Adrenocortical Response to Adrenocorticotropin in Heterozygous Familial Hypercholesterolemia*

Abstract

Receptor-mediated uptake of low density lipoproteins (LDL) provides an important source of cholesterol for corticosteroid synthesis by human adrenocortical cells grown in tissue culture. Recent studies have indicated an impaired adrenocortical response to prolonged ACTH stimulation in patients with abetalipoproteinemia (who lack plasma LDL) and in patients with homozygous familial hypercholesterolemia (FH), who have a virtual absence of high affinity LDL receptors. In the present study we examined parameters of adrenocortical function in four women with well characterized heterozygous FH to assess whether a 50% reduction in the number of LDL receptors measured in vitro influenced the response of the adrenal cortex to prolonged stimulation with ACTH. Biochemical studies of the binding, internalization, and degradation of [125I]LDL were undertaken in cultured skin fibroblasts from each patient, and all patients had reduced LDL receptor activity. The adrenocortical response to a 36-h iv infusion of alpha ACTH-(1-24) (Cortrosyn) was evaluated in the four patients with heterozygous FH and in five normal women. Stimulation with iv ACTH resulted in rapid increases in the serum concentrations of cortisol in both groups and plateau concentrations of 55-60 micrograms/dl. The rates of increase and the plateau concentrations were similar in the control and FH patients. Similarly, rates of excretion of 17-hydroxycorticosteroids and cortisol were similar in the normal subjects and FH patients. These results indicate that a 50% reduction in the number of high affinity LDL receptors due to the presence of one abnormal gene at the LDL receptor locus does not result in any impairment in the delivery of cholesterol to the adrenal cortex during conditions of maximal corticosteroid production.

The influence of mevinolin on the adrenal cortical response to corticotropin in heterozygous familial hypercholesterolemia.

“…Previous studies have established that the adrenal cortical response to prolonged ACTH infusion is impaired in patients with both abetalipoproteinemia (6, 7) and homozygous FH (8), but it is normal in patients with heterozygous FH (9). The relative contributions of de novo cholesterol biosynthesis and receptor-mediated uptake of LDL in the provision of adrenal cholesterol in patients with the latter disorder is, however, unknown.…”

“…In these studies, parameters of adrenal cortical function were normal in the basal state but the response to ACTH was mildly impaired; this suggests that the lack of either LDL or specific high-affinity LDL receptors impairs the delivery of cholesterol to the adrenal cortex under conditions of maximal stimulation. In contrast to these studies, the adrenal cortical response to ACTH is normal in patients with heterozygous FH (9). The relative contributions of receptor-mediated uptake of LDL as compared to de novo cholesterol biosynthesis within the adrenal gland of patients with heterozygous FH is, however, unknown.…”

“…In all patients, the diagnosis of heterozygous FH was based on primary hypercholesterolemia, an inheritance pattern consistent with autosomal dominant, tendon xanthomas, and the presence of primary hypercholesterolemia in other family members with an absence of multiple phenotypes in other relatives. The characteristics of the study subjects (four males and four females) are outlined in urine-free cortisol and serum cortisol were determined by radioimmunoassay as described (7)(8)(9). The adrenal response to ACTH was determined during a 36-hr continuous infusion of a-ACTH-(1-24) (Cortrosyn) in 5% glucose at a rate of 3.3 units/hr (20).…”

Cholesterol substrate pools and steroid hormone levels are normal in the face of mutational inactivation of NPC1 protein

“…These findings in the mouse are reflected in similar, although limited, observations in humans. In individuals who either lack LDLR function (homozygous familial hypercholesterolemia) or have little circulating LDL-TC (homozygous hypobetalipoproteinemia), the basal levels of circulating adrenal steroids are normal (56)(57)(58). Furthermore, the levels of these hormones also increase in such individuals in response to prolonged adrenocorticotropic hormone infusions, although these increases are not as great as seen in normal, control subjects.…”

Adrenocortical LDL receptor function negatively influences glucocorticoid output

“…Interestingly, homozygous human carriers of a mutation in the LDLR gene, familial hypercholesterolemia (FH) patients, do display a decrease in the maximal adrenal glucocorticoid output (Illingworth et al 1983). However, no significant change in adrenal steroidogenesis rates has been detected in heterozygote human LDLR mutants (Illingworth et al 1984). Importantly, lowering LDLcholesterol levels in FH patients by lovastatin (mevinolin) treatment does not further affect the adrenal glucocorticoid function (Laue et al 1987).…”