Sequential cycles of cholesterol and dolichol synthesis in mouse spleens during phenylhydrazine-induced erythropoiesis.

The results presented demonstrate that erythropoiesis in the mouse spleen was associated with cyclic changes in cholesterol and dolichol synthesis which were independent of each other. Changes in the rate of cholesterol synthesis were correlated with the level of 3-hydroxy-3-methylglutaryl-CoA reductase activity and with the rate of cell division (thymidine incorporation into DNA), but a cycle of dolichol synthesis appeared to be independent of both these parameters. Consequently the incorporation of [14C]acetate into dolichol increased 20- to 30-fold compared to the rate of cholesterol synthesis 5 to 6 days following phenylhydrazine treatment. The pathway for dolichol synthesis branches from that leading to cholesterol at the level of the intermediate farnesyl pyrophosphate, subsequent to the reaction catalyzed by the regulatory enzyme 3-hydroxy-3-methylglutaryl-CoA reductase. Previous studies showed that in several cell culture lines, and in liver, dolichol synthesis and cholesterol synthesis are regulated in a coordinated way by reductase activity. However, during the process of spermatogenesis and in developing mouse brain the regulation of dolichol synthesis appeared to be independent of cholesterol synthesis. Independent regulation of dolichol synthesis is now demonstrated in a third differentiating tissue, the erythropoietic spleen, and the results suggest that a cycle of dolichol synthesis is specifically associated with one or more stages of erythroid differentiation.