Comparison of the liquid-ordered bilayer phases containing cholesterol or 7-dehydrocholesterol in modeling Smith-Lemli-Opitz syndrome

Abstract

The cause was subsequently shown to be related to blockade of the ultimate reaction in the biosynthesis of cholesterol ( 2 ). Recessive mutations were described of the gene coding for 7-dehydrocholesterol reductase, the enzyme responsible for catalyzing the fi nal reduction of 7-dehydrocholesterol to cholesterol. A variety of deleterious mutations for 7-dehydrocholesterol reductase with distinct geographic distribution have been shown ( 3 ) and traced with a noticeably high frequency around 1% in healthy heterozygote carriers ( 4 ).The accumulation in fetal tissue of the metabolite 7-dehydrocholesterol (7-DHC) and derivative isomer 8-dehydrocholesterol is a specifi c biomarker for antenatal diagnosis of this severe condition ( 5 ) involving the central nervous system ( 6 ), masculinization, and facial and limb defects ( 7,8 ). Indeed the accumulation of precursors is constantly associated with a severe defi cit of the end-product cholesterol, which is also judged deleterious for embryo development. The teratology was originally studied by this laboratory in animal models treated with potent inhibitors of cholesterol biosynthesis ( 9 ). The results of in vivo studies are considered inconclusive with respect to whether the cholesterol defi cit or the accretion of aberrant sterol competing with membrane cholesterol is the underlying mechanism for teratology. The administration of a diet highly enriched in cholesterol to inhibitor-treated pregnant dams was proven to suppress malformations in the offspring ( 10 ). Nevertheless, it cannot be concluded that the defi cit in cholesterol alone is causal because negative Abstract The phase behavior of egg sphingomyelin (ESM) mixtures with cholesterol or 7-dehydrocholesterol (7-DHC) has been investigated by independent methods: fl uorescence microscopy, X-ray diffraction, and electron spin resonance spectroscopy. In giant vesicles, cholesterol-enriched domains appeared as large and clearly delineated domains assigned to a liquid-ordered (L o ) phase. The domains containing 7-DHC were smaller and had more diffuse boundaries. Separation of a gel phase assigned by X-ray examination to pure sphingomyelin domains coexisting with sterol-enriched domains was observed at temperatures less than 38°C in binary mixtures containing 10-mol% sterol. At higher sterol concentrations, the coexistence of liquid-ordered and liquid-disordered phases was evidenced in the temperature range 20°-50°C. Calculated electron density profi les indicated the location of 7-DHC was more loosely defi ned than cholesterol, which is localized precisely at a particular depth along the bilayer normal. ESR spectra of spin-labeled fatty acid partitioned in the liquid-ordered component showed a similar, high degree of order for both sterols in the center of the bilayer, but it was higher in the coexisting disordered phase for 7-DHC. The differences detected in the models of the lipid membrane matrix are said to initiate the deleterious consequences of the Smith-Lemli-Opitz syndrome. -Staneva, G., C. Chachaty, C. ...

7DHC-induced changes of Kv1.3 operation contributes to modified T cell function in Smith-Lemli-Opitz syndrome

“…Nevertheless, 7DHC is the prominent sterol in the SLOS membrane and the biophysical parameters of Kv1.3 gating were similarly affected in SLOS and in T cells treated with MβCD/7DHC complex. This suggests that acute loading of T cells with 7DHC mimics adequately the effect of the lipid milieu existing in SLOS on the operation of Kv1.3 [11,29,30,54,68].…”

Malformation syndromes caused by disorders of cholesterol synthesis

“…Although it substitutes for cholesterol reasonably well in raft formation ( 131 ) and behaves similarly to cholesterol in phosphatidylcholine-sterol monolayer fi lms ( 132,133 ), substitution of 7DHC for cholesterol may alter the physiochemical properties and function of cellular membranes. In comparing artifi cial vesicles formed from admixtures of either cholesterol or 7DHC and egg sphingomyelin, liquid ordered domains formed with 7DHC appeared to be smaller and had more diffuse boundaries than those formed with cholesterol ( 134 ). Data published by both Megha et al ( 135 ) and Xu et al ( 136 ) showed that, relative to cholesterol, 7DHC stabilizes lipid rafts in model membranes.…”

“…Data published by both Megha et al ( 135 ) and Xu et al ( 136 ) showed that, relative to cholesterol, 7DHC stabilizes lipid rafts in model membranes. Both Tulenko ( 137 ) and Staneva et al ( 134 ), using X-ray diffraction techniques, showed that 7DHC results in an atypical membrane organization. In addition to studies with artifi cial membranes, membranes from SLOS cells have been shown to have altered fl uidity ( 137 ), and Boesze-Battaglia ( 124 ) showed reduced membrane fl uidity in rod outer segments derived from AY9944-treated rats due to decreased content of docosahexaenoic acid.…”

Undulations Drive Domain Registration from the Two Membrane Leaflets

“…It is only clear that it requires neither cholesterol nor any other specific lipid or proteinaceous component (7,(9)(10)(11)(12). Most prevalent is the idea that the two leaflets interact at the membrane midplane via overhang.…”

“…Experiments on much larger liquid-ordered domains in model membranes (5)(6)(7) have shown strong coupling of L o domains that co-localize with L o domains in the opposing leaflet. It has never been observed that two such L o domains spontaneously decouple.…”