Lipoprotein Utilization and Cholesterol Synthesis by the Human Fetal Adrenal Gland*

Abstract

A model proposed for regulation of steroidogenesis, lipoprotein utilization and cholesterol metabolism in HFA tissue is presented in Fig 17. We envision that the role of ACTH and cAMP in steroidogenesis and cholesterol metabolism is as follows. ACTH binds to specific receptors on the surface of the cells of the HFA gland and as a consequence, adenylate cyclase is activated, leading to increased formation of cAMP. cAMP causes activation of protein kinase that leads, presumably, to phosphorylation of specific proteins. This leads to the initiation of reactions that give rise to increased activity of key enzymes and levels of proteins involved in adrenal cholesterol metabolism. Presumably, the action of ACTH causes an increase in the activity of cholesterol side chain cleavage, the rate-limiting step in the conversion of cholesterol to steroid hormones. We suggest that once the mitochondrial cholesterol side-chain cleavage system is fully activated by ACTH, the supply of cholesterol to the mitochondria becomes rate-limiting for steroidogenesis. To meet this demand for cholesterol, a further action of ACTH results in an increase in the number of LDL receptors. LDL binds to specific receptors on the cell surface that are localized in coated pits. LDL is internalized by a process of adsorptive endocytosis and the internalized vesicles fuse with lysosomes and the protein component of LDL is hydrolyzed by lysosomal proteolytic enzymes to amino acids. The cholesteryl esters of LDL also are hydrolyzed to give rise to fatty acids and cholesterol. The liberated cholesterol is available for utilization in the biosynthesis of steroid hormones and other cellular processes. In addition, ACTH stimulates the activity of HMG CoA reductase and, thus, the rate of de novo cholesterol biosynthesis. In this way sufficient cholesterol is obtained to provide for precursor cholesterol to maintain the high rate of steroid synthesis by the HFA. HDL is not utilized as a source of cholesterol by the HFA. Because of the rapid rate of utilization of LDL by the HFA, fetal plasma levels of LDL are low and the activity of the HFA is a primary determinant of these levels. Thus, in the case of anencephaly, in which the activity of the adrenal is very low, plasma levels of LDL are 2--3 times higher than in normal fetuses, whereas plasma HDL levels are similar. In addition, in the normal neonate plasma LDL levels rise rapidly after birth, and this event is coincident with the involution of the fetal zone of the adrenal. The fetal liver is likely to be the major source ultimately of the LDL-cholesterol utilized by the HFA. Consequently, factors that regulate cholesterol and lipoprotein synthesis in the fetal liver may, in turn, affect the steroidogenic activity of the HFA through regulation of the supply of cholesterol precursor. Thus, if trophic factors for the HFA other than ACTH exist, an important site of their action might be the fetal liver, rather than a direct action to influence the rate of synthesis of steroids by the fetal adrenal.

Umbilical cord blood lipoproteins. Isolation and characterization of high density lipoproteins.

“…50 The fetus represents a rapidly growing system with the resultant need for lipids as structural elements and as precursors for hormones. 51 The combined effects of these factors are manifested in the alterations in HDL size and composition found in the neonatal umbilical cord blood HDL.…”

3-Hydroxy-3-methylglutaryl coenzyme A reductase in anencephalic and normal human fetal liver.

“…We have previously suggested that the principal source of cholesterol in the fetus is by way of fetal synthesis of cholesterol de novo (1,2). Evidence to support this conclusion is derived from studies that demonstrate that no more than 20% of fetal cholesterol is derived from the maternal compartment (3)(4)(5) and that the fetal dietary source of cholesterol by way of swallowing amniotic fluid is negligible (6).…”

100th anniversary of the discovery of the human adrenal fetal zone by Stella Starkel and Lesław Węgrzynowski: how far have we come?

“…Considering steroidogenic pathways, the adrenal fetal zone carries a higher number of LDL-binding sites than definitive zone does and in both zones ACTH stimulates LDL-binding [78,79]. Similar differences are observed in de novo cholesterol synthesis and, again, ACTH stimulates this synthesis.…”

“…For most of gestation, fetal zone secretes large quantities of DHEA and DHEAS, attaining the production rate of up to 100-200 mg/day. The rate of steroid secretion by the fetal adrenals may be 5-fold higher than that by the adrenals of adults at rest [78]. Functional data indicate cortisol and DHEAS secretion as early as at weeks 6-8 of gestation, while aldosterone secretion starts after weeks 20-24 [11,75].…”