Liver injury is accompanied by trans-differentiation (activation) of hepatic stellate cells (HSC) into myofibroblasts, a key event in liver fibrogenesis that results in increased proliferation and migration. These vents are accompanied by alterations in the production of extracellular matrix components required for cell- matrix interactions and excess production of scar tissue, including type I collagen and fibronectin. Thus, nhibition of HSC trans-differentiation could prevent the subsequent events leading to excess collagen deposition, fibrosis and cirrhosis. A hallmark of HSC activation is the up-regulation of platelet-derived growth factor-beta receptor (PDGF-betaR) and their increased migratory and proliferative response to PDGF-BB. Although many studies have focused on PDGF-BB-dependent molecular events leading to cell proliferation and migration, little is known regarding the role of acetaldehyde, the first metabolite of ethanol, on PDGF- betaR expression and HSC proliferation and migration. Moreover, the role of ACH and PDGF-BB on HSC- matrix interactions remains to be investigated. Based on our previous studies, namely that acetaldehyde exerts some of its action via the accumulation of reactive oxygen species (hydrogen peroxide) and the preliminary results presented in this application we propose to investigate molecular mechanismswhereby acetaldehyde modulates the expression of PDGF-betaR in HSC. We will also study the role of ACH on the migratory and proliferative responses of HSC to PDGF-BB and on the PDGF-BB-dependent alterations in cell-matrix interactions. Our long term goal is to unravel key molecular events triggered by acetaldehyde that could lead to therapeutic intervention and thus, to prevention and/or amelioration of alcohol-induced liver fibrosis and cirrhosis.

National Institute of Health (NIH)
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
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Special Emphasis Panel (ZRG1-DIG-F (02))
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Radaeva, Svetlana
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George Washington University
Schools of Medicine
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Reyes-Gordillo, Karina; Shah, Ruchi; Arellanes-Robledo, Jaime et al. (2014) Mechanisms of action of acetaldehyde in the up-regulation of the human ?2(I) collagen gene in hepatic stellate cells: key roles of Ski, SMAD3, SMAD4, and SMAD7. Am J Pathol 184:1458-67
Shah, Ruchi; Reyes-Gordillo, Karina; Arellanes-Robledo, Jaime et al. (2013) TGF-?1 up-regulates the expression of PDGF-? receptor mRNA and induces a delayed PI3K-, AKT-, and p70(S6K) -dependent proliferative response in activated hepatic stellate cells. Alcohol Clin Exp Res 37:1838-48
Moran-Atkin, Erin; Brody, Fred; Fu, Sidney W et al. (2013) Changes in GIP gene expression following bariatric surgery. Surg Endosc 27:2492-7
Arellanes-Robledo, Jaime; Reyes-Gordillo, Karina; Shah, Ruchi et al. (2013) Fibrogenic actions of acetaldehyde are ?-catenin dependent but Wingless independent: a critical role of nucleoredoxin and reactive oxygen species in human hepatic stellate cells. Free Radic Biol Med 65:1487-1496
Ohayon, Olga; Mawasi, Nidal; Pevzner, Anna et al. (2008) Halofuginone upregulates the expression of heparanase in thioacetamide-induced liver fibrosis in rats. Lab Invest 88:627-33
Barnaeva, Elena; Nadezhda, Agladze; Hannappel, Ewald et al. (2007) Thymosin beta4 upregulates the expression of hepatocyte growth factor and downregulates the expression of PDGF-beta receptor in human hepatic stellate cells. Ann N Y Acad Sci 1112:154-60
Zhang, Yining; Ikegami, Tadashi; Honda, Akira et al. (2006) Involvement of integrin-linked kinase in carbon tetrachloride-induced hepatic fibrosis in rats. Hepatology 44:612-22
Lechuga, Carmen G; Hernandez-Nazara, Zamira H; Hernandez, Elizabeth et al. (2006) PI3K is involved in PDGF-beta receptor upregulation post-PDGF-BB treatment in mouse HSC. Am J Physiol Gastrointest Liver Physiol 291:G1051-61
Kannangai, Rajesh; Diehl, Anna Mae; Sicklick, Jason et al. (2005) Hepatic angiomyolipoma and hepatic stellate cells share a similar gene expression profile. Hum Pathol 36:341-7
Svegliati-Baroni, Gianluca; Inagaki, Yutaka; Rincon-Sanchez, Ana-Rosa et al. (2005) Early response of alpha2(I) collagen to acetaldehyde in human hepatic stellate cells is TGF-beta independent. Hepatology 42:343-52

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