In previous investigations, we have found that the liver appears to be the major source of cholesterol in the human fetus, and, in particular, a principal source of circulating low density lipo-protein-cholesterol (LDL-C). LDL-C plasma levels are low in the normal fetus, most likely due to the rapid uptake and metabolism by the fetal adrenal as precursor for steroid hormone biosynthesis. In contrast, in the anencephalic fetus the adrenals are atrophic, the rate of estrogen and glucocorticoid production is low, and the levels of LDL-C in fetal plasma are high. The purpose of the present investigation was to determine the activity of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, the primary rate-limiting enzyme of cholesterol biosynthesis, in anencephalic liver and normal fetal liver. We found that the specific activity of HMG-CoA reductase in normal fetal liver microsomes was 0.428 +/- 0.054 nmol mevalonate formed times mg-1 protein X min-1 (mean +/- SE, n = 9). The rate of HMG-CoA reductase in anencephalic liver microsome preparations was 10-fold less (0.040 +/- 0.003) (mean +/- SE, n = 7) P less than 0.001. Furthermore, we detected HMG-CoA reductase (97,000-mol wt protein) in normal human fetal liver after SDS PAGE and immunoblotting by using a monoclonal antibody directed against HMG-CoA reductase. We were unable to detect any significant quantity of HMG-CoA reductase protein in anencephalic fetal liver, which indicates that low reductase activity was due to low amounts of enzyme protein rather than inactive enzyme. In summary, we conclude that the low levels of cholesterol synthesis observed in anencephalic fetal liver are probably due to both the high levels of LDL-C in fetal plasma as well as the presence of low circulating levels of estrogens and glucocorticoids and that these factors regulate cholesterol synthesis both in vivo and in vitro in fetal liver. This occurs most probably by the modulation of the amount of HMG-CoA reductase, a primary rate-limiting and regulatory enzyme of the cholesterol biosynthetic sequence.

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