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Liver X Receptor Opens a New Gateway to Star and to Steroid Hormones

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Liver X Receptor Opens a New Gateway to Star and to Steroid Hormones Liver X receptor opens a new gateway to StAR and to steroid hormones Colin R. Jefcoate J Clin Invest. 2006;116(7):1832-1835. https://doi.org/10.1172/JCI29160. Commentary 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. Find the latest version: https://jci.me/29160/pdf commentaries 1. Perez-Figares, J.M., Jimenez, A.J., and Rodriguez, Changes in the ventricular system and the sub- expression in the dorsal midline causes cell death, E.M. 2001. Subcommissural organ, cerebrospinal commissural organ. J. Neuropathol. Exp. Neurol. abnormal differentiation of circumventricular fluid circulation, and hydrocephalus. Microsc. Res. 57:188–202. organs and errors in axonal pathfinding. Development. Tech. 52:591–607. 9. Takeuchi, I.K., Kimura, R., Matsuda, M., and Shoji, 127:4061–4071. 2. Rizvi, R., and Anjum, Q. 2005. Hydrocephalus in R. 1987. Absence of subcommissural organ in the 15. Lang, B., et al. 2006. Expression of the human PAC1 children. J. Pak. Med. Assoc. 55:502–507. cerebral aqueduct of congenital hydrocephalus receptor leads to dose-dependent hydrocepha- 3. Galarza, M. 2002. Evidence of the subcommissural spontaneously occurring in MT/HokIdr mice. Acta lus-related abnormalities in mice. J. Clin. Invest. organ in humans and its association with hydro- Neuropathol. (Berl.). 73:320–322. 116:1924–1934. doi:10.1172/JCI27597. cephalus. Neurosurg. Rev. 25:205–215. 10. Takeuchi, I.K., Kimura, R., and Shoji, R. 1988. 16. Vaudry, D., et al. 2000. Pituitary adenylate cyclase- 4. Rodriguez, E.M., Rodriguez, S., and Hein, S. 1998. The Dysplasia of subcommissural organ in congenital activating polypeptide and its receptors: from struc- subcommissural organ. Microsc. Res. Tech. 41:98–123. hydrocephalus spontaneously occurring in CWS/ ture to functions. Pharmacol. Rev. 52:269–324. 5. Vio, K., et al. 2000. Hydrocephalus induced by Idr rats. Experientia. 44:338–340. 17. Zhou, C.J., et al. 2002. PACAP and its receptors immunological blockage of the subcommissural 11. Estivill-Torrus, G., Vitalis, T., Fernandez-Llebrez, P., exert pleiotropic effects in the nervous system organ-Reissner’s fiber (RF) complex by mater- and Price, D.J. 2001. The transcription factor Pax6 by activating multiple signaling pathways. Curr. nal transfer of anti-RF antibodies. Exp. Brain Res. is required for development of the diencephalic Protein Pept. Sci. 3:423–439. 135:41–52. dorsal midline secretory radial glia that form the 18. Filipsson, K., Kvist-Reimer, M., and Ahren, B. 2001. 6. Grondona, J.M., et al. 1998. Neuraminidase injected subcommissural organ. Mech. Dev. 109:215–224. The neuropeptide pituitary adenylate cyclase-acti- into the cerebrospinal fluid impairs the assembly 12. Fernandez-Llebrez, P., et al. 2004. Msx1-deficient vating polypeptide and islet function. Diabetes. of the glycoproteins secreted by the subcommis- mice fail to form prosomere 1 derivatives, subcom- 50:1959–1969. sural organ preventing the formation of Reissner’s missural organ, and posterior commissure and 19. Greenstone, M.A., Jones, R.W., Dewar, A., Neville, fiber. Histochem. Cell Biol. 109:391–398. develop hydrocephalus. J. Neuropathol. Exp. Neurol. B.G., and Cole, P.J. 1984. Hydrocephalus and prima- 7. Rodriguez, E.M., Garrido, O., and Oksche, A. 1990. 63:574–586. ry ciliary dyskinesia. Arch. Dis. Child. 59:481–482. Lectin histochemistry of the human fetal subcom- 13. Krebs, D.L., et al. 2004. Development of hydrocepha- 20. Nakamura, Y., and Sato, K. 1993. Role of distur- missural organ. Cell Tissue Res. 262:105–113. lus in mice lacking SOCS7. Proc. Natl. Acad. Sci. U. S. A. bance of ependymal ciliary movement in develop- 8. Perez-Figares, J.M., et al. 1998. Spontaneous con- 101:15446–15451. ment of hydrocephalus in rats. Childs Nerv. Syst. genital hydrocephalus in the mutant mouse hyh. 14. Louvi, A., and Wassef, M. 2000. Ectopic engrailed 1 9:65–71. Liver X receptor opens a new gateway to StAR and to steroid hormones Colin R. Jefcoate Department of Pharmacology, University of Wisconsin Medical School, Madison, Wisconsin, USA. Liver X receptors (LXRs) broadly limit cholesterol accumulation by regu- of excess cholesterol from peripheral lating expression of genes involved in cholesterol efflux and storage. In tissues to the liver (e.g., the ABC fam- this issue of the JCI, Cummins et al. report that LXRα is involved in simi- ily of membrane transporters, including lar regulation in the adrenal cortex, but it also substantially modulates ABC transporter A1 [ABCA1], ABCG5, glucocorticoid synthesis (see the related article beginning on page 1902). ABCG8, and ABCG1), as well as hepatic LXRα deletion in mice increases the availability of adrenal cholesterol for metabolism of this cholesterol by cyto- steroid synthesis by decreasing the expression of cholesterol efflux trans- chrome P450 7A1 (CYP7Α1) to bile acids porters. Glucocorticoid synthesis requires intramitochondrial cholesterol (1). The roles of LXRs have recently been transport mediated by the steroidogenic acute regulatory protein (StAR). expanded through the study of mice defi- Surprisingly, LXR deletion and stimulation by an agonist each increase cient in LXRα and LXRβ as well as the glucocorticoid synthesis. This parallels increased expression of StAR and use of the LXR agonist T090137 (T1317), several other steroidogenic genes. which stimulates both receptors (1). Mice deficient in LXRα, LXRβ, or both recep- Liver X receptors stimulate that includes the PPAR family and recep- tors are fully functional, which indicates expression of genes tors for vitamin D, thyroid hormone, that the cholesterol transport processes that lower cholesterol and retinoic acid, which form heterodi- and fatty acid changes regulated by these Liver X receptors (LXRs) belong to a class mers with retinoid X receptors (RXRs). receptors play a modulating rather than of ligand-dependent nuclear receptors In doing so, LXRs exert transcriptional essential role. The link between the LXRs control on cholesterol and fatty acid and cholesterol homeostasis was firmly Nonstandard abbreviations used: ABCA1, homeostasis in a variety of cell types. established by the finding that mice defi- ABC transporter A1; CYP11A1, cytochrome Two forms of the LXR have been iden- cient in LXRα lose the ability to convert P450 11A1; 3β-DH, 3β-sterol dehydrogenase; tified: LXR is expressed at high levels cholesterol to bile acids in the liver and as FAS, fatty acid synthase; HSL, hormone-sensitive α lipase; LXR, liver X receptor; RXR, retinoid X in liver but also at more modest levels a result accumulate cholesterol esters in receptor; SR-B1, scavenger receptor-B1; StAR, in cells that are involved in cholesterol their liver when challenged with a choles- steroidogenic acute regulatory protein; T1317, transport and metabolism (e.g., intes- terol-rich diet (1). LXRs also have exten- LXR agonist T090137. tines, adipose, macrophages, kidney, and sive extrahepatic functions, including Conflict of interest: The author has declared that no conflict of interest exists. lung) while LXRβ is broadly expressed. regulation of fatty acid and cholesterol Citation for this article: J. Clin. Invest. 116:1832–1835 LXRs are known to control the expres- metabolism in macrophages — a critical (2006). doi:10.1172/JCI29160. sion of genes involved in the transport process in the inflammatory response 1832 The Journal of Clinical Investigation http://www.jci.org Volume 116 Number 7 July 2006 commentaries Figure 1 Effect of LXR on cholesterol trafficking in adrenal cortex cells. Cholesterol (Ch) enters adrenal cells through 2 routes that each delivers cho- lesterol 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
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