) collagen and ultimately causing hepatic fibrosis. The underlying mechanisms of this process remain largely unknown. Transforming growth factor-β1 (TGF-β1) is a potent inducer of α1(I) collagen production. Accumulating evidence has shown a potential role for TGF-β1 in alcohol-induced hepatic fibrogenesis. The aims of this study were to determine the effect of acetaldehyde on TGF-β signalling, to elucidate the underlying mechanisms as well as to evaluate its role in expression of α1(I) collagen gene in cultured HSC. It was hypothesized that acetaldehyde activated TGF-β signalling by inducing the expression of elements in the TGF-β signal transduction pathway, which might contribute to α1(I) collagen gene expression in cultured HSC. Initial results revealed that acetaldehyde activated TGF-β signalling in cultured HSC. Additional studies demonstrated that acetaldehyde stimulated the secretion and activation of latent TGF-β1, and induced the expression of the type II TGF-β receptor (Tβ-RII). Further experiments found cis- and trans-activating elements responsible for Tβ-RII gene expression induced by acetaldehyde. Activation of TGF-β signalling by acetaldehyde contributed to α1(I) collagen gene expression in cultured HSC. In summary, this report demonstrated that acetaldehyde stimulated TGF-β signalling by increasing the secretion and activation of latent TGF-β1 as well as by inducing the expression of Tβ-RII in cultured HSC. Results from this report provided a novel insight into mechanisms by which acetaldehyde stimulated the expression of α1(I) collagen in HSC and a better understanding of effects of alcohol (or acetaldehyde) on hepatic fibrogenesis.