Luteal cell 3-hydroxy-3-methylglutaryl coenzyme-A reductase activity and cholesterol metabolism throughout pregnancy in the rat

The objective of this study was to investigate changes in luteal cell cholesterol biosynthetic capacity, cholesterol accumulation, lipoprotein receptor activity, and in vivo steroidogenesis during pregnancy. Cholesterol biosynthetic capacity was assessed by measuring both the activity and the content of the rate-limiting enzyme 3-hydroxy-3-methylglutaryl coenzyme-A (HMG-CoA) reductase and by monitoring [14C]acetate incorporation into luteal sterols. The results showed that HMG-CoA reductase activity increased steadily during the first few days of pregnancy and reached a peak value on day 10. Subsequently, enzyme activity dropped precipitously and remained low until parturition. A parallel decline in the rate of conversion of 14C-labeled sterols was observed. Such changes in HMG-CoA reductase activity were not related to the phosphorylation/dephosphorylation state of the enzyme, but were due to a reduction in the amount of enzyme protein, as determined by the immunoblotting technique. Despite the highly active HMG-CoA reductase in the first half of pregnancy, very little cholesterol ester was stored, and serum progesterone concentrations were only about 50-75 ng/ml. However, from midpregnancy, the corpus luteum became capable of storing more cholesterol ester and producing more progesterone at a time when its ability to synthesize cholesterol declined. At this stage, luteal cells appear to shut off de novo synthesis and use principally exogenous cholesterol. To find out whether this is due to an increase in the number of high density lipoprotein (HDL) receptors, HDL-binding activity was determined in luteal cells throughout pregnancy. Whereas the Kd and the number of binding sites per mg protein were similar between days 6-18, the total content of HDL receptor increased markedly with the size of the corpus luteum. In summary, the present investigation indicates that pregnancy profoundly influences the ability of the corpus luteum to acquire, synthesize, and process the cholesterol substrate needed for steroidogenesis.