Regulation of 3-hydroxy-3-methylglutaryl-coenzyme A reductase and cholesterol synthesis and esterification during the first cell cycle of liver regeneration.

The regenerating rat liver provides a unique in vivo synchronized system for study of the interrelationships between mevalonate and sterol metabolism during the cell cycle. The regulation of 3-hydroxy-3-methylglutaryl-coenzyme A reductase, cholesterol synthesis and acyl coenzyme A: cholesterol acyltransferase during the first cell cycle was investigated. At 8 h postoperative and prior to onset of DNA synthesis or S phase, cholesterol synthesis was depressed in the regenerating liver relative to that in sham-operated controls. This suppression was observed whether assayed in vitro with liver homogenates utilizing radiolabeled acetate, mevalonate or water or in vivo with tritium water. In contrast, at this time point, 3-hydroxy-3-methylglutaryl-CoA reductase activity was increased in microsomes prepared both in the presence and absence of NaF. By 24 h, well into S phase and approaching mitosis, reductase activity and cholesterol synthesis both approached levels observed in the sham-operated control animals. There were no detectable changes in acyl-CoA: cholesterol acyltransferase activity at any time point. Thus, at the 8 h time point, the regulation of the three processes appeared uncoupled. The increased levels of in vitro expressed 3-hydroxy-3-methylglutaryl-CoA reductase activity compared with the decrease in the rate of both cholesterol and squalene biosynthesis suggested diversion of mevalonate into products other than squalene or sterols. We propose that this may reflect the needs of the cell for a nonsterol metabolite of mevalonate necessary for entry of cells into S phase.