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PubMed1984

Mosaicism in female hybrid hares heterozygous for glucose-6-phosphate dehydrogenase. VI. Production of monotypism in the aortas of 4 of 10 mosaic hares fed cholesterol oxidation products.

The normal aortic tissue of black women heterozygous for glucose-6-phosphate dehydrogenase (G-6-PD) usually consists of two cell phenotypes (mosaicism). By electrophoresis two G-6-PD types are demonstrated (ditypism). Advanced atherosclerotic lesions from such women not infrequently yield samples displaying only one G-6-PD type (monotypism). Possible causes for the monotypism include (1) monoclonal origin of the lesion and (2) selective growth and/or survival advantage of one phenotype over the other. We have been attempting to produce monotypism in the aortas of a hybrid hare model that displays G-6-PD mosaicism in the normal state. In the current study 14 G-6-PD mosaic hares were fed a high-cholesterol diet for 6 to 17 months. All developed extensive moderately severe (as compared to humans) atherosclerotic lesions. No monotypic samples were found. Ten hares were fed (in addition to the standard high-cholesterol diet) small doses of one of two cholesterol oxidation products (25-hydroxycholesterol or triol) for 6 to 21 months. Four of the ten developed monotypic foci in either atherosclerotic lesions or normal aortic tissue or both. The reason for giving the oxidation products was because they are cytotoxic for cells in vitro and one (25-hydroxycholesterol) had been shown to be more toxic for one phenotype than the other with cultured fibroblasts from the mosaic hares (not infrequently resulting in the culture becoming monotypic). We suggest that the monotypism observed in vivo was probably produced by a mechanism similar to that operating in vitro.

Animals↗
PubMed1985

Mosaicism in female hybrid hares heterozygous for glucose-6-phosphate dehydrogenase. VII. Evidence for selective advantage of one phenotype over the other in ditypic samples from aortas of hares fed cholesterol oxidation products.

In a previous study the authors demonstrated monotypic foci, all of timidus type, in the atherosclerotic lesions and normal aortic tissue of glucose-6-phosphate dehydrogenase (G-6-PD) mosaic hares fed 25-hydroxycholesterol or triol in addition to a high-cholesterol diet. Other hares fed the high-cholesterol diet without the cholesterol oxidation product additives did not develop monotypic foci. In the current study the question asked was whether ditypic samples from lesions or aortic mediae of the same hares fed the additives would show a higher percentage of timidus type G-6-PD than the hares fed the cholesterol alone. The results showed a significantly higher percentage of timidus type in both lesions and mediae in the groups fed either 25-hydroxycholesterol or triol than in the group fed cholesterol alone. The observations suggest that the change from ditypism to monotypism reported earlier with these cholesterol oxidation products was the result of progressive elimination of the europaeus type to leave only the timidus G-6-PD. This is consistent with the "selective advantage of one phenotype over the other" hypothesis for explaining the observed monotypism as opposed to the "genetic transformation" hypothesis.

Animals↗
PubMed1989

Steroidogenesis in Fundulus heteroclitus. II. Production of 17 alpha-hydroxy-20 beta-dihydroprogesterone, testosterone, and 17 beta-estradiol by various components of the ovarian follicle.

Fundulus heteroclitus prematurational follicles (1.3-1.4 mm) were dissected into various components and cultured in vitro to examine the type of cells involved in the synthesis of steroids upon F. heteroclitus pituitary extract (FPE) stimulation or addition of exogenous precursors (25-hydroxycholesterol or pregnenolone). Culture media and follicular tissue extracts were assayed for 17 alpha-hydroxy-20 beta-dihydroprogesterone (17 alpha-OH.20 beta-DHP), testosterone (T), and 17 beta-estradiol (E2) content using specific radioimmunoassays. Complete removal of the follicle wall (denuded oocytes) eliminated steroid accumulation induced by FPE treatment. Removal of the theca/epithelium layer (defolliculated oocytes) did not affect the steroidogenic response (17 alpha-OH,20 beta-DHP, T, E2 production) of the follicles to FPE or exogeneously added precursors (25-hydroxycholesterol or pregnenolone). Isolated theca/epithelium layers secreted only T. Isolated follicular preparations that did not contain the oocyte (theca/epithelium layers or follicle cells) secreted higher levels of steroids to the culture media than did intact follicles. We conclude from these results that (1) the follicle cells (granulosa cells) are the primary source of the various steroids produced by the F. heteroclitus ovarian follicle in response to FPE stimulation: (2) the synthesis of 17 alpha-OH,20 beta-DHP and E2 does not require the involvement of two cell types as shown in other teleosts; (3) the theca/epithelium layer is able to produce T but lacks the aromatase activity necessary for E2 synthesis; and (4) steroids synthesized in the follicle wall are both secreted to the medium and accumulated in the oocyte.

20-alpha-Dihydroprogesterone↗
PubMed1982

Connective tissue responses to oxysterols.

We studied the effect of sterols and oxidized sterols on promoting tissue inflammation and necrosis, and on causing cell death in tissue culture. The cells studied were mouse fibroblasts and macrophages, and pig vascular smooth muscle. The lipid preparations were dibromide-purified cholesterol, air-oxidized cholesterol, 25-hydroxycholesterol, cholesterol-5alpha, 6 beta-epoxide and cholestane 3 beta, 5 alpha, 6 beta-triol. Of these, the triol was most active in its cytopathic effect on cells in culture, in size of granuloma formation and in producing necrosis. The epoxide, 25-hydroxycholesterol and air-oxidized cholesterol produced rather less effect on tissues and cultures than the triol, but more than purified cholesterol and the control. The results are considered in relation to the presence of oxysterols in stored foodstuffs and their possible presence over the surface of cholesterol crystals in the tissues.

Animals↗
PubMed1996

Impaired mobilisation of cholesterol from stored cholesteryl esters in human (THP-1) macrophages.

The formation of macrophage-derived foam cells is central to the development of fatty streaks within the arterial wall, and to the progression of atherosclerosis. The unregulated deposition of cholesteryl esters, as lipid droplets within the cytoplasm of these cells, is responsible for the formation of foam cells; this process is thought to be regulated by the balance between cholesterol esterification, by acyl CoA:cholesterol acyltransferase (ACAT), and hydrolysis, by neutral cholesteryl ester hydrolase (nCEH). This study examines the importance of the balance between these two enzymes in determining the efflux of cholesterol from human (THP-1) macrophages. The presence of modified lipoprotein, or of 25-hydroxycholesterol, markedly increased cholesterol esterification in these cells and these effects were potently inhibited by the presence of the ACAT inhibitor, 447C88. In the absence of HDL, an acceptor particle, there was little or no hydrolysis of the cholesteryl ester pool and no efflux of cholesterol to the extracellular milieu; addition of HDL led to a partial (36%) reduction in cholesteryl esters, an effect which was not enhanced by the inhibition of ACAT. This suggested that the stored cholesteryl esters in human (THP-1) macrophages, unlike those in mouse peritoneal macrophages, were relatively resistant to removal by efflux to HDL. Efflux of newly synthesised free cholesterol from these macrophages was increased by HDL in a saturable manner, suggesting that the lack of reduction of stored cholesteryl esters was due to impaired mobilisation of cholesteryl esters to free cholesterol via nCEH. Indeed, nCEH activity in these macrophages was much lower than in mouse peritoneal macrophages, and appeared to be down-regulated in the presence of 25-hydroxycholesterol or modified lipoproteins; this loss of nCEH activity was prevented by the ACAT inhibitor 447C88. The efflux of stored cholesteryl esters from THP-1 macrophages therefore appears to be limited by the activity of nCEH.

Animals↗
PubMed1976

Inhibition of the conversion of cholesterol to pregnenolone in bovine adrenocortical preparations.

The inhibition of the conversion of [4-14C] cholesterol to [4-14C] pregnenolone by a number of steroids has been studied in bovine adrenocortical mitochondrial acetonedried preparations. At equimolar substrate and inhibitor concentrations (3.3 muM) the most potent inhibitors were cholesterol derivatives containing a nitrogen function at c-22, followed by derivatives containing oxygen functions at c-22 or c-20 or both. The presence of a hydroxyl group at c-17 or the replacement of the 3beta-hydroxyl group by fluorine reduced the inhibitory efficacy. In the presence of inhibitors that were also relatively good substrates of the cholesterol side-chain cleavage system, such as some cholesterol derivatives hydroxylated in the side-chain,the rate of [4-14C] pregnenolone formation increased with time as the inhibitor was consumed. (20S)-20,21-Dihydroxycholesterol exerted such an effect on the kinetics of [4-14C]pregnenolone formation, and yielded 21-hydroxypregnenolone which was identified by gas chromatography-mass spectrometry. The synthesis of (20R)-22-ketocholesterol, of (20R,22R)-22hydroxycholesterol, (20R,22S)-hydroxycholesterol, and of (20S)-desmosterol is described.

Adrenal Cortex↗
PubMed1985

Effect of lipoproteins and luteotrophins on progesterone accumulation by luteal cells from the pregnant pig.

The roles of prolactin (Prl) and LH in the maintenance of luteal function in pregnant pigs were investigated. Luteal cells from pigs between days 70 to 95 of pregnancy were dissociated and incubated for 4 h. In the absence of exogenous cholesterol, LH exhibited a dose-dependent stimulatory effect on progesterone secretion. Prl had a mild stimulatory effect on progesterone accumulation and at lower doses Prl potentiated the response to LH. Low density lipoprotein (LDL) but not high density lipoprotein (HDL) had a mild stimulatory effect on progesterone secretion. When exogenous cholesterol was provided as the substrate in the form of LDL or HDL, Prl had a striking stimulatory effect on progesterone secretion. When 25-hydroxycholesterol which bypasses the lipoprotein receptor was provided as the substrate, Prl failed to stimulate progesterone accumulation. The stimulatory effect of LH was potentiated when LDL, HDL, or 25-hydroxycholesterol were present. The results of this study suggest that LH increases the uptake of exogenous cholesterol in the form of lipoproteins and enhances the utilization of internalized cholesterol for progesterone synthesis. Prl appears to stimulate progesterone synthesis by enhancing the uptake of lipoproteins.

Animals↗
PubMed1994

Inhibitors of sterol synthesis. Effects of fluorine substitution at carbon atom 25 of cholesterol on its spectral and chromatographic properties and on 3-hydroxy-3-methylglutaryl coenzyme A reductase activity in CHO-K1 cells.

25-Fluorocholesterol (III) was prepared by treatment of 25-hydroxycholesterol (IV) with hydrogen fluoride-pyridine. Compounds III, IV, and cholesterol (I) were fully characterized by 1H and 13C NMR, and stereochemical assignments were established for the C-22 and C-23 protons. The side-chain proton assignments, which apply to most other sterols with a saturated eight-carbon side chain, were based on conformational analysis and comparisons with NMR data for 25,26,26,26,27,27,27-heptafluorocholesterol (II). The chromatographic behavior of I, II, and III were compared on thin-layer chromatography, high performance liquid chromatography, and gas chromatography. Major fragment ions in electron-impact mass spectra of III were analogous to ions of either cholesterol or desmosterol, and a similar analogy was observed for the trimethylsilyl ethers. The 25-hydroxysterol IV and the 25-fluorosterol III differed markedly in their effects on the levels of 3-hydroxy-3-methylglutaryl coenzyme A reductase activity in CHO-K1 cells. Whereas 25-hydroxycholesterol caused a approximately 66% lowering of reductase activity in cells at 0.1 microM, the 25-fluorosterol III had no effect at this concentration.

Animals↗
PubMed1986

Characterization of oxysterol-binding protein in rat embryo fibroblasts and variations as a function of the cell cycle.

A cell-free system assay involving cell freeze-thawing and protein fractionation by ammonium sulfate precipitation was developed to characterize a cytosol binding protein specific for oxysterols in rat embryo fibroblasts. This protein shared common characteristics with the oxysterol-binding protein described in L cells and in normal human lymphocytes: 8 S sedimentation coefficient, sterol-protein complex of Mr 160 600, saturability, high affinity (Kd in the range of 10(-9) M) and specificity for cholesterol derivatives oxidized on the side chain. These compounds were better inhibitors of DNA synthesis than the compounds oxidized on the nucleus, whereas no difference was found between sterols oxygenated either on the side chain or on the nucleus, as far as inhibition of hydroxymethylglutaryl-CoA reductase (HMG-CoA reductase) was concerned. Macromolecular components capable of specifically binding 25-hydroxycholesterol were also detected in the fibroblast nucleus. The cytosol oxysterol-binding protein showed a sharp increase (5-fold) in the G2M phase of the cell cycle and in exponentially growing cells (maximal binding site number/cell: 43 500, versus 8850 in confluent cells). Neither the affinity nor the sedimentation coefficient of the protein changed in either situation. The quantitative (but not qualitative) variations of oxysterol-binding protein could be related to the inhibitory effect of 25-hydroxycholesterol on DNA synthesis, which becomes critical when this sterol is added in the G2M phase of the cell cycle.

Animals↗
PubMed1992

Inhibitors of protein and RNA synthesis block the cytotoxic effects of oxygenated sterols.

Oxygenated derivatives of cholesterol are known to exhibit potent cytotoxic effects against many different cell types. The cellular basis of this cytotoxicity is not understood. Using two murine cancer cell lines (the EL4 lymphoma and the K36 leukemia cell line) and two oxygenated sterols (7-ketocholestanol and 25-hydroxycholesterol), our laboratory attempted to determine whether the cytotoxic action of oxysterols was mediated by a mechanism requiring protein or RNA synthesis. The addition of 5 microM 7-ketocholestanol or 25-hydroxycholesterol to the culture medium regularly caused the viable cell count to fall below 10-20% of control within 48-72 h. In the presence of inhibitors of protein or RNA synthesis, however, cell viability was consistently and significantly increased in a dose-dependent manner. For cultures of EL4 cells grown in the presence of 5 microM 7-ketocholestanol, for example, the addition of appropriate concentrations of cycloheximide, puromycin, emetine, and actinomycin increased the percentage of viable cells from a control value of less than 6% to 66%, 28%, 76% and 42%, respectively. Qualitatively similar results were obtained with the K36 cell line. Additional studies revealed that macromolecular synthesis inhibitors, while effective in inhibiting protein or RNA synthesis to varying degrees, did not affect the cellular uptake of 7-keto[3H]cholestanol, suggesting that their ability to protect cells against oxysterol-induced cytotoxicity was not due to an inhibition of the cellular oxysterol uptake. These observations suggest that the cytotoxicity of oxygenated sterols may be mediated by mechanisms requiring de novo protein or RNA synthesis and that oxysterol-induced cytotoxicity may provide a useful system for the identification of proteins involved in cell death.

Animals↗
PubMed1978

Pregnenolone biosynthesis in isolated cells of Snell rat adrenocortical carcinoma 494.

Adrenocorticotrophin (ACTH) produced an insignificant stimulation of pregnenolone biosynthesis from endogenous precursors in isolated cells prepared from the rat Snell adrenal carcinoma 494. On the addition of 25-hydroxycholesterol, the rate of pregnenolone synthesis increased 10-fold. These results, noting also the very low cholesterol content of the tumor cells, suggested that lack of cholesterol was responsible for the poor steroidogenic response of the cells to ACTH. Endogenous pregnenolone production was sensitive to cytochalasin B as well as cycloheximide. However, pregnenolone synthesis after the addition of 25-hydroxycholesterol was not affected by these inhibitors. Removal of cycloheximide from the cells resulted in the immediate restoration of the initial rate of pregnenolone synthesis from endogenous precursors. This suggested that cycloheximide was interfering with the action of a stable activated intracellular messenger.

Adrenal Cortex↗
PubMed1988

The albumin fraction of rat testicular fluid stimulates steroid production by isolated Leydig cells.

Rat testicular fluid (rTF), but not rat serum (rS) or plasma (rP) can further increase within 4 h maximally luteinizing hormone (LH)-stimulated or 22 R-hydroxycholesterol-supported pregnenolone production by immature rat Leydig cells in vitro. This effect of rTF is dose dependent (0.05-1.2% protein, w/v) with an increase up to 4-fold. The objective of the present study was to isolate and characterize the bioactive factor(s) in rTF. After sequential ammonium sulfate fractionation, gel filtration chromatography on Superose 12 and affinity chromatography on concanavalin A-Sepharose it was shown that the albumin fraction was a major biologically active fraction in rTF. The relative specific activity in these fractions was never greater than 1.3-1.4, which is in agreement with the purification factor required to obtain pure albumin from rTF. Commercially obtained albumin fractions from human, bovine and rat sera, up to 99% purity, also increased Leydig cell steroid production more than 3-fold when added in concentrations between 0.1 and 1% w/v in combination with LH or 22R-hydroxycholesterol. Other proteins such as hemoglobin and ovalbumin were not effective in stimulation of steroid production. Bovine serum albumin (bSA, fraction V) at concentrations of 0.25 and 1.0% (w/v), had no or minor effects on LH-stimulated steroid production by rat granulosa cells or adrenocorticotrophic hormone (ACTH)-stimulated steroid production by rat adrenal cells. These findings indicate that albumin itself or minor compounds copurified with albumin represent the main biologically active component in rTF for short-term stimulation of Leydig cell steroid production. Since bioactivity could not be demonstrated in serum which contains similar amounts of albumin as rTF, inhibitory compounds may be present in rat serum.

Albumins↗
PubMed1995

Bursal antisteroidogenic peptide alters the activity of steroidogenic enzymes in chicken granulosa cells.

We have previously reported that a peptide from chicken bursa of Fabricius, bursal antisteroidogenic peptide (BASP), inhibits luteinizing hormone-stimulated progesterone biosynthesis by chicken ovarian granulosa cells. The objective of this study was to determine the site(s) of BASP inhibition within the steroidogenic pathway of chicken granulosa cells. The effects of BASP on key steroidogenic enzymes, including adenylyl cyclase (AC), phosphodiesterase, the cholesterol side-chain cleavage enzyme complex and 3 beta-hydroxysteroid dehydrogenase were determined. Luteinizing hormone (10 ng/tube) stimulated a fivefold increase in granulosa cell progesterone production that was inhibited by BASP (0.06, 0.12 or 0.25 bursal equivalents) in a dose-dependent manner. Luteinizing hormone stimulated a sixfold increase in cyclic 3',5'-adenosine monophosphate (cAMP) formation, and this increase was potentiated by BASP in a dose-dependent manner. In addition, BASP stimulated cAMP formation in the absence of luteinizing hormone without affecting progesterone production. The AC activator forskolin (0.1 mM) stimulated a 4.5-fold increase in progesterone synthesis, which was inhibited by BASP. In the presence of forskolin. BASP increased cAMP formation in a dose-dependent manner. A fivefold increase in progesterone synthesis induced by the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine (1.0 mM) was inhibited by BASP. In the presence of 3-isobutyl-1-methylxanthine, BASP increased cAMP formation in a dose-dependent manner. Finally, 22(R)-hydroxycholesterol (250, 500, 1,000, or 2,500 ng/tube) or pregnenolone (50, 100, 200, or 500 ng/tube) resulted in up to 15- or 10-fold increases in progesterone production, respectively. Increasing concentrations of BASP caused a dose-dependent suppression of the conversion of 22(R)-hydroxycholesterol, but not pregnenolone, to progesterone. The inhibition of steroidogenesis by BASP is not associated with reduced cAMP levels, and BASP appears to strongly stimulate AC activity. In addition, these findings suggest that BASP may limit the availability of progesterone precursors by inhibiting the activity of the cholesterol side-chain cleavage enzyme complex.

1-Methyl-3-isobutylxanthine↗
PubMed1995

Regulation of the cholesterol ester cycle and progesterone synthesis by juvenile hormone in MA-10 Leydig tumor cells.

We had previously reported that juvenile hormone III (JH III) and the JH analogue 2-(4-phenoxy phenoxy)-ethoxytetrahydropyran exert inhibitory effects on progesterone synthesis by blocking cAMP production in hCG-stimulated MA-10 Leydig tumor cells. In the present study, the effects of JH analogue upon the biosynthetic pathway of progesterone synthesis have been examined. Our results demonstrated that JH analogue inhibited progesterone production even in the presence of 20-hydroxycholesterol or 25-hydroxycholesterol. Furthermore, although JH analogue inhibited pregnenolone production in hCG-stimulated MA-10 cells the activity of the 3 beta-hydroxysteroid dehydrogenase (3 beta-HSD) was unaffected. These data suggest that JH analogue might inhibit the steroidogenic pathway in Leydig tumor cells by inhibiting the activity of the cholesterol side chain cleavage (CSCC) enzymatic complex. The JH analogue was also evaluated for inhibitory actions on cholesterol availability. An important effect of this compound was the interference with the cellular process of plasma membrane cholesterol internalization. Moreover, JH analogue inhibited not only the use of cholesterol ester for steroid biosynthesis under Bt2cAMP stimulation, but also the cholesterol ester hydrolase (CEH) activity in MA-10 Leydig tumor cells.

Bucladesine↗
PubMed2004

Cell-based screen of HMG-CoA reductase inhibitors and expression regulators using LC-MS.

We present an integrated consolidation of previously reported methods for screening hydroxymethylglutaryl-coenzyme A reductase (HMGR) inhibitors in 96-well microtiter plates with rapid workup using established mammalian cell lines and liquid chromatography-mass spectrometry analysis. Inhibitors as well as expression regulators of HMGR (inducers or repressors) can be screened. To validate the method, three competitive inhibitors of HMGR (lovastatin, simvastatin, and atorvastatin), as well as a potent sterol repressor of HMGR synthesis (25-hydroxycholesterol), were assayed on two cell lines: HepG2, a human hepatic derived cell line, and L cells, a subline of NCTC clone 929 mouse fibroblasts. The direct inhibition of HMGR by statins, induction of HMGR synthesis by the same statins following incubation with the cells, and repression of HMGR synthesis by 25-hydroxycholesterol were confirmed.

Atorvastatin↗
PubMed2005

Detection of the steroidogenic acute regulatory protein, StAR, in human liver cells.

Overexpressing StAR (a mitochondrial cholesterol transporter) increases (>5-fold) the rate of 27-hydroxylation of cholesterol and the rates of bile acid synthesis in primary rat hepatocytes; suggesting that the transport of cholesterol into mitochondria is rate-limiting for bile acid biosynthesis via the CYP27A1 initiated 'acidic' pathway. Our objective was to determine the level of StAR expression in human liver and whether changes in StAR would correlate with changes in CYP27A1 activity/bile acid synthesis rates in human liver tissues. StAR mRNA and protein were detected in primary human hepatocytes and HepG2 cells by RT-PCR/Northern analysis and by Western analysis, respectively. In immunocompetition assays, liver StAR was competed away with the addition of purified human adrenal StAR. Overexpressing CYP27A1 in both cell types led to >2-fold increases in liver StAR concentration. StAR protein levels also increased approximately 2-fold with the addition of 27-hydroxycholesterol to HepG2 cell culture medium. Overexpressing StAR increased the rates of 27-hydroxylation of cholesterol/bile acid synthesis in both cell lines and increased intracellular levels of 27-hydroxycholesterol. In conclusion, human liver cells contain regulable StAR protein whose level of expression appears capable of regulating cellular cholesterol homeostasis, representing a potential therapeutic target in the management of hyperlipidemia.

Bile Acids and Salts↗
PubMed2005

Effect of raloxifene and hormone therapy on serum markers of brain and whole-body cholesterol metabolism in postmenopausal women.

OBJECTIVE: To compare the 2-year effects of raloxifene (Rlx) with oral postmenopausal hormone therapy (HT) on serum markers of brain and whole-body cholesterol metabolism. METHODS: In a randomized, double-blind, placebo-controlled trial, 95 healthy, non-hysterectomized, early postmenopausal women received either daily Rlx 60 mg (n = 24), Rlx 150 mg (n = 23), HT (conjugated equine estrogens 0.625 mg/medroxyprogesterone acetate 2.5 mg; n = 24), or placebo (n = 24). Fasting blood samples were collected at baseline and after 6, 12, and 24 months of treatment for measurement of serum concentrations of cholesterol by means of gas-liquid chromatography; 24S-hydroxycholesterol (cerebrosterol), lathosterol, and the plant sterol campesterol by means of gas-liquid chromatography-mass spectrometry. The analyses were performed retrospectively from serum samples stored at -70 degrees C for 5 years. RESULTS: Twenty-four months of treatment with raloxifene 150 mg was associated with a significant reduction in serum cholesterol concentrations (-10%, P = 0.007). The ratio of 24S-hydroxycholesterol to cholesterol, a serum marker of brain cholesterol metabolism, showed a significant increase after 6 and 12 months with raloxifene 150 mg but not after 24 months (P = 0.001). The ratio of lathosterol to cholesterol, a marker of whole-body cholesterol synthesis, increased with raloxifene 60 mg (P = 0.163), raloxifene 150 mg (P < 0.001), as well as with HT (P = 0.005). The ratio of campesterol to cholesterol, a marker of cholesterol absorption rate, was significantly reduced with HT (P = 0.002). CONCLUSION: Two-year treatment with raloxifene or HT had no influence on brain cholesterol metabolism, while whole-body cholesterol synthesis, assessed by the ratio of lathosterol to cholesterol, increased during raloxifene and HT.

Alzheimer Disease↗
PubMed2004

Cholesterol in neurologic disorders of the elderly: stroke and Alzheimer's disease.

Mechanisms for the regulation of intracellular cholesterol levels in various types of brain and vascular cells are of considerable importance in our understanding of the pathogenesis of a variety of diseases, particularly atherosclerosis and Alzheimer's disease (AD). It is increasingly clear that conversion of brain cholesterol into 24-hydroxycholesterol and its subsequent release into the periphery is important for the maintenance of brain cholesterol homeostasis. Recent studies have shown elevated plasma concentrations of 24-hydroxycholesterol in patients with AD and vascular dementia, suggesting increased brain cholesterol turnover during neurodegeneration. The oxygenases involved in the degradation and excretion of cholesterol, including the cholesterol 24-hydroxylase and the 27-hydroxylase, are enzymes of the cytochrome P-450 family. This review focuses on the newly recognized importance of cholesterol and its oxygenated metabolites in the pathogenesis of ischemic stroke and AD. The reduction in stroke and AD risk in patients treated with cholesterol-lowering statins is also discussed.

Aged↗