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PubMed2005

Human StarD5, a cytosolic StAR-related lipid binding protein.

Recently identified StarD5 belongs to the StarD4 subfamily, a subfamily of steroidogenic acute regulatory related lipid transfer (START) domain proteins that includes StarD4 and StarD6, proteins whose functions remain unknown. The objective of this study was to confirm StarD5's protein localization and sterol binding capabilities as measures to pursue function. Using rabbit polyclonal antibody against newly purified human histidine-tagged/StarD5 protein, StarD5 was detected in human liver. In parallel studies, increased expression of StarD5 in primary hepatocytes led to a marked increase in microsomal free cholesterol. Cell fractionation studies demonstrated StarD5 protein in liver cytosolic fractions only, suggesting StarD5 as a directional cytosolic sterol carrier. Supportive in vitro binding assays demonstrated a concentration-dependent binding of cholesterol by StarD5 similar to that of the cholesterol binding START domain protein StarD1. In contrast to selective cholesterol binding by StarD1, StarD5 bound the potent regulatory oxysterol, 25-hydroxycholesterol, in a concentration-dependent manner. StarD5 binding appeared selective for cholesterol and 25-hydroxycholesterol, as no binding was observed for other tested sterols. The ability of StarD5 to bind not only cholesterol but also 25-hydroxycholesterol, a potent inflammatory mediator and regulatory oxysterol, raises basic fundamental questions about StarD5's role in the maintenance of cellular cholesterol homeostasis.

Adaptor Proteins, Vesicular Transport↗
PubMed1984

Reevaluation of the effects of cytochalasins on steroidogenesis: studies on hamster granulosa cells.

Cytochalasin B (CB), a drug that inhibits microfilament polymerization, as well as having other actions, such as inhibition of hexose transport, is reported to block tropic hormone-stimulated steroidogenesis. Cytochalasin D (CD) is a more effective inhibitor of microfilament polymerization than CB, but has no effect on hexose transport. We reevaluated the effects of these inhibitors of microfilament function on steroid formation by freshly isolated granulosa cells from PMSG-primed hamsters. These cells have been shown to produce increased progesterone in response to tropic stimuli using endogenous steroidogenic precursors during short term incubation. In addition, they use exogenous substrate in the form of hydroxysterols for steroid production. Thus, we could examine effects of CB and CD on the metabolism of exogenous and endogenous sterol substrates. To determine the specificity of actions of cytochalasins, the metabolism of other steroid intermediates was examined: the conversion of pregnenolone to progesterone and the conversion of androstenedione to estradiol. Also, the oxidation of [14C]octanoate to 14CO2, a process that occurs in the mitochondria, was examined. Both CB and CD (1-10 micrograms/ml) inhibited LH- and 8-bromo-cAMP-stimulated progesterone production. Neither cytochalasin inhibited the production of progesterone in response to pregnenolone, nor were endogenous pregnenolone levels increased in the presence of CB or CD. Treatment with CB, but not CD, resulted in decreased progesterone production in response to hydroxycholesterol and decreased the side-chain cleavage of [3H]25-hydroxycholesterol. CB completely blocked the conversion of androstenedione to estradiol, whereas the aromatase reaction was unaffected by CD. CB, but not CD, significantly reduced the oxidation of [14C]octanoate to 14CO2 by hamster granulosa cells. Our findings demonstrate significant differences in the effects of CB and CD on granulosa cells. CB, in contrast to CD, has wide-spread effects on granulosa cell function, interfering with the metabolism of hydroxycholesterols, the oxidation of fatty acids, and aromatization. The failure of CD to interfere with these same functions suggests a more specific action of CD on the steroidogenic machinery. We conclude that microfilaments play an important role in the process of steroid formation from endogenous substrate. CD appears to affect a post-cAMP step between the conversion of cholesterol to pregnenolone, presumably the delivery of endogenous cholesterol to the mitochondria.

3-Hydroxysteroid Dehydrogenases↗
PubMed1990

Continuous and pulsatile infusions of luteinizing hormone have identical effects on steroidogenic capacity and sensitivity of Leydig cells in rats passively immunized against gonadotropin-releasing hormone.

Adult male rats were passively immunized against GnRH and given iv infusions of saline or 60 or 300 ng NIDDK ovine LH-24/100 g BW.24 h in continuous regimens of 2.5 or 12.5 ng/100 g BW.h and pulsatile regimens of 1-min pulses of 5 or 25 ng/100 g BW every 2 h. Control animals were treated with nonimmune serum and saline. After 10 days of in vivo treatment, Leydig cells were purified and incubated in vitro with 1) increasing concentrations of hCG (0-50 mIU/ml) in the presence or absence of methylisobutylxanthine, 2) a maximally stimulatory concentration of 8-bromo-cAMP (8-Br-cAMP; 1 mM), and 3) a saturating concentration of 25-hydroxycholesterol (10 microM). LH receptor concentrations were quantified by [125I]hCG binding assay. Maximum testosterone production in the presence of hCG, 8-Br-cAMP, or 25-hydroxycholesterol was reduced by more than 90% in Leydig cells from anti-GnRH serum-treated rats (compared to that in cells from control rats), and this reduction in steroidogenic capacity was prevented in a dose-dependent manner by concurrent infusion of LH in either the continuous or pulsatile regimens. These results confirm that the trophic actions of LH on Leydig cells in vivo 1) do not depend on pulsatile secretion of the hormone, and 2) include induction/maintenance of one or more of the enzymes catalyzing the conversion of cholesterol to testosterone. Trophic actions on constituents or processes before cholesterol side-chain cleavage were not apparent; in vivo treatments had no obvious differential effects on hCG-stimulated, 8-Br-cAMP-stimulated, or 25-hydroxycholesterol-supported testosterone production. Sensitivity to hCG was increased (EC50 for stimulation of testosterone production was decreased) by passive immunization against GnRH, and this effect was prevented in a dose-dependent manner by concurrent infusion of LH in either the continuous or pulsatile regimens. Thus, intermittent exposure to low concentrations of LH in vivo desensitizes Leydig cells as effectively as continuous exposure. Neither specific binding of [125I]hCG nor the effect of methylisobutylxanthine on sensitivity to hCG in vitro differed among treatment groups. Therefore, both the trophic and desensitizing actions of LH appear to occur by mechanisms that are independent of changes in available LH receptor concentration and phosphodiesterase activity.

1-Methyl-3-isobutylxanthine↗
PubMed1991

Tumor necrosis factor alpha inhibits gonadotropin action in cultured porcine Leydig cells: site(s) of action.

In the present study, we have tested the direct effects of tumor necrosis factor-alpha (TNF-alpha) on basal and human (h)CG-stimulated testosterone secretion by cultured purified Leydig cells isolated from immature porcine testes. TNF-alpha reduced (as much as 90% decrease) hCG-stimulated, but not basal testosterone secretion in a dose- and time-dependent manner. The maximal and half-maximal effects were, respectively, 3.75 ng/ml (2.2 x 10(-10) M) and 0.66 ng/ml (3.9 x 10(-11) M) of TNF-alpha after 48 h treatment. TNF-alpha antagonizes the gonadotropin hormonal action by affecting at least two types of biochemical steps. First, TNF-alpha reduced LH/hCG binding to a maximal decrease of 45% obtained with 2 ng/ml of TNF-alpha after 48 h of treatment. TNF-alpha also inhibited (44% decrease) hCG-stimulated cAMP production in optimal conditions (20 ng/ml, 72 h). Second, TNF-alpha significantly (P less than 0.001) reduced testosterone secretion stimulated with 8-bromo-cAMP (3 x 10(-3) M) in a similar range (86% decrease) to that observed with the gonadotropin. Such an observation indicates that the antigonadotropic action of the cytokine is exerted in a predominant manner at a step(s) located beyond cAMP formation. Furthermore, incubation of Leydig cells with 22R-hydroxycholesterol (5 micrograms/ml, 2 h) reversed most of the inhibitory effect of TNF-alpha on androgen production. Indeed, the TNF-alpha (20 ng/ml, 72 h) inhibitory effect on testosterone production was limited to about 20% (P less than 0.03) in Leydig cells supplied with 22R-hydroxycholesterol. Such a moderate effect of the cytokine in the presence of 22R-hydroxycholesterol compared with that observed when androgen secretion was stimulated with the gonadotropin (up to 90% inhibition) indicate that TNF-alpha acts by dramatically reducing cholesterol substrate availability in the mitochondria. Such an effect of TNF-alpha is directly exerted on Leydig cells since TNF-alpha receptors (dissociation constant approximately 5.4 x 10(-10) M) are present in primary cultures of purified porcine Leydig cells. Together, the present findings show that in Leydig cells TNF-alpha antagonizes the gonadotropin action on testosterone formation predominantly through a decrease in the availability of cholesterol substrate in the mitochondria.

8-Bromo Cyclic Adenosine Monophosphate↗
PubMed1999

Effects of NTE-122, a novel acyl-CoA:cholesterol acyltransferase inhibitor, on cholesterol esterification and secretions of apolipoprotein B-containing lipoprotein and bile acids in HepG2.

We studied the effect of NTE-122 (trans-1,4-bis[[1-cyclohexyl-3-(4-dimethylamino phenyl) ureido]methyl]cyclohexane), a novel acyl-CoA:cholesterol acyltransferase (ACAT) inhibitor, on intracellular cholesterol esterification and the secretion of apolipoprotein B100 (apoB)-containing lipoprotein and bile acids in the human hepatoma cell line HepG2. NTE-122 markably inhibited [3H]oleate incorporation into cholesteryl esters in HepG2 cells incubated with 5 microg/ml 25-hydroxycholesterol as a stimulus for ACAT (IC50=6.0 nM). On the other hand, NTE-122 did not affect [3H]oleate incorporation into triglycerides and phospholipids and [14C]acetate incorporation into cholesterol. The stimulation of ACAT by 25-hydroxycholesterol caused significant increases in the secretion of radiolabeled cholesteryl esters, radiolabeled triglycerides and apoB mass. NTE-122 pronouncedly inhibited the secretion of radiolabeled cholesteryl esters in proportion to the inhibition of cellular cholesterol esterification, and it significantly reduced the secretion of radiolabeled triglycerides and apoB mass in HepG2 cells incubated with 25-hydroxycholesterol. Furthermore, NTE-122 increased the secretion of bile acids synthesized from [14C]-cholesterol. These results suggest that NTE-122 is capable of exhibiting anti-hyperlipidemic effects by reducing both the cholesterol content and the amount of secreted very low-density lipoprotein and enhancing the excretion of bile acid from the liver.

Acetates↗
PubMed1992

Localization of prostaglandin F2 alpha inhibition of lipoprotein use by bovine luteal cells.

Prostaglandin F2 alpha (PGF2 alpha) inhibits lipoprotein-stimulated progesterone production by bovine luteal cells in vitro and the objective of this study was to localize the site of action of PGF2 alpha. Cultured bovine luteal cells were treated with PGF2 alpha for seven days, and then with either lipoproteins or 25-hydroxycholesterol in the presence of aminoglutethimide (which inhibits cholesterol side-chain cleavage) for the final 48 h. The effects of PGF2 alpha on progesterone production, cellular cholesterol content, mitochondrial cholesterol content and cholesterol side-chain cleavage activity were determined. As expected, PGF2 alpha inhibited (P less than 0.05) lipoprotein-stimulated progesterone production. However, PGF2 alpha did not inhibit low-density lipoprotein-stimulated, or high density lipoprotein-stimulated, increases in cellular cholesterol (P less than 0.05) or inhibit lipoprotein-induced increases in mitochondrial cholesterol content (P less than 0.05). Additionally, cholesterol content of mitochondria increased (P less than 0.05) in the presence of PGF2 alpha alone. To determine if the PGF2 alpha-induced inhibition of steroidogenesis occurred at, or after, the side-chain cleavage reaction, we treated cells with the readily diffusable sterol, 25-hydroxycholesterol. Prostaglandin F2 alpha did not inhibit 25-hydroxycholesterol-stimulated progesterone production (P less than 0.05). Prostaglandin F2 alpha may therefore exert its luteolytic effect at a site after cholesterol transport to the mitochondria but before cholesterol side-chain cleavage.

Aminoglutethimide↗
PubMed1993

Stage-dependent modulation of Sertoli cell steroid production in dogfish (Scyliorhinus canicula).

Seminiferous lobules of dogfish (Scyliorhinus canicula) testis comprise cysts formed by steroid-producing Sertoli cells associated with germ cells at an identical stage of spermatogenesis. These lobules were isolated in four populations corresponding to lobules with spermatogonia (A), spermatocytes (B), early spermatids (C) and late spermatids (D). They were used for steroid radioimmunoassay or incubated with 22 alpha-hydroxycholesterol or with dibutyryl cyclic AMP (dibutyryl cAMP) to measure steroid production. Our results indicate that progesterone was the major steroid in seminiferous lobules at all stages of spermatogenesis except in lobules A. Furthermore, marked changes in the distribution of steroids were observed according to the stage of spermatogenesis; progesterone, 4-androstenedione, testosterone and 17 alpha-hydroxy,20 beta-dihydroprogesterone concentrations were highest in lobules D, whereas dihydrotestosterone concentrations decreased during spermatogenesis. No significant stage-related change was observed for 3 alpha-diol and 3 beta-diol. Incubation experiments revealed that the isolated seminiferous lobules at all stages can synthesize steroids from hydroxycholesterol and that lobules D have the highest basal contents of androstenedione and testosterone. Furthermore, when dibutyryl cAMP and 10 mumol hydroxycholesterol l-1 were added together to the cultures, an enhancement of the steroid secretion was observed rather than a change in synthesis. Our results also indicated that the responsiveness of the lobules to dibutyryl cAMP varies according to the stage of spermatogenesis and to the steroid assayed. Overall, this study indicated that germ cells probably markedly influence Sertoli cell steroidogenesis in the adult dogfish testis.

Androgens↗
PubMed1993

Cytotoxicity of oxysterols on cultured smooth muscle cells from human umbilical arteries.

The lethal effect of 25- and 26-hydroxycholesterol on smooth muscle cells derived from human umbilical arteries was investigated. The extent of cellular death corresponded with increasing oxysterol concentrations and incubation times. Incubation of the cells with 0.5, 2.5, or 10 micrograms/ml of 25- or 26-hydroxycholesterol revealed a proportionality between the degree of cellular death and oxysterol concentration over the 5 days of the experiment. Correlation coefficients among the degree of cellular death, the exposing period, and oxysterol concentration were significantly different (P < 0.05). However, none of these changes were noted in the smooth muscle cells cultured for 5 days in a medium containing the same concentration of cholesterol or 0.5% ethanol. An increase in the concentration of either serum or cholesterol in the culture medium did not significantly reduce the cytotoxicity of 2.5 micrograms/ml of 26-hydroxycholesterol. The results of this study suggest that oxysterols have an injurious effect on arterial cells, and that the injurious effect could not be altered by cholesterol, which was present at a serum concentration 12 times higher than that of oxysterols.

Cell Death↗
PubMed2001

Key regulatory oxysterols in liver: analysis as delta4-3-ketone derivatives by HPLC and response to physiological perturbations.

A number of oxysterols have been implicated in metabolic regulation. Key among these are (24S),25-epoxycholesterol and (24S)-hydroxycholesterol, high affinity ligands for the nuclear transcription factor liver X receptor alpha; 27-hydroxycholesterol, a bile acid synthetic intermediate; and 25-hydroxycholesterol, which has been used to study regulation of lipid metabolism by the sterol regulatory element-binding protein family of transcription factors. Investigation of the physiological importance of these compounds in vivo has been hampered by lack of analytical methods to reproducibly and accurately determine their concentrations in tissues. This article describes a method designed to determine quantitatively the amounts of these important side-chain oxysterols by derivatization to the Delta4-3-ketones followed by high performance liquid chromatography. The method was validated with known standards and then was used to determine the concentrations of these oxysterols in rodent liver under various physiological conditions. All four oxysterols were present in the picogram per milligram protein range and have distinct subcellular distributions and responses to physiological perturbations in vivo.

Animals↗
PubMed2001

Regulation of sterol regulatory element-binding proteins by cholesterol flux in CaCo-2 cells.

The regulation of sterol regulatory element-binding proteins (SREBP) by cholesterol flux was studied in the intestinal cell line CaCo-2. CaCo-2 cells were incubated for 18 h with micelles containing 5 mM taurocholate and 500 microM oleic acid or micelles containing either 200 microM cholesterol or 150 microM lysophosphatidylcholine. In some incubations, an ACAT inhibitor was added or 25-hydroxycholesterol was substituted for cholesterol. The SREBP-1a transcript was 2-fold more abundant than the SREBP-1c transcript. In cells incubated with micelles containing cholesterol, rates of cholesterol synthesis were decreased and rates of esterification were increased. Cholesterol synthesis was decreased further by ACAT inhibition. Cholesterol influx decreased mRNA levels of SREBP-2, HMG-CoA synthase, HMG-CoA reductase, and fatty acid synthase. ACAT inhibition modestly suppressed gene expression further. Neither SREBP-1a nor SREBP-1c mRNA levels were altered by cholesterol. Despite decreases in gene expression of the sterol-responsive genes by cholesterol, the amounts of precursor and mature forms of SREBP-1 and SREBP-2 were not altered. In contrast, if 25-hydroxycholesterol was substituted for cholesterol, both the precursor and mature forms of SREBP-2 were decreased. The polar sterol decreased the mature form of SREBP-1 but the amount of the precursor form was unchanged. In cells incubated with micelles containing lysophosphatidylcholine, which causes cholesterol to efflux from cells, sterol-responsive gene expression was increased. The amounts of precursor and mature forms of SREBP-1 and SREBP-2, however, were not altered. In contrast, if the cells were depleted of cholesterol by incubating them with lovastatin and cyclodextrin, the mature forms of SREBP-1 and SREBP-2 were increased, as were mRNA levels for the sterol-responsive genes. The data would suggest that cholesterol influx/efflux regulates mRNA levels of sterol-responsive genes independently of changes in the amount of mature SREBP. In contrast, 25-hydroxycholesterol influx or cholesterol depletion alters the amount of mature SREBP, leading to the regulation of sterol-responsive gene expression.

CCAAT-Enhancer-Binding Proteins↗
PubMed2002

Induction of monocyte differentiation and foam cell formation in vitro by 7-ketocholesterol.

Oxidized LDL (OxLDL) is composed of many potentially proatherogenic molecules, including oxysterols. Of the oxysterols, 7-ketocholesterol (7-KC) is found in relatively large abundance in OxLDL, as well as in atherosclerotic plaque and foam cells in vivo. Although there is evidence that 7-KC activates endothelial cells, its effect on monocytes is unknown. We tested the hypothesis that 7-KC may induce monocyte differentiation and promote foam cell formation. THP-1 cells were used as a monocyte model system and were treated with 7-KC over a range of concentrations from 0.5 to 10 microg/ml. Changes in cell adhesion properties, cell morphology, and expression of antigens characteristic of differentiated macrophages were monitored over a 7-day period. 7-KC promoted cells to firmly adhere and display morphologic features of differentiated macrophages; this effect was time and dose dependent and was markedly more potent than cholesterol treatment (45% of cells became adherent after 7 days of treatment with 7-KC at 10 microg/ml vs. less then 5% for control cells, P < 0.01). Similar effects were obtained when LDL enriched with 7-KC or OxLDL were added to THP-1 cells. 7-KC-differentiated cells expressed CD11b, CD36, and CD68, phagocytized latex beads, and formed lipid-laden foam cells after exposure to acetylated LDL or OxLDL. In contrast to 7-KC, oxysterols with known cell regulatory effects such as 25-hydroxycholesterol, 7beta-hydroxycholesterol, and (22R)-hydroxycholesterol did not effectively promote THP-1 differentiation. In conclusion, these results demonstrate for the first time that 7-KC, a prominent oxysterol formed in OxLDL by peroxidation of cholesterol, may play an important role in promoting monocyte differentiation and foam cell formation. These studies also suggest that 7-KC induces monocyte differentiation through a sterol-mediated regulatory pathway that remains to be characterized.

CD36 Antigens↗
PubMed1992

Expression of 7 alpha-hydroxylase in non-hepatic cells results in liver phenotypic resistance of the low density lipoprotein receptor to cholesterol repression.

The goal of this study was to understand why the expression of low density lipoprotein (LDL) receptors by the liver is poorly down-regulated by cholesterol. We examined the hypothesis that 7 alpha-hydroxylase may indirectly induce the expression of the LDL receptor by metabolizing, i.e. inactivating oxysterol repressors. Non-hepatic Chinese hamster ovary cells, transfected with a plasmid encoding 7 alpha-hydroxylase, expressed both the mRNA and functional activity of this liver-specific enzyme. In the presence of 5% serum, expression of the LDL receptor by transfected cells was > 20 times that of non-transfected cells despite a 50% increased content of cholesterol ester. Both cell types displayed an almost complete repression of the LDL receptor by the oxysterol 25-hydroxycholesterol, suggesting that transcriptional control of the LDL receptor gene remained intact in the transfected cells. However, only cells expressing 7 alpha-hydroxylase showed a derepression of the LDL receptor with time. This transient sensitivity to 25-hydroxycholesterol repression was attributed to a 3-fold greater rate of metabolism of [3H]25-hydroxycholesterol. The paradoxical induction of LDL receptor mRNA in transfected cells having greater amounts of cholesterol esters suggests that 7 alpha-hydroxylase may preferentially use oxysterols rather than cholesterol as substrates. The combined data are consistent with the proposal that 7 alpha-hydroxylase indirectly induces the LDL receptor gene by metabolizing (inactivating) oxysterol repressors. Liver-specific expression of 7 alpha-hydroxylase can account for the relative resistance of hepatic LDL receptors to down-regulation.

Actins↗
PubMed1977

Localization of the interference of ascorbic acid deficiency with bile acid biogenesis.

The catabolism of 26-14C-cholesterol and of 26-14C-7alpha-hydroxycholesterol, the first stage in the transformation of cholesterol to bile acids, was studied in guinea-pigs with chronic latent vitamin C deficiency. Vitamin C deficiency markedly inhibited the oxidation of 26-14C-cholesterol to 14CO2, but did not significantly affect the catabolism of 26-14C-7alpha-hydroxycholesterol. The distribution of 14C in the tissues and body fluids of control and vitamin-deficient guinea pigs injected with labelled 7alpha-hydroxycholesterol was likewise the same. Ascorbic acids is probably needed only for 7alpha-hydroxylation of cholesterol, while the other stages of bile acid biogenesis are independent of vitamin C.

Animals↗
PubMed1991

Interrelationships between mevalonate metabolism and the mitogenic signaling pathway in T lymphocyte proliferation.

Upon stimulation with antigen or antibodies directed at the CD3.T cell receptor complex, T lymphocytes undergo a series of biochemical events that result in DNA synthesis and cellular proliferation. The purpose of the current study was to explore the role of mevalonic acid and its metabolites in this process. Stimulation of freshly isolated human T cells with immobilized anti-CD3 monoclonal antibody (mAb) results in the induction of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase message, with maximum induction occurring at 24 h of culture, approximately 12 h before the onset of DNA synthesis. Protein kinase C (PKC) probably mediates this induction, as H7, which inhibits PKC and cyclic nucleotide-dependent protein kinases, but not HA1004, which inhibits all of these protein kinases except PKC, completely abrogates the appearance of HMG-CoA reductase message. The importance of HMG-CoA reductase induction and mevalonate production in cell cycle progression was demonstrated by the observation that either 25-hydroxycholesterol, which inhibits this induction, or lovastatin, a competitive inhibitor of HMG-CoA reductase, inhibited anti-CD3-induced T cell mitogenesis in a dose-dependent manner. The presence of lovastatin during the first 24-36 h of culture results in a progressive delay of cell cycle progression, whereas this agent, when present only for the first 12 h of culture, had no effect on T cell proliferation. These results suggest that mevalonate is required for cell cycle progression from mid-G1 into late G1. Exogenous mevalonate overcomes the antiproliferative effect of lovastatin but not of 25-hydroxycholesterol. Since 25-hydroxycholesterol suppresses the metabolism of mevalonic acid at multiple points, this result suggests that one or more metabolites of mevalonate, rather than mevalonate itself, plays an essential role in cell cycle progression. One metabolite of mevalonate, farnesol pyrophosphate, may play such a role, since free farnesol suppresses anti-CD3 mAb-induced T cell proliferation in a concentration-dependent manner. In mAb is associated with PKC-dependent induction of HMG-CoA reductase which, in turn, leads to the generation of mevalonic acid and its metabolites, one or more of which play a requisite role in cell cycle progression.

Antibodies, Monoclonal↗
PubMed1991

[Alterations of the aortic endothelium ultrastructure after the administration of cholesterol oxidation products to rabbits].

Intravenous administration of 7 alpha-hydroxycholesterol and cholestane-triol at the dose of 2.5 mg/kg produces, one day later, ultrastructural alteration of aortic endothelial cells such as cytoplasmic vacuolation, protruding and crateriform surface defects, subendothelial oedema with a subsequent exfoliation of endotheliocytes. The endothelial damage was more pronounced after the administration of equal doses of cholestane-triol as compared to 7 alpha-hydroxycholesterol. Ultrastructural changes 10 days after oral administration of 500 mg/kg cholesterol mixed with its auto-oxidation products were similar to those developing after cholestane-triol and 7 alpha-hydroxycholesterol. Cholesterol free of the oxidation products at the same doses did not produce alterations in the rabbit aortic endothelium.

Animals↗
PubMed1990

[Interactions of lipid micelles with blood proteins].

Interaction of lipid micelles (LM), containing cholesterol and hydroxycholesterol, with human serum lipoproteins was investigated. It was shown that cholesterol-containing LM interact with low density lipoproteins (LDL). Selectivity of LM-LDL interaction depended on the cholesterol content of micelles and almost did not depend on the composition of LM core. Up to 90% of LDL were bound with cholesterol-saturated LM. By means of gel chromatography it was shown that interaction of cholesterol- and 7-hydroxycholesterol-containing micelles with serum led to the partial fusion of LDL with LM and LDL-LM complex formation, as well as to the cholesterol and 7-hydroxycholesterol transfer from micelles to LDL. The obtained results indicate that cholesterol-containing LM can be used for the delivery of oxidized cholesterol to cells involving LDL and receptor-dependent pathway of their capture by peripheral cells.

Cholesterol↗
PubMed1987

Effects on membrane function by cholesterol oxidation derivatives in cultured aortic smooth muscle cells.

Autoxidation derivatives of cholesterol known to affect cholesterol content of the cells were shown to alter some membrane associated functions in cultured aortic smooth muscle cells. For study of membrane-bound enzymes, Na+,K+-ATPase and 5'-nucleotidase were measured cytochemically by electron microscopy. Cells incubated with 10 ug/ml of cholestane-3 beta,5 alpha,6 beta-triol and 25-hydroxycholesterol for 24 to 48 hours showed marked inhibition of both enzyme activities. For study of carrier-mediated hexose transport, radiolabeled 2-deoxy-D-glucose was utilized. The uptake of this labeled compound was measured in the cells preincubated with oxidation derivatives of cholesterol for various time periods. Cholestane-3 beta,5 alpha,6 beta-triol had a rapid inhibitory effect on hexose transport, which was reversible after removal of the sterol from the medium. Hexose transport was not significantly altered by 25-hydroxycholesterol after up to 8 hours incubation. Two underlying mechanisms are possible. The prompt onset of the effect of cholestane-3 beta,5 alpha,6 beta-triol may be attributable to an incorporation of the sterol into the cell membranes. On the other hand, 25-hydroxycholesterol, a potent inhibitor of cholesterol biosynthesis, may have a delayed effect on membrane function by depleting the cholesterol available for membrane synthesis.

5'-Nucleotidase↗
PubMed1987

Cholesterol sulfate inhibits adrenal mitochondrial cholesterol side chain cleavage at a site distinct from cytochrome P-450scc. Evidence for an intramitochondrial cholesterol translocator.

Cholesterol sulfate inhibits (K1/2, 6 microM) the side chain cleavage of exogenous cholesterol in intact rat adrenal mitochondria. Inhibition is at a site other than cytochrome P-450scc: the spin state of the hemoprotein is not perturbed, and its activity is unaffected as judged by the failure to inhibit the metabolism both of 25-hydroxycholesterol and of endogenous cholesterol in a mitochondrial "steroidogenic pool." In contrast, 25-hydroxycholesterol, known to interact with the cytochrome, prevented the cleavage of both endogenous and exogenous cholesterol and produced the expected optical changes in the hemoprotein. Inhibition was specific, since a variety of related compounds including pregnenolone sulfate were not effective. Metabolic conversion to other species was insufficient to account for inhibition, indicating that cholesterol sulfate is the effective molecule. A hallmark of an inhibitor of a transport system is that disruption of the barrier to transport eliminates inhibition. Sonic disruption of mitochondria abated by 70% the effect of cholesterol sulfate, but did not affect inhibition by 25-hydroxycholesterol. Thus, the cholesterol sulfate appears to inhibit an intramitochondrial cholesterol translocation system that functions to move cholesterol into a steroidogenic pool. The high content of cholesterol sulfate in adrenal cortex (Drayer, N.M., Roberts, K.D., Bandi, L., and Lieberman, S. (1964) J. Biol. Chem. 239, 3112-3114) suggests a possible regulatory role for this molecule.

Adrenal Glands↗