Cholesterol oxysterols

Rat aorta control Atherosclerotic aorta human Atherosclerosis 1 +1 TOF-SIMS (MSI) Cholesterol, oxysterol, and diacylglycerols detected and localized (32)... 

In another study, the in vitro modulation of rat adipocyte ghost membrane fluidity by cholesterol oxysterols was investigated [55]. It was found that cholesterol oxy-sterols interact differently with rat adipocyte membranes. Cholestanone interacts predominantly with the phospholipids located at the inner leaflet (e.g. PE), whereas cholesterol interacts preferably with the phospholipids (PC) of the outer layer. 

In this article, through a survey of scientific literature, we will develop a number of relationships through which we form hypotheses that will correlate cholesterol, oxysterols, and DHEA with stress and cardiovascular health. 

Although cholesterol is about 10-fold less reactive in autoxidation than PUFA there is still interest in the products that have been associated with oxidant stress. Cholesterol, free and bound to ester, is measured after separation into free and ester cholesterol by selective extraction and hydrolysis using gas chromatography-tandem mass spectrometry (GC/MS/MS) [61]. Oxidized cholesterol, oxysterols, can be analyzed using LC-MS/MS with a minimum of manipulation or by using GC/MS/MS after derivatization [62-66]. 

CYP7A1 catalyzes the 7a-hydroxylation of cholesterol, the first and rate limiting step of bile acid synthesis. This is also the principal way to eliminate cholesterol. CYP7B1 is primarily expressed in brain and catalyzes the synthesis of various neurosteroids and also the 7a-hydroxylation of oxysterols. 

Peroxidation is also catalyzed in vivo by heme compounds and by lipoxygenases found in platelets and leukocytes. Other products of auto-oxidation or enzymic oxidation of physiologic significance include oxysterols (formed from cholesterol) and isoprostanes (prostanoids). 

Studies conducted by Barenghi eta.1. (1990) and Lodge etal. (1993) independently have demonstrated the facile, multicomponent analysis of a wide range of PUFA-derived peroxidation products (e.g. conjugated dienes, epoxides and oxysterols) in samples of oxidized LDL by high-field H-NMR spectroscopy. Figure 1.9 shows the applications of this technique to the detection of cholesterol oxidation products (7-ketocholesterol and the 5a, 6a and 5/3,60-epoxides) in isolated samples of plasma LDL pretreated with added coppcr(Il) or an admixture of this metal ion with H2O2, an experiment conducted in the authors laboratories. 

Extensive studies in vitro from many groups have confirmed that exposure of LDL to a variety of pro-oxidant systems, both cell-free and cell-mediated, results in the formation of lipid hydroperoxides and peroxidation products, fragmentation of apoprotein Bioo, hydrolysis of phospholipids, oxidation of cholesterol and cholesterylesters, formation of oxysterols, preceded by consumption of a-tocopherol and accompanied by consumption of 8-carotene, the minor carotenoids and 7-tocopherol. 

Venkateswaran, A, Laffitte, BA, Joseph, SB, Mak, PA, Wilpitz, DC, Edwards, PA, and Tontonoz, P, 2000. Control of cellular cholesterol efflux by the nuclear oxysterol receptor LXR alpha. Proc Natl Acad Sci USA91, 12097-12102. 

As mentioned earlier, oxidation of LDL is initiated by free radical attack at the diallylic positions of unsaturated fatty acids. For example, copper- or endothelial cell-initiated LDL oxidation resulted in a large formation of monohydroxy derivatives of linoleic and arachi-donic acids at the early stage of the reaction [175], During the reaction, the amount of these products is diminished, and monohydroxy derivatives of oleic acid appeared. Thus, monohydroxy derivatives of unsaturated acids are the major products of the oxidation of human LDL. Breuer et al. [176] measured cholesterol oxidation products (oxysterols) formed during copper- or soybean lipoxygenase-initiated LDL oxidation. They identified chlolcst-5-cnc-3(3, 4a-diol, cholest-5-ene-3(3, 4(3-diol, and cholestane-3 3, 5a, 6a-triol, which are present in human atherosclerotic plaques. 

This isoform was found as the result of a mouse deficient in the oxysterol 7a-hydroxylase gene (CYP7B1 in humans), which nonetheless did not accumulate 24-hydroxy cholesterol from the CYP46pathway, suggesting the existence of another 7ot-hydroxylase (Li-Hawkins et al., 2000). However, very httle evidence exists for its expression in human brain. Nishimura et al. quantified CYP39A1 mRNA by RT-RT-PCR and reported some 100-fold less than they reported for CYP51 mRNA (Nishimura et al., 2003). There is no other evidence for the expression of this isoform in the brain as of this writing and this is beheved to be the first report of its kind. The isoform has been shown to be sexually dimorphic in the liver (Li-Hawkins et al., 2000). 

The health impairing and toxic elfects of oxidation of lipids are due to loss of vitamins, polyenoic fatty acids, and other nutritionally essential components formation of radicals, hydroperoxides, aldehydes, epoxides, dimers, and polymers and participation of the secondary products in initiation of oxidation of proteins and in the Maillard reaction. Dilferent oxysterols have been shown in vitro and in vivo to have atherogenic, mutagenic, carcinogenic, angiotoxic, and cytotoxic properties, as well as the ability to inhibit cholesterol synthesis (Tai et ah, 1999 Wpsowicz, 2002). 

Formation of mevalonate. The conversion of acetyl CoA to acetoacetyl CoA and then to 3-hydroxy-3-methylglutaryl CoA (3-HMG CoA) corresponds to the biosynthetic pathway for ketone bodies (details on p. 312). In this case, however, the synthesis occurs not in the mitochondria as in ketone body synthesis, but in the smooth endoplasmic reticulum. In the next step, the 3-HMG group is cleaved from the CoA and at the same time reduced to mevalonate with the help of NADPH+H 3-HMG CoA reductase is the key enzyme in cholesterol biosynthesis. It is regulated by repression of transcription (effectors oxysterols such as cholesterol) and by interconversion... 

Cholesterol is an important structural component of cellular membranes, where it plays a role in modulating membrane fluidity and phase transitions, and, together with sphingomyelin, forms lipid rafts or caveolae, which are sites where proteins involved in diverse signaling pathways become concentrated. Furthermore, cholesterol is a precursor of oxysterols, steroid hormones, and bile acids. 

Mammalian cells acquire cholesterol either by de novo synthesis from acetyl-coen-zyme A (CoA) or via the low-density lipoprotein (LDL)-receptor-mediated uptake of LDL particles that contain cholesterol esterified with long-chain fatty acids. These LDL cholesterol esters are subsequently hydrolyzed in lysosomes, after which free cholesterol molecules become available for synthesis of membranes, steroid hormones, bile acids, or oxysterols [1]. 

The initial steps in BA synthesis are characterised by the introduction of a hy-droxylic group in the la position, or in position 27, followed by another in the la position into the cholesterol nucleus. Both synthetic pathways (the neutral and the acidic pathways) possess a distinct microsomal 7-oxysterol hydroxylase, which is regulated by different genes. The most recently described disorder of BA synthesis is cholesterol 7a-hydroxylase deficiency, in which their decreased production through the classical pathway is partially balanced by activation of the alternative pathway. Cholesterol levels increase in the liver, with a consequent low-density lipoprotein hypercholesterolemia, and cholesterol gallstones may result, although there is no liver disease. In contrast, a defect in the conversion of 27-hydroxy-cholesterol to la,27-dihydroxy-cholesterol due to deficiency of the oxysterol 7a-hydroxylase specific for the alternate pathway, causes severe neonatal liver disease [8]. 

He X., Jenner A. M., Ong W. Y., Farooqui A. A., and Patel S. C. (2006). Lovastatin modulates increased cholesterol and oxysterol levels and has a neuioprotective effect on rat hippocampal neurons after kainate injury. J. Neuropathol. Exp. Neurol. 65 652-663. 

D. Bochelen, M. Mersel, P. Behr and P. Lutz, Effects of oxysterol treatment on cholesterol biosynthesis and reactive astrocyte proliferation in injured rat brain cortex, J. Neurochem. 65 (1995) 2194-2200. 

The effects of cholesterol and cholesterol-derived oxysterols on adipocyte ghost membrane fluidity has been studied. It has been found that cholesterol and oxysterols interact differently with rat adipocyte membranes. Cholesterol interacts more with phosphatidylcholine located at the outer lipid bilayer whereas, for example, cholestanone seems to interact more with phospholipids located at the inner layer... 

Two other new nuclear receptors have been shown to increase epidermal differentiation the LXR and the FXR. Farnesol and juvenile hormone activate the FXR leading to improved epidermal differentiation. Two genes encode for the LXR proteins, LXR alpha and LXR beta, and both are activated by various oxysterols the most potent being 22(R)-hydroxycholesterol, 24(S)-hydroxycholesterol, 24(S) 25-epoxycholesterol and 7-hydroxy cholesterol. Cholestenoic acid also acts on this receptor. In vitro these agents also increased epidermal filaggrin levels.129,130... 

Oxysterols are defined as oxygenated derivatives of cholest-5-en-3(3-ol (cholesterol) (Figure 18.1) or precursors of CHOL that may be formed directly by autoxidation or by the action of a specific monooxygenase, or that may be secondary to enzymatic or nonenzymatic lipid peroxidation (Guardiola et al., 1996 Schroepfer, 2000 Bjorkhem and Diczfalusy, 2002). These OS may be formed in the human body by endogenous free-radical attack on CHOL or by enzymatic processes, mainly in the biosynthesis of bile acids and steroid hormones. In addition, OS may be formed exogenously by autoxidation of CHOL in foods. The nomenclature and abbreviations of OS are presented in Table 18.1. It should be emphasized at this point that the OS that occur in... 

Bjorkhem, I. 2002. Do oxysterols control cholesterol homeostasis J. Clin. Invest. 110, 725-730. Bjorkhem, I., Diczfalusy, U. 2002. Oxysterols. Friends, foes, or just fellow passengers Arterio-scler. Thromb. Vase. Biol. 22, 734-742. 

Emanuel, H.A. Hassel, C. A., Addis, P.B., Bergmann, S.D., Zavoral, J.H. 1991. Plasma cholesterol oxidation products in human subjects fed a meal rich in oxysterols. J. Food Sci. 56, 843-847. 

Schroepfer, Jr., G.J. 2000. Oxysterols modulators of cholesterol metabolism and other processes. Physiol. Rev. 80, 361-554. 

Vine, D.F., Mamo, J.C.L., Beilin, L.J., Mori, T.A., Croft, K.D. 1998. Dietary oxysterols are incorporated in plasma triglyceride-rich lipoproteins, increase their susceptibility to oxidation and increase aortic cholesterol concentration in rabbits. J. Lipid Res. 39, 1995-2004. 

Wolf, G. 1999. The role of oxysterols in cholesterol homeostasis. Nutr. Rev. 57, 196-198... 

Cholesterol is absorbed by intestinal epithelial cells via a Niemann-Pick Cl-Like 1 (NPCILI) protein. This is the target of a number of anti-hyperhpidaemic drugs used to lower cholesterol levels. Examples include miglustafi aUopregnanolone, oxysterols and cyclodextrins all are able to slow the progress of the disease, but none as yet provides an... 

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