Activation of IP3-protein kinase C-alpha signal transduction pathway precedes the changes of plasma cholesterol, hepatic lipid metabolism and induction of low-density lipoprotein receptor expression in 17-beta-oestradiol-treated rats

The intracellular concentration of cholesterol is regulated by the balance between endogenous synthesis and exogenous uptake. Oestrogens have been rep orted to be involved in the physiological regulation of cellular cholestero l content. Relevant reports have focused on long-term responses and there i s a lack of information about the relationship between the timing of the oe strogen effect and the regulation of cholesterol homeostasis. The aim of th is work has been to set up a systematic picture of the short-term effects i nduced by oestrogen on hepatic lipid metabolism in vivo and the involvement of some relevant signal transduction pathways. At intervals after oestroge n administration (30 min to 6 h), oestrogen receptor expression and changes in liver cAMP, IP3 and protein kinase C-alpha (PKC-alpha) were followed. C hanges in the expression of the low density lipoprotein receptor at mRNA an d protein levels, and of hydroxy-methyl-glutaryl-CoA reductase activity hav e been verified. At the same time, the content of hepatic cholesterol, ubiq uinone and dolichol and of plasma cholesterol have been determined. Changes of rab 5 and rab 8, small GTP-binding prenylated proteins involved in the transfer of neosynthesised proteins through the cell, have been also checke d. In vivo treatment with oestradiol produced no change in cyclic AMP but a rapid increase in IP3, increased PKC-alpha localisation on the membranes a nd enhanced expression of the low density lipoprotein receptor in the liver occurred, PKC inhibition completely prevented any increase in low density lipoprotein receptor mRNA in isolated and perfused rat liver. Early changes of ubiquinone and dolichol content and a later reduction in hepatic hydrox y-methyl-glutaryl-CoA reductase activity and plasma cholesterol content wer e also detectable. A functional role of the IP3-protein kinase C-alpha path way in the induction of the low density lipoprotein receptor is suggested.