High density lipoprotein as a source of cholesterol for adrenal steroidogenesis: a study in individuals with low plasma HDL-C

Abstract

The synthesis and secretion of adrenal steroid hormones for regulating stress responses, electrolyte homeostasis, and maintenance of secondary sexual characteristics depends upon the availability of the precursor cholesterol ( 1 ). To secure a continuous cholesterol supply, the adrenal glands can synthesize cholesterol, metabolize intracellular esterifi ed cholesterol, or obtain cholesterol from circulating lipoproteins ( 1 ). Although exact data are lacking, plasma lipoproteins have been suggested to contribute more than 75% of all cholesterol required for adrenal steroidogenesis ( 2, 3 ), but the current literature gives little insight in associations between plasma lipoprotein levels and adrenal function in humans.With respect to a role for low-density lipoprotein (LDL), it has been shown that LDL receptor-defi cient patients suffering from familial hypercholesterolemia display normal urinary excretion of both 17 hydroxycorticosteroids (17-OHCS) and 17 ketogenic steroid metabolites (17-KS) indicative of unaffected adrenal function ( 4, 5 ). In addition, low or absent LDL cholesterol (LDL-C) in carriers of one or two defective APOB alleles respectively did not affect basal adrenal function either ( 6 ). Combined this suggests that LDL is probably not playing a major role in delivering cholesterol for steroid hormone production in humans. Associations with HDL cholesterol (HDL-C) have thus far only been studied in critically ill patients. In one Abstract Few studies have addressed the delivery of lipoprotein-derived cholesterol to the adrenals for steroid production in humans. While there is evidence against a role for low-density lipoprotein (LDL), it is unresolved whether high density lipoprotein (HDL) contributes to adrenal steroidogenesis. To study this, steroid hormone profi les in urine were assessed in male subjects suffering from functional mutations in ATP binding cassette transporter A1 (ABCA1) (n = 24 ), lecithin:cholesterol acyltransferase (LCAT) (n = 40), as well as in 11 subjects with low HDL cholesterol (HDL-C) without ABCA1/LCAT mutations. HDL-C levels were 39% lower in the ABCA1, LCAT, and low HDL-C groups compared with controls (all P < 0.001). In all groups with low HDL-C levels, urinary excretion of 17-ketogenic steroids was reduced by 33%, 27%, and 32% compared with controls (all P < 0.04). In seven carriers of either type of mutation, adrenocorticotropic hormone (ACTH) stimulation did not reveal differences from normolipidemic controls. In conclusion, this study shows that basal but not stimulated corticosteroid metabolism is attenuated in subjects with low HDL-C, irrespective of its molecular origin. These fi ndings lend support to a role for HDL as a cholesterol donor for basal adrenal steroidogenesis in humans.

Diethylstilbestrol decreased adrenal cholesterol and corticosterone in rats

“…Plasma lipoprotein deficiency in mice as a result of feeding with probucol is associated with decreased adrenal cortex cholesterol levels, a lower basal and stress-induced plasma glucocorticoid level (Hoekstra et al 2010). Recently, in low-HDL-cholesterol subjects, adrenal steroids have been reduced to about 30% of the normal values for controls due to insufficiency of the source for adrenal steroidogenesis (Bochem et al 2013). These previous studies and our results in this study support the hypothesis that reduction of adrenal steroidogenesis is due to adrenal cholesterol insufficiency, which might be caused by the reduction in serum HDL/cholesterol level in DES-treated rats.…”

Adrenocortical LDL receptor function negatively influences glucocorticoid output

“…A genetic defect in proteins involved in the formation and cellular uptake of HDL-cholesteryl esters is associated with a diminished adrenal glucocorticoid output in experimental mouse models (Cai et al 2008, Hoekstra et al 2008, 2009) as well as in humans (Vergeer et al 2011, Bochem et al 2013. HDL-cholesterol thus appears to be of crucial importance for an optimal production of glucocorticoids by the adrenals in vivo.…”

Effects of Phytosterols as Food Additives on Adrenal and Reproductive Endocrine Function during Sexual Maturation in Male Japanese Quail (<i>Coturnix coturnix japonica</i>)

“…Adrenal glands and gonads may preferentially use different sources of cholesterol (lipoproteins) for steroidogenesis. Human and rodent adrenals utilize HDL-C (Yang et al, 2004;Bochem et al, 2013); in contrast, testicular steroidogenesis mostly depends upon a continuous supply of cholesterol derived from either de-novo synthesis or from uptake of circulating LDL-C level (Dobs et al, 2000). Conversely, PS effectively reduced LDL-C levels, while HDL-C and triglyceride levels were not significantly altered (Moghadasian and Frohlich, 1999;Calpe-Berdiel et al, 2009).…”