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Liver X receptor opens a new gateway to StAR and to steroid hormones
Colin R. Jefcoate
Colin R. Jefcoate
Published July 3, 2006
Citation Information: J Clin Invest. 2006;116(7):1832-1835. https://doi.org/10.1172/JCI29160.
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Commentary

Liver X receptor opens a new gateway to StAR and to steroid hormones

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Abstract

Liver X receptors (LXRs) broadly limit cholesterol accumulation by regulating expression of genes involved in cholesterol efflux and storage. In this issue of the JCI, Cummins et al. report that LXRα is involved in similar regulation in the adrenal cortex, but it also substantially modulates glucocorticoid synthesis (see the related article beginning on page 1902). LXRα deletion in mice increases the availability of adrenal cholesterol for steroid synthesis by decreasing the expression of cholesterol efflux transporters. Glucocorticoid synthesis requires intramitochondrial cholesterol transport mediated by the steroidogenic acute regulatory protein (StAR). Surprisingly, LXR deletion and stimulation by an agonist each increase glucocorticoid synthesis. This parallels increased expression of StAR and several other steroidogenic genes.

Authors

Colin R. Jefcoate

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Figure 1

Effect of LXR on cholesterol trafficking in adrenal cortex cells.

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Effect of LXR on cholesterol trafficking in adrenal cortex cells.
Choles...
Cholesterol (Ch) enters adrenal cells through 2 routes that each delivers cholesterol to StAR for steroid synthesis: the LDL/endosome transfer pathway and the HDL/SR-B1/lipid droplet transfer pathway. Cholesterol leaves the cell by transfer from lipid droplets to caveolin (Cav) and then to the ABCA1 pump. LXR stimulates this pathway by increasing the level of ABCA1. Lipid droplets are very extensive in adrenal cells and comprise 95% cholesterol esters (ChE) due to high acyl-CoA:cholesterol acyltransferase (ACAT) activity. Cholesterol is transferred to StAR after activation of HSL, which hydrolyzes ChE to free cholesterol. The endosome transfer of cholesterol to StAR is mediated by the Nieman-Pick type C (NPC) transporter and the StAR-like protein MLN64. StAR mediates transfer of Ch to CYP11A1 inside the mitochondria, which initiates all steroidogenesis. In adrenals, 3β-DH generates progesterone and the activity of 3 cytochrome P450 enzymes (CYP11B1, CYP21, and CYP17) generates cortisol. LXR produces transcriptional changes by combining with RXR in the nucleus. Gene activation is shown as dashed lines. Some effects are mediated by the large increase in a second transcription factor, SREBP-1c, which is stored as an inactive precursor in the ER. StAR is a gene that is activated by both activated SREBP-1c and LXR. LXR-stimulated genes and pathways are highlighted in red. Other cholesterol transfer pathways are shown in blue. For further details, see ref. 3. LDL-R, LDL receptor.

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