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

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.

Publication

Liver X receptor opens a new gateway to StAR and to steroid hormones. (2006) Colin R. Jefcoate. J Clin Invest. 2006 Jul 3;116(7):1832-1835. Figure: F1. All organisms Drosophila melanogaster Homo sapiens

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