desmosterol and 24-25-epoxycholesterol

Evidence is emerging that during the development of Alzheimer's disease (AD), changes in the synthesis and metabolism of cholesterol and progesterone are occurring that may or may not affect the progression of the disease. The concept arose from the recognition that dehydrocholesterol 24-reductase (DHCR24/Seladin-1), one of the nine enzymes in the endoplasmic reticulum that determines the transformation of lanosterol to cholesterol, is selectively reduced in late AD. As a consequence, the tissue level of desmosterol increases, affecting the expression of ABC transporters and the structure of lipid rafts, both determinants of amyloid-β processing. However, the former effect is considered beneficial and the latter detrimental to processing. Other determinants of desmosterol tissue levels are 24,25 epoxycholesterol and the ABCG1 and ABCG4 transporters. Progesterone and its metabolites are determinants of tissue levels of desmosterol and several other sterol intermediates in cholesterol synthesis. Animal models indicate marked elevations in the tissue levels of these sterols at early time frames in the progression of neurodegenerative diseases. The low level of neuroprogesterone and metabolites in AD are consonant with the low level of desmosterol and may have a role in amyloid-β processing. The sparse data that has accumulated appears to be a sufficient basis for proposing a systematic evaluation of the biologic roles of sterol intermediates in the slowly progressive neurodegeneration characteristic of AD.

Topics: Aged; Alzheimer Disease; Amyloidogenic Proteins; Animals; ATP Binding Cassette Transporter, Subfamily G; ATP Binding Cassette Transporter, Subfamily G, Member 1; ATP-Binding Cassette Transporters; Brain; Cholesterol; Desmosterol; Disease Models, Animal; Disease Progression; Humans; Mice; Nerve Tissue Proteins; Oxidoreductases Acting on CH-CH Group Donors; Progesterone

The oxysterol 24(S),25-epoxycholesterol (24,25EC) can affect cholesterol metabolism at multiple points. Previously, we proposed that 24,25EC has an especially significant role in fine-tuning cholesterol synthesis, since it parallels cholesterol production, and without it, acute cholesterol synthesis is exaggerated. 24,25EC is structurally similar to desmosterol, a substrate for the enzyme 3β-hydroxysterol ∆(24)-reductase (DHCR24, also called Seladin-1) which catalyzes a final step in cholesterol synthesis. In this study, we reveal a novel mode by which 24,25EC can regulate cholesterol synthesis, by interfering with DHCR24, resulting in the rapid accumulation of the substrate desmosterol, at the expense of cholesterol. This effect was independent of DHCR24 protein levels, and was observed in multiple mammalian cell-lines, including those of hepatic and neuronal origin. Conversely, overexpression of DHCR24 blunted the inhibition by 24,25EC. We also determined that the specificity of this effect was restricted to certain side-chain oxysterols, notably those oxygenated at C-25. Importantly, endogenous levels of 24,25EC, manipulated by genetic and pharmacological methods, were sufficient to reduce DHCR24 activity. Together, our work introduces a novel role for 24,25EC in cholesterol homeostasis, through its rapid inhibition of cholesterol synthesis at DHCR24. Also, our work provides new insights into a little studied area, the post-transcriptional regulation of DHCR24, an important enzyme in human health and disease.

Topics: Animals; CHO Cells; Cholesterol; Cricetinae; Cricetulus; Desmosterol; Gene Expression Regulation, Enzymologic; Hep G2 Cells; Humans; Nerve Tissue Proteins; Oxidoreductases Acting on CH-CH Group Donors

Characterization of cholesterol homeostasis in male mice with a genetic inactivation of 3beta-hydroxysteroid-delta24-reductase, causing replacement of almost all cholesterol with desmosterol.. There was an increase in hepatic sterol synthesis and markedly increased fecal loss of neutral sterols. Fecal excretion of bile acids was similar in knockout mice and in controls. The composition of bile acids was changed, with reduced formation of cholic acid. It was shown that both Cyp7a1 and Cyp27a1 are active toward desmosterol, consistent with the formation of normal bile acids from this steroid. The levels of plant sterols were markedly reduced. Hepatic mRNA levels of 3-hydroxy-3-methylglutaryl (HMG) coenzyme A (CoA) reductase, Srebp-1c, Srebp-2, Cyp7a1, Abcg5, Abcg8, and Fas were all significantly increased.. The changes in hepatic mRNA levels in combination with increased biliary and fecal excretion of neutral steroids, reduced tissue levels of plant sterols, increased plasma levels of triglyceride-rich VLDL, are consistent with a strong activation of LXR-targeted genes. The markedly increased fecal loss of neutral sterols may explain the fact that the Dhcr24-/- mice do not accumulate dietary cholesterol. The study illustrates the importance of the integrity of the cholesterol structure--presence of a double bond in the steroid side-chain is compatible with life but is associated with serious disturbances in sterol homeostasis.

Topics: Animals; ATP Binding Cassette Transporter, Subfamily G, Member 5; ATP-Binding Cassette Transporters; Bile; Bile Acids and Salts; Cholestanetriol 26-Monooxygenase; Cholesterol; Cholesterol 7-alpha-Hydroxylase; Desmosterol; DNA-Binding Proteins; Feces; Gene Expression Regulation; Homeostasis; Hydroxymethylglutaryl CoA Reductases; Lipid Metabolism; Lipids; Lipoproteins; Liver; Liver X Receptors; Male; Mice; Mice, Knockout; Nerve Tissue Proteins; Orphan Nuclear Receptors; Oxidoreductases Acting on CH-CH Group Donors; Phytosterols; Receptors, Cytoplasmic and Nuclear; RNA, Messenger; Substrate Specificity; Time Factors

Efforts to improve the synthesis of 24(S),25-epoxycholesterol (1) from stigmasterol (3) have included identification of 6 alpha-hydroxy-i-steroid 11 as a byproduct from the ozonolysis of 9 and an attempt to effect conversion of sulfone 14 to diol 18 via Payne rearrangement and nucleophilic trapping of epoxide 25, which led instead to 27 and 28 (97% yield). A more efficient synthesis of 1 was achieved via coupling of cuprate 21 with allylic acetate 31 to give 73% of 16, in the most efficient conversion yet of a C22 intermediate to desmosterol (5) or its acetate 6.

Topics: Catalysis; Cholesterol; Desmosterol; Magnetic Resonance Spectroscopy