Liver X receptors regulate adrenal cholesterol balance

Abstract

Cholesterol is the obligate precursor to adrenal steroids but is cytotoxic at high concentrations. Here, we show the role of the liver X receptors (LXRα and LXRβ) in preventing accumulation of free cholesterol in mouse adrenal glands by controlling expression of genes involved in all aspects of cholesterol utilization, including the steroidogenic acute regulatory protein, StAR, a novel LXR target. Under chronic dietary stress, adrenal glands from Lxrαβ −/− mice accumulated free cholesterol. In contrast, wild-type animals maintained cholesterol homeostasis through basal expression of genes involved in cholesterol efflux and storage (ABC transporter A1 [ABCA1], apoE, SREBP-1c) while preventing steroidogenic gene (StAR) expression. Upon treatment with an LXR agonist that mimics activation by oxysterols, expression of these target genes was increased. Basally, Lxrαβ -/-mice exhibited a marked decrease in ABCA1 and a derepression of StAR expression, causing a net decrease in cholesterol efflux and an increase in steroidogenesis. These changes occurred under conditions that prevented the acute stress response and resulted in a phenotype more specific to the loss of LXRα, including hypercorticosteronemia, cholesterol ester accumulation, and adrenomegaly. These results imply LXRα provides a safety valve to limit free cholesterol levels as a basal protective mechanism in the adrenal gland, where cholesterol is under constant flux. IntroductionThe adrenal cortex is responsible for synthesizing glucocorticoid hormones that are essential for survival under stress. This endocrine pathway is acutely regulated by the hypothalamicpituitary-adrenal axis in response to stress through the release of ACTH from the anterior pituitary. ACTH signals the adrenal gland to increase the expression of a cascade of enzymes required for the conversion of cholesterol into biologically active glucocorticoids. The initial and rate-limiting step in this cascade is mediated by the steroidogenic acute regulatory protein (StAR) that transfers cholesterol from the outer to the inner mitochondrial membrane (1, 2). Inside the mitochondria, cytochrome P450 11A1 (CYP11A1) cleaves the cholesterol side chain to form pregnenolone (3), which can be further converted by a series of enzymes (e.g., type I 3β-hydroxysteroid dehydrogenase/D 5 -D 4 -isomerase) to all steroid hormones produced by the adrenal cortex. Because the stress response is intended to be of limited duration, tight regulation of this system is maintained by the negative feedback of circulating glucocorticoids on the hypothalamus and pituitary that decreases ACTH secretion and ultimately turn off glucocorticoid production (4, 5).

The synthetic liver X receptor agonist GW3965 reduces tissue factor production and inflammatory responses in human islets in vitro

“…1a, b). Because LXRs have a profound effect on serum glucocorticoid levels and secretion from the adrenal gland [21], we evaluated the effect of glucocorticoids on the expression levels of LXR-α and LXR-β. However, we found no evidence for an effect of the glucocorticoid methylprednisolone,1 μg/ml, on the expression of these genes in human islets (Fig.…”

Meta-analysis of adrenocortical tumour genomics data: novel pathogenic pathways revealed

“…The adrenal gland expresses LXRA and LXR beta (LXRB, NR1H2). LXRs have pivotal roles in adrenal cholesterol metabolism, and influence steroid hormone production (Cummins et al, 2006). LXR alpha (LXRA, NR1H3) was significantly underexpressed in ACCs in three studies (Giordano et al, 2009;To¨mbo¨l et al, 2009;de Reynie`s et al, 2009) that may be related to the already described loss of chr11p11 (Figure 3; Supplementary Table 3).…”

“…Co-treatment with 9-cis retinoic acid and thiazolidinedione had additive effects in vitro (Betz et al, 2005;Ferruzzi et al, 2005). Expression of several genes targeted by LXRA and PPARG has been confirmed in the adrenal cortex, including ATP-binding cassette A1 and G1 (ABCA1, ABCG1), apolipoprotein E and C1 (APOE, APOC1), sterol regulatory element-binding transcription factor 1 (SREBF1), scavenger receptor-B1 (SCARB1) (Cummins et al, 2006).…”

Ectopically Expressed Pro-group X Secretory Phospholipase A2 Is Proteolytically Activated in Mouse Adrenal Cells by Furin-like Proprotein Convertases

“…Although the mechanism has not been completely delineated, GX sPLA 2 appears to negatively regulate adrenal glucocorticoid production through transcriptional suppression of StAR, most likely by reducing the activation of LXR (13). StAR represents the rate-limiting protein in steroid hormone production, and many of the factors known to regulate steroidogenesis, including LXR, have their effect by targeting StAR (16,25,26).…”