In previous investigations, we found high rates of cholesterol synthesis in human fetal liver tissue, second only to rates in fetal adrenal tissue. Previous estimates of the amount of cholesterol in the fetus derived from the maternal compartmentare in the range of 20%. Thus, the liver may be the principal source of circulating lipoproteins in the human fetus, as is true in the human adult.Low density lipoprotein is the major source of cholesterol used for fetal adrenalsteroidogenesis; therefore, it follows that factors regulating cholesterol synthesis in the human fetal liver may indirectly control the rate of steroid secretionby the adrenal cortex. The purpose of the present investigation was to determine if hormones, particularly those produced by the fetal-placental unit, might serveto stimulate cholesterol synthesis in the human fetal liver. The rate of cholesterol biosynthesis was determined by measuring the rate of incorporation of [3H]water into [3H]cholesterol in hepatocytes maintained in culture or by determination of the specific activity of 3‒ hydroxy‒ 3‒ methylglutaryl coenzyme A reductase in microsomal preparations from human fetalliver. The addition of dexamethasone (10‒ 10‒ l0-6 M) stimulated cholesterol synthesis up to 2- to 4-fold between days 2 and 6 of exposure. When human fetal liver cells were maintained in the presence of dexamethasone (10-7 M), the activity of 3-hydroxy-3-methylglutaryl coenzymeA reductase in microsomal fractions was stimulated 4-fold compared to that in control cells. Cortisol also stimulated cholesterol biosynthesis in a concentration-dependent manner. The addition of 17β-estradiol (E2) to the culture medium resultedin stimulation of cholesterol biosynthesis in a concentration-dependent manner from 10-10-10-7 M. The rate of cholesterol synthesis when E2 was present (10-7 M) was 4-fold greater than that in untreated cells. Stimulation of cholesterol synthesis by E2 was maintained between 2-7 days of incubation with E2 Estrone, estriol, and E2(10-6 M) caused similar increases (3‒ to 4‒ fold) in the rates of cholesterol synthesis in human fetal hepatocytes. Finally, progesterone in concentrations greater than 10-6 M significantly stimulated cholesterol synthesis in human fetal liver cells. In contrast, other hormones and factors, including insulin, glucagon, PRL, GH, dehydroepiandrosterone and its sulfate, epidermalgrowth factor, fibroblast growth factor, T3, (Bu)2cAMP, andcholera toxin, had no effect on the rate of cholesterol synthesis in human fetal liver cells. In summary, estrogens, glucocorticoids, and progesterone produced bythe fetal-placental unit stimulate the rate of cholesterol synthesis in human fetal liver cells.
ASJC Scopus subject areas
- Endocrinology, Diabetes and Metabolism
- Clinical Biochemistry
- Biochemistry, medical