COLLAGEN-SYNTHESIS BY LIVER STELLATE CELLS IS RELEASED FROM ITS NORMAL FEEDBACK-REGULATION BY ACETALDEHYDE-INDUCED MODIFICATION OF THE CARBOXYL-TERMINAL PROPEPTIDE OF PROCOLLAGEN

Acetaldehyde stimulates collagen synthesis in stellate cells and forms adducts with procollagen in the liver of alcoholics, To assess the po ssibility that modification of the carboxyl-terminal propeptide by ace taldehyde affects its capacity to exert a feedback inhibition of colla gen synthesis after splitting from procollagen, the propeptide was pre pared by gel filtration of the bacterial collagenase digests of procol lagen type I (obtained from 10(9) calvaria fibroblasts of newborn rats ) and reacted with either 250 mM acetaldehyde and 100 mM CNBH3 or with 170 mu M acetaldehyde without reducing agents, to mimick in vivo cond itions, The unmodified propeptide produced a concentration-dependent i nhibition of collagen synthesis by Ito cells, By contrast, the acetald ehyde-modified propeptide produced a lesser inhibition of procollagen synthesis in the cells, associated with a greater accumulation of coll agen in the media, The incubation with 170 mu M acetaldehyde and, to a lesser extent, 50 mM ethanol produced collagenase-digestible adducts in stellate cells, Thus, the formation of acetaldehyde adducts with th e carboxyl-terminal propeptide of procollagen may account, at least in part, for the stimulatory effect of acetaldehyde on collagen synthesi s by stellate cells and may lead to collagen accumulation through a de crease of the normal feedback regulation of collagen synthesis by the propeptide.