Cholesterol sulfate

Cholesterol sulfate 13C2 labeled 465c 467c 50-300 [79]... 

Recessive X-linked ichthyosis (RXLI) is a dermatological condition that is caused by steroid sulfatase deficiency (STSD), although the mechanism by which the deficiency causes the characteristic scaly skin has not been adequately explained. RXLI is the most common genetic disorder of steroid metabolism, affecting about 1 2000 males. Epstein and workers [16] first demonstrated that serum cholesterol sulfate was elevated in the condition, and this compound has become the preferred analyte for diagnosis. The serum level is more than tenfold greater than normal in the condition. 

An LC-MS method for quantification has been available for many years [79] using 13C2 cholesterol sulfate as an internal standard. The deuterated material is now commercially available (CDN or ISOTEC). Negative-ion ESI-MS is used for quantitation and m/z 365 (M-II, analyte) and 367 (M-H", internal standard) are monitored. The mean cholesterol sulfate level in 166 cases of RXLI was 4859 1589 pg/dl and for normal individuals 186 112 pg/dl (n = 109). 

Epstein EH Jr, Krauss RM, Shackleton CH (1981) X-linked ichthyosis increased blood cholesterol sulfate and electrophoretic mobility of low-density lipoprotein. Science 214 659-660... 

Shackleton CH, Reid S (1989) Diagnosis of recessive X-linked ichthyosis quantitative HPLC/ mass spectrometric analysis of plasma for cholesterol sulfate. Clin Chem 35 1906-1910... 

Cholesterol and cholesterol sulfate have been isolated and identified in the urine of normal and pregnant women. Increased interest is certain to arise concerning the measurement of these... 

In recessive X-linked ichthyosis, the amount of cholesterol sulfate in the stratum corneum is increased due to a deficiency in cholesterol sulfatase deficiency [69,70], Lipid analysis of scales reveals a nearly 10-fold increase in the cholesterol sulfate to free cholesterol ratio as compared to healthy stratum corneum [71]. Previous x-ray diffraction studies on isolated ceramide mixtures revealed that increased cholesterol sulfate levels induce the formation of a fluid phase, which is likely to reduce the skin barrier function [72]. 

Cholesterol sulfate is another intercellular lipid. Addition of low levels of cholesterol sulfate, as observed in normal healthy stratum corneum, to lipid mixtures has little effect on the phase behavior at room temperature. However, addition of high levels of cholesterol sulfate, at levels similar to that observed in the skin disease recessive X-linked ichthyosis, promotes the formation of the long periodicity phase, induces the formation of a fluid phase, and increases the solubility of cholesterol in the lamellar phases [72,80],... 

Zettersten, E., et al. Recessive x-linked ichthyosis Role of cholesterol-sulfate accumulation in the barrier abnormality. J Invest Dermatol 111 784. 

Williams, M.L., and P.M. Elias. 1981. Stratum corneum lipids in disorders of cornification Increased cholesterol sulfate content of stratum corneum in recessive x-linked ichthyosis. J Clin Invest 68 1404. 

Bouwstra, J.A., et al. 1999. Cholesterol sulfate and calcium affect stratum corneum lipid organization over a wide temperature range. J Lipid Res 40 2303. 

J. A. Bouwstra, G. S. Gooris, F. E. R. Dubbelaar, A. M. Weerheim, M. Ponec, Cholesterol sulfate, and fatty acids affect the skin stratumcorneum hpids organisation, J. Invest. Dermatol. Proc. 3 69-74 (1998). 

Fig. 6.11 Schematic representation of initial structures of the DPPC/cho-lesterol and DPPC/cholesterol sulfate membranes. PL phopholipid, CH cholesterol, CS cholesterol sulfate. Left system A, middle system B [73], right DPPC/cholesterol sulfate [75]...

Smondyrev and Berkowitz [73] performed a rather long simulation (2 ns) of a system with a low cholesterol content (ratio of 1 8 or 11 mol%) and of two systems that contained cholesterol at 1 1 molar ratio and differed in the arrangement of the cholesterol molecules (Figure 6.11). In the simulation with low cholesterol content, the area per lipid was about 62 A2, close to that found in a simulation of pure DPPC for the first approximately 800 ps. However, after this time it started to decrease and reached a value of 58.3 A2 after an additional 500 ps, where it remained for the last 750 ps of the simulation. In the simulation with high cholesterol content, the area per DPPC-cholesterol heterodimer surface area showed also a decrease over the simulation time that was approximately exponential (Table 6.7). In system A (Figure 6.11), with a more uniform distribution of cholesterol, the surface area tended to decrease over the full simulation time of 2 ns, whereas for system B a stable and somewhat lower value was obtained after 1 ns. Although the authors concluded that system A, with more uniformly distributed cholesterol, might be trapped in a metastable state, this system was used in a later publication for comparison of the effects caused by cholesterol sulfate (see below). 

Tab. 6.8 Average number of hydrogen bonds per DPPC or cholesterol oxygen, formed with water molecules reported from several simulations. Data for DPPC and DPPC-cholesterol are taken from ref. 73 and data for DMPC-cholesterol sulfate are from ref. 75. Data for DMPC-cholesterol are taken from ref. 71 and data for pure DM PC are taken from ref. 74 and 106.

Oxygens Pure DPPC DPPC-cholesterol 11 mol% 50 mol%a DPPC-cholesterol sulfate 50 mol% Pure DM PC DM PC cholesterol 22 mol%... 

The elucidation of the molecular genetics RXI has had a major impact on our understanding of stratum corneum turnover. Individuals with RXI lack an enzyme, cholesterol sulfatase,3,4 which catalyzes the transformation of cholesterol sulfate (CS) to cholesterol and free sulfate. As a result there is an accumulation of CS in the stratum corneum intercellular space. Possible mechanisms by which this change in intercellular lipid composition of the stratum corneum can cause disturbances in desquamation, leading to ichthyosis, will be discussed later. 

Enzyme activation Activation of SCCE Enzyme inhibition Cholesterol sulfate Antileukoprotease... 

The composition of the stratum corneum intercellular lipids may have profound effects on desquamation. In addition to modifying effects on, for example, proteolytic enzymes and their substrates,34 lipids may also be directly involved in corneocyte cohesion. The effects of cholesterol sulfate have already been mentioned. In addition to RXI, there are a number of other hereditary diseases with disorders of desquamation associated with disturbances in lipid metabolism. Furthermore, scaling as a result of treatment with lipid-lowering drugs has been observed (for review, see References 1 and 2). 

Sato, J., Denda, M., Nakanishi, J., Nomura, J., and Koyama, J., Cholesterol sulfate inhibits proteases that are involved in desquamation of stratum corneum, J. Invest. Dermatol., Ill, 189, 1998. 

Chida, K., Murakami, A., Tagawa, T., Ikuta, T., and Kuroki, T., Cholesterol sulfate, a second messenger for the n isoform of protein kinase C, inhibits promotional phase in mouse skin carcinogenesis, Cancer Res., 55, 4865, 1995. 

Denning, M., Kazanietz, M., Blumber, P., and Yuspa, S., Cholesterol sulfate activates multiple protein kinase C isoenzymes and induces granular cell differenation in culture murine keratinoyctes, Cell Growth Differ., 6, 1619, 1995. 

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