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

Andrea E Bochem,Adriaan G Holleboom,Johannes A Romijn,Menno Hoekstra,Geesje M Dallinga-Thie,Mahdi M Motazacker,G.Kees Hovingh,Jan A Kuivenhoven,Erik S.G Stroes

doi:10.1194/jlr.p033449

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 profiles 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 findings lend support to a role for HDL as a cholesterol donor for basal adrenal steroidogenesis in humans.

Highlights

Few studies have addressed the delivery of lipoprotein-derived cholesterol to the adrenals for steroid production in humans
With respect to a role for low-density lipoprotein (LDL), it has been shown that LDL receptor-deficient 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]
While this study showed that cholesterol delivery to the adrenals via the high density lipoprotein (HDL)-scavenger receptor type B1 (SRB1) pathway is important for adrenal steroidogenesis in humans, it is unclear whether plasma HDL cholesterol (HDL-C) levels are associated with adrenal steroidogenesis in humans

Summary

Introduction

Few studies have addressed the delivery of lipoprotein-derived cholesterol to the adrenals for steroid production in humans. Male subjects with HDL-C levels below the fifth percentile were screened for mutations in ABCA1 and LCAT [17, 19], of which the functionality was assessed in previously published studies [17, 20, 21]. HDL-C levels were 39% lower in carriers of ABCA1 or LCAT mutations and in the low HDL-C group, compared with normolipidemic controls (P < 0.001).

Results

Conclusion