Expression of low and high density lipoprotein receptor genes in human adrenals

Abstract

Corticosteroids are synthesized from cholesterol which may arise from de novo synthesis or from the uptake of low or high density lipoproteins (LDL or HDL). In the present study, we compared the expression and regulation patterns of LDL receptor and CLA-1 (CD36 and LIMPII Analogous-1, an HDL receptor) genes in adult human adrenocortical tissues to shed more light on the relative contribution of LDL and HDL in human adrenal steroidogenesis. By screening 64 normal and pathological adrenal samples by Northern blotting, we found a positive correlation between LDL receptor and CLA-1 mRNA expression in the adrenal tissues (r = 0.547; spearman rank correlation test P < 0.01). Adrenal tissues adjacent to Cushing's adenomas contained consistently less LDL receptor and CLA-1 mRNA than normal adrenals (Mann-Whitney P < 0.05). In primary cultures of normal adrenal cells, accumulation of both LDL receptor and CLA-1 mRNAs was upregulated by ACTH in a dose-and time-dependent manner, with an earlier induction of LDL receptor than CLA-1 mRNA expression. (Bu) 2 cAMP also increased the levels of these two mRNAs. Addition of LDL, but not HDL, into the culture medium increased cortisol production in untreated adrenocortical cells. Both LDL and HDL enhanced ACTH-induced cortisol production, with the effect of LDL much stronger than that of HDL. Our data show that LDL receptor and CLA-1's expression is ACTH-dependent and occurs in parallel in human adrenal tissues. LDL rather than HDL may be used as the preferential source of cholesterol for steroidogenesis in human adult adrenocortical cells.

Scavenger receptor class B type I-mediated uptake of serum cholesterol is essential for optimal adrenal glucocorticoid production

“…In addition to the "HDL receptor" SR-BI, adrenals express the LDL receptor, which is involved in the whole particle endocytosis of the ApoB-containing lipoproteins VLDL and LDL (12). Importantly, the expression of SR-BI and the LDL receptor and steroidogenesis are coordinately regulated by activators of both glucocorticoid (dibutyryl cAMP and ACTH) and mineralocorticoid (PMA) synthesis in adrenocortical cells both in vitro and in vivo (24,(26)(27)(28)(29)(30)(31), leading to the generally accepted suggestion that the LDL receptor may also contribute to adrenal steroid hormone synthesis in vivo. However, it has never been experimentally defined to what extent the LDL receptor indeed allows optimal adrenal hormone production, i.e., corticosterone production.…”

The hepatoadrenal syndrome: A common yet unrecognized clinical condition*

“…Recently, mouse SR-B1 (scavenger receptor, class B, type 1) and its human homolog (CLA-1) have been identified as the highaffinity HDL receptors mediating selective cholesterol uptake (30)(31)(32). These receptors are expressed at high levels in the parenchymal cells of the liver and the steroidogenic cells of the adrenal glands, ovary, and testis (33). CLA-1 messenger RNA is highly expressed in human adrenals, and the accumulation of CLA-1 messenger RNA is regulated by adrenocorticotropin in primary cultures of normal human adrenocortical cells (34).…”

Early steps in steroidogenesis: intracellular cholesterol trafficking

“…Patients with low LDL cholesterol secondary to congenital abetalipoproteinemia have normal basal cortisol concentrations and mildly impaired cortisol secretion in response to adreno-corticotropic hormone (ACTH) ( 64 ), and those treated with high doses of statins have no impairment in cortisol secretion ( 65 ), suggesting that endogenous synthesis can suffi ce ( 66 ). Rodents differ from most other mammals in using cholesterol from circulating HDL taken up by SR-B1 as their principal source of cholesterol for steroidogenesis; HDL and SR-B1 appear to play minor roles in human steroidogenesis (67)(68)(69) ( Fig. 2 ).…”