Chromatin sphingomyelin changes in cell proliferation and/or apoptosis induced by ciprofibrate.

It has been shown that neutral-sphingomyelinase and sphingomyelin-synthase activities are present in chromatin and they modify the sphingomyelin (SM) content. The activity of the first enzyme is stimulated and the second inhibited, when the hepatocytes enter into the S-phase after partial hepatectomy, thus suggesting that ceramide may have a pivotal role in cell proliferation. An opposite function was attributed to ceramide in hepatocytes which undergo apoptosis after lobular ligature. In order to clarify this point, a model was developed in which the same liver cells undergo proliferation followed by induced apoptosis. To this purpose, the rats were treated for 7 days with ciprofibrate and then left without treatment for 4 days. During the treatment, the peroxisome enzyme markers increase their activity and the number of proliferating cells increases, reaching a maximum after 3 days of treatment, as shown by the number of cells positive for the proliferating cell nuclear antigen. At the same time, the chromatin sphingomyelinase activity reaches the maximum, while a similar increase is not found in the cytoplasm or in the isolated nuclei. On the contrary, SM-synthase activity is depressed in chromatin, but not in the nuclei in which a peak is shown after 3 days of ciprofibrate treatment. After drug withdrawal, the hepatocytes undergo apoptosis as confirmed by the increase of Bax and tissue transglutaminase (tTGase) expression; the chromatin SM increases as a consequence of an increase of SM-synthase activity. It can be hypothesised that chromatin SM may have a role in cell duplication by influencing the chromatin structure stability. Copyright 2003 Wiley-Liss, Inc.