Biological activities of oxysterols

Smith, Leland L.; Johnson, Betty H.

doi:10.1016/0891-5849(89)90136-6

Cited by 324 publications

(166 citation statements)

References 381 publications

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“…37 It has been suggested that free radical-mediated processes, which include cholesterol as a target for oxidative modification, play an important role in the pathogenesis of atherosclerosis. 21 Cholesterol oxidation products may be one of the agents responsible not only for vascular injury as discussed above but may also be responsible for the inhibition of NO production by the vascular endothelium. 38 There is evidence that the lipoxygenase pathway is a mediator of angiotensin II, implicating a role for humoral factors such as angiotensin II in mediating oxidative stress responses in the vessel wall.…”

Section: Discussionmentioning

confidence: 99%

“…[11][12][13][14][15][16] Because cholesterol oxides (ChOx) have been ubiquitously identified in human plasma and atheromatous lesions, their involvement in the atherogenic process is receiving increasing scrutiny. [17][18][19][20][21] ChOx may influence the atherogenic process in several ways, since they are cytotoxic toward the cellular components of the arterial wall, [22][23][24] increase vascular permeability, 25 promote cholesterol ester formation and accumulation, 26 -28 inhibit prostaglandin I 2 synthesis by endothelial cells, 29 and perturb cholesterol biosynthesis. 30,31 Previously, we and others have shown that cholesterol feeding of New Zealand White rabbits leads to increased plasma and aortic wall cholesterol oxide content, 7,32 which is reduced with the antioxidant agent probucol.…”

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confidence: 99%

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Probucol Reduces Oxysterol Formation in Hypertensive Rabbits

et al. 2000

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Abstract-The role of lipid peroxidation during the pathogenesis of atherosclerosis has been described through numerous studies and has provided compelling evidence for free radical-mediated processes that link hypertension with atherosclerosis. However, there remains only limited information concerning peroxidative processes in hypertension and their modulation by antioxidants. In the present study, the formation of cholesterol oxidation products was used as a measure of in vivo lipid peroxidation after hypertension induced by coarctation of the aorta in New Zealand White rabbits. The rabbits were fed a standard chow diet devoid of cholesterol or cholesterol oxidation products such that the measured cholesterol oxides in the plasma and aortic tissues would most plausibly arise from endogenous oxidation of cholesterol. After 12 weeks of hypertension, all of the measured cholesterol oxides increased significantly over baseline levels in the surgically coarctated animals; however, this increase was significantly less in hypertensive probucol-treated animals. Similarly, the cholesterol oxide content of aortic tissue from the surgically coarctated animals was significantly greater than that found in normotensive control aortas, and probucol treatment significantly reduced the increase in cholesterol oxide content of aortic tissue relative to that of hypertensive animals not receiving the antioxidant. These findings in hypertensive animals suggest that cholesterol oxidation products measured in plasma and aortic tissue can be derived from endogenous free radical activity and that this activity is enhanced under specific pathological conditions. (Hypertension. 2000;36:436-441.)

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Probucol Reduces Oxysterol Formation in Hypertensive Rabbits

et al. 2000

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“…Finally, 22(R)-hydroxycholesterol is present in adrenal extracts at micromolar concentrations. Other oxysterols are present in the circulation or in tissue extracts at concentrations that are nanomolar or lower (25).…”

Section: (S)25-epoxycholesterol and 24(s)-hydroxycholesterol Are Pmentioning

confidence: 99%

Activation of the Nuclear Receptor LXR by Oxysterols Defines a New Hormone Response Pathway

Lehmann¹,

Kliewer²,

Moore³

et al. 1997

Journal of Biological Chemistry

1,120

847

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Accumulation of cholesterol causes both repression of genes controlling cholesterol biosynthesis and cellular uptake and induction of cholesterol 7␣-hydroxylase, which leads to the removal of cholesterol by increased metabolism to bile acids. Here, we report that LXR␣ and LXR␤, two orphan members of the nuclear receptor superfamily, are activated by 24(S),25-epoxycholesterol and 24(S)-hydroxycholesterol at physiologic concentrations. In addition, we have identified an LXR response element in the promoter region of the rat cholesterol 7␣-hydroxylase gene. Our data provide evidence for a new hormonal signaling pathway that activates transcription in response to oxysterols and suggest that LXRs play a critical role in the regulation of cholesterol homeostasis.Cholesterol (CH) 1 is a major structural constituent of cellular membranes and serves as the biosynthetic precursor for bile acids and steroid hormones. Animal cells can obtain CH endogenously through de novo synthesis from acetyl-CoA or exogenously through receptor-mediated endocytosis of low density lipoproteins. Cells must balance the internal and external sources of CH so as to maintain mevalonate biosynthesis while at the same time avoiding the accumulation of excess CH, which can result in diseases such as atherosclerosis, gallstones, and several lipid storage disorders (1).CH homeostasis is maintained in part through feedback regulation of the low density lipoprotein receptor gene and at least two genes encoding enzymes in the CH biosynthetic pathway, 3-hydroxy-3-methylglutaryl coenzyme A synthase and 3-hydroxy-3-methylglutaryl coenzyme A reductase (1). Although increases in dietary CH lead to the inhibition of expression of these genes in vivo, it remains unclear whether CH or CH metabolites are responsible for this inhibition (2). Experiments performed in vitro using several different cell lines have indicated that derivatives of CH that are oxygenated on the CH side chain are significantly more potent in the suppression of sterol biosynthesis than CH (3). These oxysterols are produced through the actions of P450 enzymes in various metabolic pathways including bile acid synthesis in the liver and sex hormone synthesis in the adrenal glands. The in vitro activities of oxysterols together with their presence in vivo suggests that oxysterols may serve in metabolic feedback loops to regulate CH homeostasis.Although CH and its oxysterol metabolites can repress gene transcription, in at least one instance dietary CH has been shown to stimulate gene expression. Expression of the cholesterol 7␣-hydroxylase (CYP7A) gene, which encodes the enzyme responsible for the initial and rate-limiting step in the conversion of CH to bile acids (4), is up-regulated in rats fed a CH-rich diet (5-7). This stimulatory effect provides a regulatory mechanism whereby excess dietary CH can be converted to more polar bile acids for subsequent removal from the body. Although the molecular mechanism is unknown, induction of CYP7A expression in the presence of CH occurs at the level...

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“…Oxysterols are able to elicit changes in cholesterol synthesis, cell growth, and membrane composition, and can cause immunosuppression (3)(4)(5)(6)(7)(8). These activities have led to many studies of oxysterols, usually as toxins in the environment and foods (9,10), or as implicated in atherosclerosis (11)(12)(13)(14).…”

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confidence: 99%

Structure‐apoptotic potency evaluations of novel sterols using human leukemic cells

Johnson

Russell

Крылов

et al. 2000

Lipids

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Three oxidized analogs of cholesterol have been characterized for their ability to cause apoptotic cell death in CEM-C7-14 human leukemic cells. In addition to testing 15-ketocholestenol (K15), 15-ketocholestenol hydroxyethyl ether (CK15), and 7-ketocholesterol hydroxyethyl ether (CK7), an oxysterol of known apoptotic response, 25-hydroxycholesterol (25OHC), served as a standard for comparison. Growth studies based on dye exclusion by viable cells while using a sublethal concentration of oxysterols ranked their potency for cell kill as 25OHC > K15 > CK15 > CK7. Both the TUNEL assay (terminal deoxynucleotidyl transferase-mediated dUTP-X nick end labeling), which quantifies the amount of DNA nicks caused by a toxic agent, and the MTT assay, which measures cell metabolism and thus reflects cell viability, substantiated the same rank order. An ELISA assay for evaluating release of DNA fragments into the cytosol after treatment gave a similar potency order. The oncogene c-myc mRNA was suppressed by all three oxysterols, with 25OHC and K15 being the most potent suppressors. Hoechst and Annexin V staining documented that these oxysterols kill cells by an apoptotic pathway as evidenced by condensation of nuclear chromatin and plasma membrane inversion, respectively. From these in vitro studies, we believe that 25OHC, K15, and possibly CK15 have the potential to be chemotherapeutic agents.Paper no. L8259 in Lipids 35, 305-315 (March 2000).Both glucocorticoids and oxysterols can cause apoptosis of certain cells. For this action, glucocorticoids require a specific cytosolic protein, the glucocorticoid receptor (GR). No oxysterol receptor has been unequivocally identified, although two cellular proteins do specifically bind oxysterols: the oxysterol binding protein (OBP) and LXR, a member of the nuclear receptor family of proteins. As yet it is not certain that either protein is required for oxysterols' apoptotic actions. In our test system, the human leukemic cell line CEM, analysis of the events following addition of either class of steroid shows similarities at several points. These include a delay of about 1 d before the activation of caspases and nucleases, which occurs around the time of overt apoptosis. During this initial phase of cell death when the steroidal effects can be reversed, both types of steroids cause profound suppression of the oncogene product, cMyc (1,2). Because of their apoptotic action, glucocorticoids are used widely as antileukemic drugs. The similarity of effects of oxysterols suggests that they also might have therapeutic usefulness, alone, or in conjunction with glucocorticoids. Oxysterols are able to elicit changes in cholesterol synthesis, cell growth, and membrane composition, and can cause immunosuppression (3-8). These activities have led to many studies of oxysterols, usually as toxins in the environment and foods (9,10), or as implicated in atherosclerosis (11-14). The relatively greater sensitivity of certain malignant, as opposed to normal, cells offers an opportunity to use...

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Biological activities of oxysterols

Cited by 324 publications

References 381 publications

Probucol Reduces Oxysterol Formation in Hypertensive Rabbits

Probucol Reduces Oxysterol Formation in Hypertensive Rabbits

Activation of the Nuclear Receptor LXR by Oxysterols Defines a New Hormone Response Pathway

Structure‐apoptotic potency evaluations of novel sterols using human leukemic cells

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