Synthesis Of 25-hydroxycholesterol Research Articles

A Concise Synthesis of 25-Hydroxycholesterol from Hyodesoxycholic Acid

A simple, efficient and economical method has been developed for the synthesis of 25-hydroxycholesterol in seven steps from hyodesoxycholic acid with an overall yield of 39%. The preparation of the 3β-tetrahydropyranyloxychol-5-en-24-al from 3β-tetrahydropyranyloxychol-5-en-24-oic acid methyl ester with di-isobutylaluminium hydride was achieved instead of using the conventional two-step reaction, thus avoiding the use of the toxic oxidant CrO3. The terminal product was obtained by hydroxybromination of desmosterol with N-bromosuccinimide/H20, followed by reduction and deprotection of the halohydrins with LiAlH4. This simplified route gave an increased overall yield and used economical and environmentally benign reagents.

Rapid proteasomal elimination of 3-hydroxy-3-methylglutaryl-CoA reductase by interferon-[formula omitted] in primary macrophages requires endogenous 25-hydroxycholesterol synthesis

Interferons (IFNs) play a central role in immunity and emerging evidence suggests that IFN-signalling coordinately regulates sterol biosynthesis in macrophages, via Sterol Regulatory Element-Binding Protein (SREBP) dependent and independent pathways. However, the precise mechanisms and kinetic steps by which IFN controls sterol biosynthesis are as yet not fully understood. Here, we elucidate the molecular circuitry governing how IFN controls the first regulated step in the mevalonate-sterol pathway, 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR), through the synthesis of 25-Hydroxycholesterol (25-HC) from cholesterol by the IFN-inducible Cholesterol-25-Hydroxylase (CH25H). We show for the first 30-min of IFN stimulation of macrophages the rate of de novo synthesis of the Ch25h transcript is markedly increased but by 120-min becomes transcriptionally curtailed, coincident with induction of the Activating Transcription Factor 3 (ATF3) repressor. We demonstrate ATF3 induction by Toll-like receptors is strictly dependent on IFN-signalling. While the SREBP-pathway dependent rates of de novo transcription of Hmgcr are relatively unchanged in the first 90-min of IFN treatment, we find HMGCR enzyme levels undergo a rapid proteasomal-mediated degradation, defining a previously unappreciated SREBP-independent mechanism for IFN-action. These events precede a sustained marked reduction in Hmgcr RNA levels involving SREBP-dependent mechanisms. We demonstrate that HMGCR proteasomal-degradation by IFN strictly requires the synthesis of endogenous 25-HC and functionally couples HMGCR to CH25H to coordinately suppress sterol biosynthesis. In conclusion, we quantitatively delineate proteomic and transcriptional levels of IFN-mediated control of HMGCR, the primary enzymatic step of the mevalonate-sterol biosynthesis pathway, providing a foundational framework for mathematically modelling the therapeutic outcome of immune-metabolic pathways.

25-Hydroxycholesterol secreted by macrophages in response to Toll-like receptor activation suppresses immunoglobulin A production

25-Hydroxycholesterol is produced in mammalian tissues. The function of this oxysterol is unknown. Here we describe a central role for 25-hydroxycholesterol in regulating the immune system. In initial experiments, we found that stimulation of macrophage Toll-like receptors (TLR) induced expression of cholesterol 25-hydroxylase and the synthesis of 25-hydroxycholesterol. Treatment of naïve B cells with nanomolar concentrations of 25-hydroxycholesterol suppressed IL-2-mediated stimulation of B cell proliferation, repressed activation-induced cytidine deaminase (AID) expression, and blocked class switch recombination, leading to markedly decreased IgA production. Consistent with these findings, deletion of the mouse cholesterol 25-hydroxylase gene caused an increase in serum IgA. Conversely, inactivation of the CYP7B1 oxysterol 7alpha-hydroxylase, which degrades 25-hydroxycholesterol, decreased serum IgA. The suppression of IgA class switching in B cells by a macrophage-derived sterol in response to TLR activation provides a mechanism for local and systemic negative regulation of the adaptive immune response by the innate immune system.

Synthetic Studies on Vitamin D Analogues VI. A New Synthesis of 25-Hydroxycholesterol from Lithocholic Acid

Abstract The conversion of lithocholic acid (1) into 25-hydroxycholesterol (10) via methyl 3β-hydroxy-5-cholenate (6) is described.

A synthesis of 25-hydroxycholesterol

A synthesis of 25-hydroxycholesterol

A synthesis of 25-hydroxycholesterol

A synthesis of 25-hydroxycholesterol

Synthesis of 25-hydroxycholesterol from 3β-hydroxyandrost-5-en-17-one. A method for stereospecific construction of a sterol side-chain

The side-chain of 25-hydroxycholesterol was constructed stereospecifically on the androstane skeleton via addition of an ethyl acetate unit to C-17 and sub-sequent alkylation of the resulting ester C-20 with a C5 unit; the remaining carbon atom (C-27) was added by a Grignard reaction.

C-25 hydroxylation of cholesterol derivatives

Irradiation of saturated cholestane derivatives with peracetic acid resuted in ydroxylation at the 25- and 5α-positions; this method is used for the synthesis of 25-hydroxycholesterol.