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PubMed2004

Effects of 25-hydroxycholesterol on cholesterol esterification and sterol regulatory element-binding protein processing are dissociable: implications for cholesterol movement to the regulatory pool in the endoplasmic reticulum.

The regulatory pool of cholesterol is located in the endoplasmic reticulum (ER) and is key to how mammalian cells sense and respond to changes in cellular cholesterol levels. The extent of cholesterol esterification by the ER-resident protein, acyl-coenzyme A:cholesterol acyl-transferase (ACAT), has become the standard method for monitoring cholesterol transport to the ER and is assumed to reflect the regulatory pool of ER cholesterol. The oxysterol, 25-hydroxycholesterol (25HC), is thought to trigger intracellular cholesterol transport to the ER. In support of this contention, we confirmed previous reports that 25HC activates cholesterol esterification and is a potent suppressor of the sterol regulatory element-binding protein (SREBP) pathway. Processing of the ER membrane-bound SREBP into a soluble transcription factor is controlled by cholesterol levels in the ER. In this study, we addressed whether or not cholesterol esterification necessarily reflects cholesterol movement to the cholesterol homeostatic machinery in the ER as determined by SREBP processing. We found that three agents that inhibited the ability of 25HC to induce cholesterol esterification (progesterone, nigericin, and monensin) did not have a corresponding effect on 25HC suppression of SREBP processing. Moreover, ACAT inhibition did not alter the sensitivity of SREBP processing to 25HC. Therefore, cholesterol esterification by the ER-resident protein ACAT is dissociable from cholesterol transport to the cholesterol homeostatic machinery in the ER. In light of our results, we question the security of previous work that has inferred cholesterol transport to the ER regulatory pool based solely on cholesterol esterification.

Animals↗
PubMed2004

Cholesterol and 25-hydroxycholesterol inhibit activation of SREBPs by different mechanisms, both involving SCAP and Insigs.

The current paper demonstrates that cholesterol and its hydroxylated derivative, 25-hydroxycholesterol (25-HC), inhibit cholesterol synthesis by two different mechanisms, both involving the proteins that control sterol regulatory element-binding proteins (SREBPs), membrane-bound transcription factors that activate genes encoding enzymes of lipid synthesis. Using methyl-beta-cyclodextrin as a delivery vehicle, we show that cholesterol enters cultured Chinese hamster ovary cells and elicits a conformational change in SREBP cleavage-activating protein (SCAP), as revealed by the appearance of a new fragment in tryptic digests. This change causes SCAP to bind to Insigs, which are endoplasmic reticulum retention proteins that abrogate movement of the SCAP.SREBP complex to the Golgi apparatus where SREBPs are normally processed to their active forms. Direct binding of cholesterol to SCAP in intact cells was demonstrated by showing that a photoactivated derivative of cholesterol cross-links to the membrane domain of SCAP. The inhibitory actions of cholesterol do not require the isooctyl side chain or the Delta5-double bond of cholesterol, but they do require the 3beta-hydroxyl group. 25-HC is more potent than cholesterol in eliciting SCAP binding to Insigs, but 25-HC does not cause a detectable conformational change in SCAP. Moreover, a photoactivated derivative of 25-HC does not cross-link to SCAP. These data imply that cholesterol interacts with SCAP directly by inducing it to bind to Insigs, whereas 25-HC works indirectly through a putative 25-HC sensor protein that elicits SCAP-Insig binding.

Animals↗
PubMed2006

Induction of adaptive response and enhancement of PC12 cell tolerance by 7-hydroxycholesterol and 15-deoxy-delta(12,14)-prostaglandin J2 through up-regulation of cellular glutathione via different mechanisms.

Increasing evidence suggests an adaptive response induced by reactive oxygen species and other physiologically existing oxidative stimuli. We have recently reported that a variety of lipid peroxidation products at sublethal concentrations could induce adaptive response and enhance PC12 cell tolerance, although the detailed underlying molecular mechanisms have not been clearly clarified. In the present study, we found that both 7-hydroxycholesterol (7-OHCh) and 15-deoxy-delta(12,14)-prostaglandin J2 (15d-PGJ2) at sublethal concentrations significantly increased the cellular GSH as well as the enzyme activity of glutamate-cysteine ligase (GCL), the rate-limiting enzyme of GSH synthesis. Depletion of cellular GSH by buthionine sulfoximine completely abolished the adaptive response. Interestingly, treatment with 15d-PGJ2 significantly increased the gene expression of both subunits of GCL in an NF-E2-related factor 2 (Nrf2)-dependent manner, whereas neither 7-OHCh induced any considerable changes on the GCL gene expression nor did the Nrf2-small interfering RNA treatment exert any appreciable effects on the GSH elevation and subsequent adaptive response induced by 7-OHCh. These results demonstrate that the adaptive response induced by both 7-OHCh and 15d-PGJ2 is mediated similarly through the up-regulation of GSH but via different mechanisms.

Animals↗
PubMed2005

The role of the mitochondria in apoptosis induced by 7beta-hydroxycholesterol and cholesterol-5beta,6beta-epoxide.

Oxysterols are oxygenated derivatives of cholesterol that may be formed endogenously or absorbed from the diet. Significant amounts of oxysterols have frequently been identified in foods of animal origin, in particular highly processed foods. To date, oxysterols have been shown to possess diverse biological activities; however, recent attention has focused on their potential role in the development of atherosclerosis. Oxysterols have been reported to induce apoptosis in cells of the arterial wall, a primary process in the development of atheroma. The aim of the present study was to identify the role of the mitochondria in the apoptotic pathways induced by the oxysterols 7beta-hydroxycholesterol (7beta-OH) and cholesterol-5beta,6beta-epoxide (beta-epoxide) in U937 cells. To this end, we investigated the effects of these oxysterols on mitochondrial membrane potential, caspase-8 activity, the mitochondrial permeability transition pore and cytochrome c release. 7beta-OH-induced apoptosis was associated with a loss in mitochondrial membrane potential after 2 h, accompanied by cytochrome c release from the mitochondria into the cytosol after 16 h. Pre-treatment with a range of inhibitors of the mitochondrial permeability transition pore protected against 7beta-OH-induced cell death. In contrast, beta-epoxide induced a slight increase in caspase-8 activity but had no effect on mitochondrial membrane potential or cytochrome c release. The present results confirm that 7beta-OH-induced apoptosis occurs via the mitochondrial pathway and highlights differences in the apoptotic pathways induced by 7beta-OH and beta-epoxide in U937 cells.

Apoptosis↗
PubMed1991

Influence of 26-hydroxycholesterol on the composition and function of gel-filtered platelets.

The influence of 26-hydroxycholesterol (26-OH-CHOL) on the structure and function of gel-filtered rat platelets, as a model membrane, was studied in vitro. Its influence on structure was determined by a fatty acid and a phospholipid analysis of the platelet lipids and on function by the cytoplasmic calcium concentration of the platelets exposed to increasing concentrations of 26-OH-CHOL for various periods of time. The intracellular free calcium (Ca2+)i of the gel-filtered rat platelets was monitored by a fluorescent probe (quin 2) after incubation in a 37 degrees C water bath with 1 mM Ca2+ and 20 microM quin 2/AM. The presence of 26-OH-CHOL in the incubation media changed both the phospholipid composition and the mixed fatty acid composition in the membrane and increased the intracellular free Ca2+ level of the platelets. As the incubation of platelets with cholesterol (CHOL) or esterified 26-OH-CHOL did not increase intracellular Ca2+ levels, these results indicate that the hydrophilic free 26-hydroxy group in 26-OH-CHOL may have influenced the enzymes catalyzing the synthesis of the phospholipid in the platelet membrane so as to allow it to become more and more "leaky" to Ca2+. Such a fundamental change in membrane structure and function may be responsible for the development of atherosclerosis in the intimal layer of the coronary arteries.

Animals↗
PubMed2001

Cholesterol dynamics in the foetal and neonatal brain as reflected by circulatory levels of 24S-hydroxycholesterol.

UNLABELLED: Oxysterols, particularly those hydroxylated in the steroid side-chain, are formed from cholesterol by specific cytochrome P450 enzymes and may facilitate elimination of cholesterol from extrahepatic sources. In humans, the greatest portion of circulating 24S-hydroxycholesterol (24S-OH-Chol) is derived from the brain and the absolute concentration depends on age. In the present study, concentrations of 24S-OH-Chol and for comparison 27-OH-Chol were determined by a highly sensitive isotope dilution method using gas chromatography-mass spectrometry in serum samples from normal preterm and term neonates and those with Rhesus haemolytic disease, taken serially for diagnostic purposes. Serum concentrations of cholesterol, 24S-OH-Chol and 27-OH-Chol were similar in venous versus arterial cord blood of 6 term neonates. Serum concentrations of 24S-OH-Chol and 27-OH-Chol in 12 small for gestational age (SGA) preterm neonates were significantly lower than those in 12 appropriate for gestational age (AGA) preterm neonates (p < 0.001), and also lower than those in 12 SGA (0 < 0.001) and 12 AGA term neonates (p < 0.05). Serum cholesterol was significantly higher in preterm than in term neonates (p < 0.001). 24S-OH-Chol serially determined in 8 infants with Rhesus haemolytic disease increased 5-6-fold during the first 3 mo after birth (from 42 +/- 20 ng ml(-1) to 227 +/- 71 ng ml(-1)). 27-OH-Chol increased simultaneously from 30 +/- 14 ng ml(-1) to 100 +/- 39 ng ml(-1). CONCLUSION: Serum concentrations of 24S-OH-Chol increased 5-6-fold after birth. This could be an indication of normal cholesterol metabolism in the developing neonatal brain.

Brain↗
PubMed2001

alpha-Tocopherol, but not gamma-tocopherol inhibits 7 beta-hydroxycholesterol-induced apoptosis in human U937 cells.

Oxysterols, particularly those oxidised at position 7, are toxic to cells in culture and have been shown to induce apoptosis in cell types such as vascular endothelial cells, smooth muscle cells and monocytes. The precise mechanism by which oxysterols induce apoptosis is unknown but may involve the generation of oxidative stress. In the present study we examined the ability of alpha-TOC, alpha-TOC acetate (alpha-TOCA) and gamma-TOC to protect against 7 beta-hydroxycholesterol (7 beta-OHC)-induced apoptosis of human monocytic U937 cells. 7 beta-OHC is one of the most commonly detected oxysterols in foods and its level in plasma has been positively associated with an increased risk of atherosclerosis. The present study demonstrates a significant decrease in cell membrane integrity and cellular glutathione levels when U937 cells were treated with 30 microM 7 beta-OHC. DNA fragmentation also occurred, as measured by agarose gel electrophoresis, and the number of apoptotic cells increased as assessed by nuclear morphology. Analysis by HPLC showed that there was a greater incorporation of gamma-TOC into U937 cells after a 48 h incubation, than either alpha-TOC or alpha-TOCA. However, despite the increased uptake of gamma-TOC, only alpha-TOC, and not gamma-TOC or alpha-TOCA was effective at inhibiting 7 beta-OHC-induced apoptosis in U937 cells.

Antioxidants↗
PubMed2004

Detection of lipid peroxidation in vivo: total hydroxyoctadecadienoic acid and 7-hydroxycholesterol as oxidative stress marker.

It is important to assess the oxidative injury in vivo accurately and inclusively, as the oxidative stress induced by various oxidants in a random and destructive fashion is considered to play an important role in the pathophysiology of a number of human disorders and diseases. We have developed an improved method for the measurement of lipid peroxidation in vivo, where total hydroxyoctadecadienoic acids (HODE) and 7-hydroxycholesterol (FCOH) were determined by GC/MS analysis from physiological samples after reduction with sodium borohydride and saponification by potassium hydroxide. In this method, both free and ester forms of hydroperoxides and ketones as well as hydroxides of linoleate and cholesterol are measured as HODE and FCOH, respectively. The ratio of stereo-isomers, (E,E)-HODE/(E,Z)-HODE, could be also measured. The plasma concentrations of total HODE were obtained as 76.5, 666 and 2225 nM for human, rat and mouse, respectively. It was found that HODE and FCOH could be measured satisfactorily by the present method from plasma, erythrocyte and urine of humans and experimental animals. It was also found that HODE in urine arose from both free and ester forms, while 8-iso-prostaglandin F2alpha was present primarily as a free acid form. As the concentrations of HODE were much higher than 8-iso-prostaglandin F2alpha, HODE may well be used as a good oxidative marker in vivo.

Adult↗
PubMedDate not supplied

Involvement of calcium in 7beta -hydroxycholesterol and cholesterol-5beta,6beta -epoxide-induced apoptosis.

Oxidized low-density lipoprotein (oxLDL) is believed to play a central role in the development of atherosclerosis. The induction of apoptosis in cells of the arterial wall is a critical event in the development of atheroma. 7beta-Hydroxycholesterol (7beta-OH) and cholesterol-5beta,6beta-epoxide (beta-epoxide) are components of oxLDL and have previously been shown to be potent inducers of apoptosis. The exact mechanism through which these oxysterols induce apoptosis remains to be fully elucidated. A perturbation of intracellular calcium homeostasis has been found to trigger apoptosis in many experimental systems. The aim of the present study was to determine the involvement of calcium signaling in 7beta-OH and beta-epoxide-induced apoptosis. To this end, the authors employed the calcium channel blockers verapamil and nifedipine and inhibitors of calpain activation, ALLM and ALLN. Verapamil protected against the decrease in viability induced by 7beta-OH whereas nifedipine had a protective effect in both 7beta-OH and beta-epoxide-treated cells, though these compounds did not restore viability to control levels. Verapamil, nifedipine, and ALLM prevented apoptosis induced by beta-epoxide. None of the compounds employed in the current study protected against 7beta-OH-induced apoptosis. Our results implicate calcium signaling in the apoptotic pathway induced by beta-epoxide and also highlight differences between apoptosis induced by 7beta-OH and beta-epoxide.

Apoptosis↗
PubMed2002

Insufficient dietary vitamin e increases the concentration of 7beta-hydroxycholesterol in tissues of rats fed salmon oil.

This study was conducted to determine the interaction between the type of dietary fat (coconut oil or salmon oil) and the vitamin E concentration of the diet [10, 20, 40 or 240 mg alpha-tocopherol equivalents (alpha-toc)/kg] in relation to the concentration of 7beta-hydroxycholesterol (7beta-OH) in liver, plasma, LDL and erythrocytes of rats. In the rats whose diet contained salmon oil, the concentration of 7beta-OH was dependent on the dietary vitamin E concentration. Rats whose diet contained 10 mg alpha-toc/kg had significantly higher concentrations of 7beta-OH in all samples studied than those whose diet contained 20, 40 or 240 mg alpha-toc/kg. Increasing the dietary vitamin E concentration from 40 to 240 mg alpha-toc/kg did not reduce the concentration of 7beta-OH in any samples. In the rats whose diet contained coconut oil, the concentration of 7beta-OH was independent of the dietary vitamin E concentration in all samples. The study shows that insufficient vitamin E in the diet increases the formation of 7beta-OH in rats fed salmon oil, whereas a dietary vitamin E supply in excess of the requirement does not lower 7beta-OH concentrations compared with an adequate vitamin E supply.

Animals↗
PubMed2002

Testosterone regulates 25-hydroxycholesterol production in testicular macrophages.

Recently, we found that testicular macrophages produce 25-hydroxycholesterol (25-HC) and express 25-hydroxylase, the enzyme that converts cholesterol to 25-HC. In addition, 25-HC may be an important paracrine factor mediating the known interactions between macrophages and neighboring Leydig cells, because it is efficiently converted to testosterone by Leydig cells. The purpose of the present study was to determine if testosterone can regulate the production of 25-HC in rat testicular macrophages, representing a potential negative-feedback loop from Leydig cells. We found that expression of 25-hydroxylase mRNA and production of 25-HC by cultured testicular macrophages were significantly inhibited by testosterone at 10 micro g/ml. This dose of testosterone did not have an effect on cell viability and did not change the rate of mRNA degradation in the presence of actinomycin D. These studies indicate that production of 25-HC is negatively regulated by testosterone, which may be representative of a paracrine negative-feedback loop.

Animals↗
PubMed1987

The effect of human chorionic gonadotropin, dibutyryl cyclic adenosine 3',5'-monophosphate, prostaglandins, and 25-hydroxycholesterol on acute progesterone secretion by dissociated rabbit luteal cells in vitro: evidence for independent effect of human chorionic gonadotropins and lipoproteins.

Although estradiol is the established luteotropic hormone in the rabbit, the corpus luteum also contains a luteinizing hormone (LH)-activated adenylate cyclase system and cyclic adenosine 3',5'-monophosphate (cAMP)-dependent protein kinase, which suggests that LH and cAMP may play a physiological role in regulating luteal progesterone production. The present study examined whether human chorionic gonadotropin (hCG) and cAMP derivatives stimulate progesterone production by dispersed rabbit luteal cells in static and perifusion incubations. Results of this study show that progesterone production by rabbit luteal cells is significantly stimulated (p less than 0.05) by hCG concentrations at or greater than 0.1 IU/ml or by dibutyryl cAMP concentrations at or greater than 5 mM. Both agents produce maximal stimulations of approximately 4-fold. However, neither prostaglandin E2 or F2 alpha at concentrations of 0.1-3.0 micrograms/ml altered progesterone secretion. When luteal cells were incubated with maximal concentrations of hCG and lipoproteins together, the resultant progesterone secretion was additive. This suggests that the effects of hCG and lipoprotein are independent. Both responses could be blocked completely by cycloheximide (10(-4) M), and thus appear to be dependent on protein synthesis. The cholesterol derivative 25-hydroxycholesterol (20 micrograms/ml) partially overcame the steroidogenic block by cycloheximide, suggesting that transport of cholesterol, regardless of its origin, into mitochondria was an essential protein-mediated event in these cells. Inhibition of the side-chain-cleavage enzyme by aminoglutethamide blocked progesterone production by rabbit luteal cells in vitro. Although estradiol may dominate in the regulation of luteal progesterone production physiologically, this study clearly demonstrates that potential mechanisms do exist in the rabbit corpus luteum for cAMP-mediated stimulation of progesterone production in the rabbit.

Animals↗
PubMed1994

25-Hydroxycholesterol induces reorganization of lysosomes in normal but not Niemann-Pick disease type C astrocytes.

25-hydroxycholesterol (25-OHC), an oxysterol that potently regulates cellular cholesterol metabolism, induced formation of novel fibrillar structures in normal mouse astrocytes as observed by fluorescence microscopy with the cholesterol probe, filipin. These fibrils were identified as lysosomes by their immunoreactivity for the lysosome associated membrane glycoprotein (LAMP). In contrast, astrocytes derived from the Niemann-Pick disease type C (NPC) mutant mouse were resistant to this oxysterol-induced lysosomal reorganization. NPC astrocytes have abnormal intracellular cholesterol storage as observed by brightly positive filipin staining of their lysosomes. These results show that lysosomal cholesterol storage in NPC astrocytes is associated with a block in oxysterol-mediated fibrillar reorganization of lysosomes.

Animals↗
PubMed2005

Inhibition of cholesterol biosynthesis by 25-hydroxycholesterol is independent of OSBP.

25-hydroxycholesterol (25-HC) is a potent suppressor of cholesterol synthesis gene transcription in cultured cells. A high affinity binding protein for 25-HC, oxysterol-binding protein (OSBP), has been identified from tissue cytosol. OSBP translocates from the cytosol to the Golgi apparatus membranes after addition of 25-HC to cell cultures and is thought to mediate 25-HC action on cholesterol metabolism through association to the Golgi apparatus. However, direct evidence to prove this hypothesis was lacking. In this study, we knocked down expression of OSBP by using duplex siRNAs specific for OSBP to examine the relationship between OSBP and 25-HC-induced inhibition of cholesterol synthesis gene transcription. We found that decreasing OSBP expression by approximately 90% did not affect 25-HC-induced inhibition of transcription of 3-hydoxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase and squalene epoxidase to any extent. Exogenous lysophosphatidylcholine (LPC), which is known to cause the efflux of cellular cholesterol into the medium and to increase cholesterol synthesis, was found to rescue the 25-HC-induced down-regulation of sterol regulated genes, while LPC did not affect 25-HC-induced association of OSBP with the Golgi apparatus. These results suggest that inhibition of cholesterol biosynthesis genes by 25-HC is OSBP-independent.

Cholesterol↗
PubMed2004

25-hydroxycholesterol acts in the Golgi compartment to induce degradation of tyrosinase.

Oxysterols play a significant role in cholesterol homeostasis. 25-Hydroxycholesterol (25HC) in particular has been demonstrated to regulate cholesterol homeostasis via oxysterol-binding protein and oxysterol-related proteins, the sterol regulatory element binding protein, and the rate-limiting enzyme of cholesterol biosynthesis, hydroxymethylglutaryl coenzyme A reductase. We have examined the effect of 25HC on pigmentation of cultured murine melanocytes and demonstrated a decrease in pigmentation with an IC(50) of 0.34 microM and a significant diminution in levels of melanogenic protein tyrosinase. Pulse-chase studies of 25HC-treated cells demonstrated enhanced degradation of tyrosinase, the rate-limiting enzyme of melanin synthesis, following endoplasmic reticulum (ER) and Golgi maturation. Protein levels of GS28, a member of an ER/cis-Golgi SNARE protein complex, were also diminished in 25HC-treated melanocytes, however levels of the ER chaperone calnexin and the cis-Golgi matrix protein GM130 were unaffected. Effects of 25HC on tyrosinase were completely reversed by 4 alpha-allylcholestan-3 alpha-ol, a sterol identified by its ability to reverse effects of 25HC on cholesterol homeostasis. Finally, the addition of 25HC to lipid deficient serum inhibited correct processing of tyrosinase. We conclude that 25HC acts in the Golgi compartment to regulate pigmentation by a mechanism shared with cholesterol homeostasis.

Animals↗
PubMed2005

Oxysterol 22(R)-hydroxycholesterol induces the expression of the bile salt export pump through nuclear receptor farsenoid X receptor but not liver X receptor.

Oxysterols are intermediates in the synthesis of bile acids and steroid hormones from cholesterol and function as ligands for liver X receptor (LXR). Bile salt export pump (BSEP) is responsible for canalicular secretion of bile acids and is tightly regulated by its substrates bile acids through nuclear receptor farnesoid X receptor (FXR). In a microarray study using human hepatocytes, BSEP was markedly induced not only by chenodeoxycholic acid (CDCA) but also by oxysterol 22(R)-hydroxycholesterol [22(R)-OHC]. We hypothesized that the expression of BSEP was induced by oxysterols through activation of LXR. To test the hypothesis, human primary hepatocytes or hepatoma cells were treated with 22(R)-OHC, and expression of BSEP was determined. The level of BSEP mRNA was increased as much as 5-fold upon oxysterol induction. In contrast to our hypothesis, the oxysterol-induced up-regulation of BSEP is mediated through FXR but not LXR. BSEP promoter activity was markedly induced by 22(R)-OHC in the presence of FXR but not LXRs. Mutation of the FXR element IR1 in the BSEP promoter significantly reduced its ability to respond to oxysterol induction. To determine whether 22(R)-OHC and CDCA bind to similar structural features of FXR, site-directed mutagenesis was performed in the FXR ligand binding domain. Mutation of residues R331 and I352 abolished activation mediated by CDCA and 22(R)-OHC. In contrast, substitution of residues L340 and R351 differentiated CDCA- and 22(R)-OHC-mediated activation. In conclusion, oxysterol 22(R)-OHC functions as an FXR ligand to induce BSEP expression and differs in the binding with FXR from CDCA.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2003

Effects of dietary 27-hydroxycholesterol on cholesterol metabolism and bile acid biosynthesis in the hamster.

27-hydroxycholesterol (27OH-Chol) is an important endogenous oxysterol resulting from the action of sterol 27-hydroxylase (CYP27A1) on cholesterol in the liver and numerous extrahepatic tissues. It may act as a modulator of cholesterol and bile acid metabolism. The effects of 27OH-Chol on the main enzymes and receptors of cholesterol metabolism were investigated by feeding male hamsters a diet supplemented with 27OH-Chol (0.1% w/w) for 1 week. Intestinal scavenger class B, type I (SR-BI) protein level was decreased (-65%), but hepatic expression was increased (+34%). Liver 3beta-hydroxy-3beta-methyl glutaryl coenzyme A reductase (-58%), cholesterol 7alpha-hydroxylase (-54%), oxysterol 7alpha-hydroxylase (-44%), and sterol 12alpha-hydroxylase (-70%) activities were all decreased. Bile acid composition was changed (fourfold increase in the chenodeoxycholic/cholic acid ratio). This study demonstrates that dietary 27OH-Chol modulates major enzymes of cholesterol metabolism and alters the biliary bile acid profile, making it more hydrophobic, at least at this level of intake. Its effects on SR-BI protein levels are organ dependent. The properties of 27OH-Chol or its metabolites on cholesterol metabolism probably result from the activation of specific transcription factors.

Animals↗
PubMed1999

25-hydroxycholesterol increases eicosanoids and alters morphology in cultured pulmonary artery smooth muscle and endothelial cells.

25-hydroxycholesterol (25-OHC) is an oxidized derivative of cholesterol that has been implicated in the early development of arteriosclerosis. Changes in arterial smooth muscle cell (SMC) migration and proliferation have also been linked to the pathophysiology of arteriosclerosis. SMCs undergo "activation" in response to vascular injury by changing phenotypically and by increasing prostaglandin G/H synthase-2 (PGHS-2) protein levels and eicosanoid release. Activation is thought to be important in atheroma formation and arteriosclerosis progression. 25-OHC induces SMCs to change morphologically, increase PGHS-2, and increase eicosanoid release. Confluent monolayers were treated with 25-OHC (10 microg/mL) or the PGHS-2 inducer interleukin-1beta (1 ng/mL) for 18 hours at 37 degrees C. The 18-hour treatment resulted in morphological changes. After uptake of [(14)C]arachidonic acid, released radiolabeled arachidonic acid products were extracted and chromatographed by both normal and reverse-phase high-performance liquid chromatography systems. 25-OHC-treated cells increased their prostaglandin production, with the major component comigrating with a prostaglandin-E(2) standard. HETEs and epoxyeicosatrienoic acids were not affected. Immunoprecipitation analysis of treated and control cell lysates using anti-PGHS-1 and -2 and anti-alpha-actin primary antibodies indicated PGHS-2 induction over control and no change in contractile proteins. These changes are consistent with SMC activation, which occurs in vascular injury models. The notion that oxysterols can activate vascular SMCs may be important in ultimately understanding the pathophysiology of atheroma formation.

Actins↗