Acetaldehyde (AC), an alcohol metabolite, induces type I Collagen production in hepatic stellate cells (HSC), constituting a critical part of the pathogenesis of alcoholic cirrhosis. However, little is known about the mechanism of the AC effects. One feature of the activated Collagen producing HSC is the loss of retinoid storage. Our study, based on the hypothesis that the loss of retinoic acid (RA) plays a role in alcoholic cirrhosis, has indicated that a) RA inhibits the basal activity of a2(I) Collagen promoter and represses the AC induced activation of the promoter in transdifferentiated HSC; b) RA induces the expression of RA receptor b (RARb) while AC decreases RARb land retinoid X receptor alpa (RXR a) in HSC; c) the RA effect on a2(I) Collagen promoter does not occurs at the RA response element (RARE) site we studied. RAR and RXR are known to function as heterodimers. RXR can also act independently of RAR. We hypothesize that RXR a is an equally essential part of the regulation of a 2(I) collagen promoter by RA, and that the cis-acting element(s) in the promoter may preferentially interact with RXR in the RA-RAR/RXR regulatory mechanism.
Our Specific Aims are to: 1) examine the regulatory role of RXR in CC2(l) Collagen expression in HSC and the influence of RA and AC on RXR expression in HSC; 2) determine whether RAR and/or RXR bind to the rat a2(I) Collagen promoter and characterize the nature of the binding; and 3) identify other possible trans-acting factor(s), such as the cofactors of nuclear retinoid receptors), SP-1 and AP-2, in the R-A regulatory pathway on a2(I) Collagen expression specifically in HSC. We hope that this project will extend our understanding of the mechanism(s) for the activation of type I Collagen expression in liver fibrogenesis and ultimately lead to potential treatment and prevention of cirrhosis. This project is the continuation of ongoing studies the candidate has performed under the mentorship of Dr. Esteban Mezey who has made ma or contributions in the field of alcoholic liver pathogenesis. It is an essential part of the structured career development plan, to extend Dr. Wang's knowledge and to further develop her skills, leading to an independent academic career.
|Wang, Lan; Potter, James J; Rennie-Tankersley, Lynda et al. (2007) Effects of retinoic acid on the development of liver fibrosis produced by carbon tetrachloride in mice. Biochim Biophys Acta 1772:66-71|
|Wang, Lan; Tankersley, Lynda Rennie; Tang, Mei et al. (2002) Regulation of the murine alpha(2)(I) collagen promoter by retinoic acid and retinoid X receptors. Arch Biochem Biophys 401:262-70|