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What Dictates the Accumulation of Desmosterol in the Developing Brain?

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What Dictates the Accumulation of Desmosterol in the Developing Brain? The FASEB Journal • Hypothesis What dictates the accumulation of desmosterol in the developing brain? ʈ Maurice Jansen,*,‡ Wei Wang,*,‡ Dario Greco,†,§ Gian Carlo Bellenchi, ʈ Umberto di Porzio, Andrew J. Brown,¶ and Elina Ikonen*,‡,1 *Institute of Biomedicine, Anatomy, and †Research Unit of Molecular Medicine, University of Helsinki, Helsinki, Finland; ‡Minerva Foundation Institute for Medical Research, Helsinki, Finland; ʈ §Department of Bioscience and Nutrition, Karolinska Institute, Stockholm, Sweden; Institute of Genetics and Biophysics, Naples, Italy; and ¶School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, New South Wales, Australia ABSTRACT The brain is the most cholesterol-en- and differs from cholesterol only by an additional riched tissue in the body. During brain development, double bond in the isooctyl tail, between carbons 24 desmosterol, an immediate precursor of cholesterol, and 25. This conversion is catalyzed by the enzyme transiently accumulates up to 30% of total brain sterols. 3␤-hydroxysterol 24-reductase (DHCR24; Fig. 1A). In- This massive desmosterol deposition appears to be terestingly, brain desmosterol levels change during present in all mammalian species reported so far, normal aging (2, 3) and DHCR24 may play a role in including humans, but how it is achieved is not well neurodegeneration, as it was found to be down-regu- understood. Here, we propose that desmosterol accu- lated in the brains of patients with Alzheimer disease mulation in the developing brain may be primarily (DHCR24 is also called seladin-1, for selective Alzhei- ␤ caused by post-transcriptional repression of 3 -hydrox- mer’s disease indicator 1; refs. 4, 5, but see also ref. 6). ysterol 24-reductase (DHCR24) by progesterone. Fur- The accumulation of desmosterol in the developing thermore, distinct properties of desmosterol may serve brain is remarkable because of its quantity. Desmos- to increase the membrane active pool of sterols in the terol can accumulate up to 30% of total brain sterols, brain: desmosterol cannot be hydroxylated to generate while cholesterol precursors in other tissues rarely 24S-hydroxycholesterol, a brain derived secretory ste- exceed 1%. With this large amount, desmosterol rep- rol, desmosterol has a reduced propensity to be ester- ified as compared to cholesterol, and desmosterol may resents an important constituent of membranes and activate LXR to stimulate astrocyte sterol secretion. lipoproteins in the developing brain (7). This regulated accumulation of desmosterol by proges- During the 1960s and 1970s, researchers reported terone-induced suppression of DHCR24 may facilitate the accumulation of desmosterol in the developing the rapid enrichment and distribution of membrane brains of several species, including rats (2, 8), mice (9), sterols in the developing brain.—Jansen, M., Wang, W., rabbits (2), fowl (10), guinea pigs (2) and humans (2, Greco, D., Bellenchi, G. C., di Porzio, U., Brown, A. J., 11). Desmosterol was found to accumulate before the and Ikonen, E. What dictates the accumulation of period of myelination (2), but the mechanisms in- desmosterol in the developing brain? FASEB J. 27, volved and the possible physiological relevance of this 865–870 (2013). www.fasebj.org phenomenon were not extensively studied. More re- cently, it has become evident that despite the small Key Words: progesterone ⅐ 3␤-hydroxysterol 24-reductase ⅐ liver X structural difference, desmosterol behaves very differ- receptor ⅐ cholesterol precursor ⅐ central nervous system ently from cholesterol. Disruption of the DHCR24 gene results in the accumulation of desmosterol and is Since the early 1960s, it has been known that in the accompanied by multiple congenital anomalies in hu- developing mammalian brain, there is a transient accu- mans and mice (12, 13). On the molecular level, mulation of the cholesterol precursor desmosterol (1, desmosterol acts as a strong liver X receptor (LXR) 2). Desmosterol is the penultimate precursor of choles- agonist (14, 15), has an altered propensity to be hy- terol in the Bloch pathway of cholesterol biosynthesis droxylated (16, 17), and binds less avidly to caveolin (18) as compared to cholesterol. Furthermore, its bio- physical membrane behavior differs from that of cho- Abbreviations: ABCA1, ATP binding cassette transporter A1; ApoE, apolipoprotein E; CHO, Chinese hamster ovary; DAC, 20,25-diazacholesterol; DHCR7, 7-dehydrocholesterol 1 Correspondence: Haartmaninkatu 8, 00290 Helsinki, Fin- reductase; DHCR24, 3␤-hydroxysterol 24-reductase; EV, empty land. E-mail: elina.ikonen@helsinki.fi vector; HPLC, high-performance liquid chromatography; doi: 10.1096/fj.12-211235 HPTLC, high-performance thin-layer chromatography; LXR, This article includes supplemental data. Please visit http:// liver X receptor; SQLE, squalene epoxidase. www.fasebj.org to obtain this information. 0892-6638/13/0027-0865 © FASEB 865 Figure 1. Sterol analysis of the developing mouse brain. A) Conversion from desmosterol to cholesterol. Structural difference between cholesterol and desmosterol is indicated with gray shading. B) Amount of desmosterol relative to total unesterified sterol, total cholesterol, and total protein (meansϮse; nϭ5-7). C) HPLC chromatograms of unesterified sterol fraction in adult and P0.5 mouse brain, I, injection; L, lathosterol; Ch, cholesterol; Z, zymosterol; De, desmosterol. D) Amount of total esterified and unesterified sterols relative to total protein (means Ϯ se; nϭ5–6). lesterol, as desmosterol is less efficient in promoting tracted lipids were separated by high-performance thin-layer membrane order (19, 20). chromatography (HPTLC) in hexane:diethylether:acetic acid Together, these observations point to the possibility (80:20:1, v/v). To separate cholesterol from desmosterol and other precursors, extracted lipids were subjected to Ag- that the accumulation of desmosterol in the developing HPTLC in chloroform:acetone (19:1, v/v) as described pre- brain is physiologically regulated and functionally rele- viously (22), or to Ag–high-performance liquid chromatogra- vant. Here, we propose that desmosterol accumulation phy (HPLC) in hexane:acetone (8:2, v/v) as described may be orchestrated by post-transcriptional repression previously (7, 23). of DHCR24 via the major gestational steroid hormone, progesterone. Furthermore, we discuss distinct proper- DHCR24 inhibition by progesterone and PCR ties of desmosterol that may assist in increasing the content and facilitating delivery of membrane sterols in Inhibition of DHCR24 by progesterone was analyzed as the brain. previously described (22) and quantitative real-time PCR was performed as reported previously (24). A detailed description of these procedures is included in Supplemental Material. MATERIALS AND METHODS Ethics statement RESULTS AND DISCUSSION The animal studies were approved by the Experimental In the developing mouse brain, desmosterol accumu- Animal Committee of the University of Helsinki. lates between E14 and postnatal day 10 (P10), peaking during the first postnatal week (Fig. 1B). During this Brain samples period, no other sterol precursors accumulate signifi- cantly (Fig. 1C), and the total sterol content increases Brain samples from wild-type C57BL6 mice were snap-frozen substantially (Fig. 1D). The growth of neuronal cell Ϫ in liquid nitrogen and stored at 70°C until use. Whole processes is very active during this time and is followed brains were analyzed from embryonic day 14.5 (E14.5) em- by the initiation of synaptogenesis. bryos and whole brains, excluding cerebellum and brain stem, from E17.5 and older animals. DHCR24 transcript levels during the period of Sterol analysis desmosterol accumulation Lipids were extracted from cells or tissue homogenate in PBS To gain insight into the mechanisms leading to the as reported previously (21). For neutral lipid analysis, ex- desmosterol accumulation, we analyzed whether the 866 Vol. 27 March 2013 The FASEB Journal ⅐ www.fasebj.org JANSEN ET AL. Figure 2. Real-time PCR analysis of the expression of genes involved in late cholesterol biosynthesis in the developing mouse brain (meansϮsd; nϭ6). varying desmosterol content around the perinatal pe- cellular processes by both transcriptional and post- riod could result from transcriptional regulation of transcriptional regulation. Because these steroid hor- DHCR24. We compared the expression profile of mones are present in the developing brain (28), we DHCR24 mRNA with that of two other genes involved investigated whether progesterone can inhibit DHCR24 ac- in cholesterol biosynthesis: squalene epoxidase (SQLE), a tivity via a post-transcriptional mechanism. To this end, rate-controlling enzyme in prelanosterol cholesterol we used Chinese hamster ovary (CHO) cells stably express- biosynthesis (25), and 7-dehydrocholesterol reductase ing DHCR24 under a viral promoter (CHO-DHCR24; (DHCR7), the enzyme that reduces the double bond in ref. 22), which induces substantially higher DHCR24 7-dehydrocholesterol, which is the immediate precur- protein levels than those in the corresponding control sor of cholesterol in the Kandutsch-Russell pathway of (empty vector) stable cells (CHO-EV; Fig. 3). Notably, cholesterol synthesis. We found that the expression of progesterone did not decrease DHCR24 protein levels, DHCR24 remains relatively constant until P3 and then either ectopic (Fig. 3) or endogenous (not shown, decreases significantly during the next 10 d (Fig. 2). The expression profiles of SQLE and DHCR7
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