Aldehydes potentiate alpha(2)(I) collagen gene activity by JNK in hepatic stellate cells

Hepatic stellate cells (HSCs) are responsible for type I collagen depositio n in liver fibrosis that leads to cirrhosis. The purpose of this study was to examine potential molecular signals that lead to increased alpha (2)(I) collagen gene expression by acetaldehyde. the primary metabolite of alcohol and malondialdehyde (MDA), a lipid peroxidation product known to be associ ated with chronic liver injury. MDA and the combination of MDA and acetalde hyde were employed to determine the effect on alpha (2)(I) collagen gene ex pression as assessed by transient transfection analysis and reverse transcr iptase polymerase chain reaction (RT-PCR). Immunoblot and subsequent immuno precipitation analysis examined stress-activated protein kinase (SAPK) acti vity. Cotransfection with a dominant negative mutant for c-jun nuclear kina se (dnJNK1) was also employed with the (YZ(I) collagen promoter. MDA increa sed alpha (2)(I) collagen gene expression nearly 2.5- to 3-fold, however th ere was no synergistic effect of the combination of acetaldehyde and MDA on alpha (2)(I) collagen gene activation and expression. Acetaldehyde, MDA, o r both significantly increased JNK activity when compared to untreated stel late cells. The dnJNK1 expression vector abrogated alpha (2)(I) collagen tr ansgene activity. In conclusion, JNK activation appears to be critical in t he signaling cascade of oxidative metabolites of chronic alcohol-related li ver injury and collagen gene activation. (C) 2001 Elsevier Science Inc.