Alcohol-induced liver cirrhosis is one of the major causes of death worldwide. Strong evidence has established that acetaldehyde, ethanol's first metabolite, is fibrogenic per e and enhances type I collagen production by hepatic stellate cells. Despite major efforts by several laboratories, relatively little is known pertaining the molecular events underlying this stimulatory effect. Thus, it is our long-term goal to integrate cellular and molecular events into a unified picture that explains how acetaldehyde stimulates type I collagen gene transcription in the liver.
The specific aims of this proposal: 1) To characterize the cis-regulatory elements and trans-acting factors, active in hepatic stellate cells of human origin, mediating acetaldehyde-induced human alpha2(I) collagen gene up-regulation; 2) To elucidate key molecular mechanisms by which acetaldehyde modulates the activity and/or binding of the transcription factors that interact with the acetaldehyde- responsive element of the human alpha2(I) collagen gene; and 3) To determine whether acetaldehyde stimulates human alpha2(I) collagen gene expression directly, or through an autocrine loop involving enhanced production and/or activation of transforming growth factor-beta in human hepatic stellate cells. A better characterization of the molecular events underlying enhanced COL1A2 gene expression in hepatic stellate cells, will enhance our understanding of the pathophysiology of ethanol- induced liver fibrosis, and will allow in the near future, to develop new therapies aimed at counteracting the devastating effects of this disease.
