Increased plasma levels of oxysterols, in vivo markers of oxidative stress, in patients with familial combined hyperlipidemia: Reduction during atorvastatin and fenofibrate therapy

Arca, Marcello; Natoli, Silvia; Micheletta, Fausta; Riggi, Sara; Angelantonio, Emanuele Di; Mestice, Anna; Antonini, Térésa; Antonini, R; Diczfalusy, Ulf; Iuliano, Luigi

doi:10.1016/j.freeradbiomed.2006.12.013

Cited by 76 publications

(57 citation statements)

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“…Our work was aimed at the analysis of the cytotoxic effects of oxysterols at the molecular level in liver-derived cell lines. Previous studies on oxysterol-mediated cell cytotoxicity were carried out using concentrations between 10 À4 and 10 À5 M, largely exceeding the highest concentrations found in human plasma (ranging from 0.2 to 2 Â 10 À7 M) (Savouret et al, 2001;Arca et al, 2007). The concentrations used in the present study (from 10 À9 to 10 À5 M) are closer to physiological concentrations and have been previously reported in human diseases, such as atherosclerosis, myocardial infarction, and chronic hepatitis (Biasi et al, 2004;Corradini et al, 2005).…”

Section: Latina Italysupporting

confidence: 51%

“…High concentrations of 7-K cause oxidative burst that occurs very early after cell intoxication and may lead to programmed cell death (Lemaire et al, 1998;Leonarduzzi et al, 2006). 7-K, a major sterol constituent of plasma in humans, was detected at concentrations ranging between 0.2 and 2 Â 10 À7 M in patients (Savouret et al, 2001;Arca et al, 2007). Unfortunately, actually, a bias exists between the experimental protocols used to investigate oxysterols effects in in vitro studies and the species and amounts present in vivo.…”

Section: Discussionmentioning

confidence: 99%

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7‐ketocholesterol and 5,6‐secosterol modulate differently the stress‐activated mitogen‐activated protein kinases (MAPKs) in liver cells

Anticoli

Arciello

Mancinetti

et al. 2009

Journal Cellular Physiology

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Enhanced oxidative stress is a common feature of liver diseases and contributes to chronic liver disease (CLD) progression by inducing fibrogenesis during liver regeneration. Peroxidation products of cholesterol metabolism, named oxysterols, are new and reliable markers of oxidative stress in vivo. Patients affected by CLDs present high plasma levels of oxysterols, raising the question of the origin and biological relevance of these compounds in the pathophysiology of chronic liver damage. The aim of this study was to examine the molecular basis of the biological effects of oxysterols on liver-derived cells, HepG2 and Huh7. Cells were treated with different concentrations (10(-9) to 10(-5) M) of 7-ketocholesterol used as a reference, and 5,6-secosterol, a recently discovered oxysterol. FACS investigations, caspase-3 activation, and Sytox Green immunofluorescent assay showed that pathological concentrations of oxysterols induced necrosis (30-50%) after 48 h of treatment. The two analyzed compounds displayed a similar, but not identical, behavior. In fact, 5,6-secosterol, but not 7-ketocholesterol, induced cell senescence. Notably, low concentrations of 5,6-secosterol caused a sustained activation of ERK1/2, inducing cell proliferation, this unexpected behavior should be better characterized by further studies. Since enhanced oxidative stress is known to worsen liver chronic hepatitis and frequently results in overall decreased cellular survival, our data suggest the important and different role oxysterols may have in interfering with physiological liver tissue regeneration in injured human liver. Antioxidant treatment may provide a highly specific and effective mean to counteract the common consequences of oxidative stress on chronic hepatitis, such as fibrosis/cirrhosis and liver failure.

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Section: Latina Italysupporting

confidence: 51%

Section: Discussionmentioning

confidence: 99%

7‐ketocholesterol and 5,6‐secosterol modulate differently the stress‐activated mitogen‐activated protein kinases (MAPKs) in liver cells

Anticoli

Arciello

Mancinetti

et al. 2009

Journal Cellular Physiology

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“…Larsson et al (2006) showed that increased levels of 7β-HC and 7-KC may play an important role in the induction of oxidative stress in atheroma plaques by stimulating production of ROS and decreasing cellular antioxidants. Increased COPs levels (mainly 7-KC and 7β-HC) have been reported in disease states where oxidative stress was increased such as diabetes mellitus (Abo et al, 2000) or familial combined hyperlipidemia (Arca et al, 2007). In addition, significantly higher concentrations of blood COPs were found in the blood of diabetic and hypercholesterolemic patients than in the blood of control subjects (Szuchman et al, 2008).…”

Section: Atherosclerosis Induced By Oxysterolsmentioning

confidence: 97%

Oxysterols: A world to explore

Otaegui-Arrazola

Menéndez-Carreño

Ansorena

et al. 2010

Food and Chemical Toxicology

198

181

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Oxysterols (oxidized derivatives of cholesterol an phytosterols) can be generated in the human organism through different oxidation processes, some requiring enzymes.Furthermore, oxysterols are also present in food due to lipid oxidation reactions caused by heating treatments, contact with oxygen, exposure to sunlight, etc., and they could be absorbed from the diet, at different rates depending on their side chain lenght.In the organism, oxysterols can follow different routes: secreted into the intestinal lumen, esterified and distributed by lipoproteins to different tissues or degraded, maily in the liver. Cholesterol oxidation products (COPs) have shown citotoxicity, apoptotic and pro-inflammatory effects and they have also been linked with chronic diseases including atherosclerotic and neurodegenerative processess. In the case of phytosterols oxidation products (POPs), the evidences for toxic effects need more research. Nevertheless, current knowledge suggest their relation to cytotoxic and proapoptotic effects, although at higher concentrations than COPs.Recently, new beneficial biological activities of oxysterols are being under research. Whereas COPs are associated with cholesterol homeostasis mediated by different mechanisms, the implication of POPs is not clear yet.Available literature on sources of oxysterols in the organism, metabolism, toxicity and potential benefitial effects of these compounds are reviewed in this paper.2

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“…Both cholesterol-rich foods of animal origin and human plasma are known to contain appreciable levels of oxysterols, which may be either absorbed from the diet or formed in vivo [1][2][3][4][5]. The involvement of oxysterols in the pathogenesis of atherosclerosis has widely been studied because of the ability of certain oxysterols to induce apoptosis in cells of the vascular wall.…”

Section: Introductionmentioning

confidence: 99%

The role of calcium in apoptosis induced by 7β‐hydroxycholesterol and cholesterol‐5β,6β‐epoxide

Lordan

O’Brien

Mackrill

2009

J Biochem & Molecular Tox

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Oxysterols, such as 7beta-hydroxy-cholesterol (7beta-OH) and cholesterol-5beta,6beta-epoxide (beta-epoxide), may have a central role in promoting atherogenesis. This is thought to be predominantly due to their ability to induce apoptosis in cells of the vascular wall and in monocytes/macrophages. Although there has been extensive research regarding the mechanisms through which oxysterols induce apoptosis, much remains to be clarified. Given that experimental evidence has long associated alterations of calcium (Ca(2+)) homeostasis to apoptotic cell death, the aim of the present study was to determine the influence of intracellular Ca(2+) changes on apoptosis induced by 7beta-OH and beta-epoxide. Ca(2+) responses in differentiated U937 cells were assessed by epifluorescence video microscopy, using the ratiometric dye fura-2. Over 15-min exposure of differentiated U937 cells to 30 muM of 7beta-OH induced a slow but significant rise in fura-2 ratio. The Ca(2+) channel blocker nifedipine and the chelating agent EGTA blocked the increase in cytoplasmic Ca(2+). Moreover, dihydropyridine (DHP) binding sites identified with BODIPY-FLX-DHP were blocked following pretreatment with nifedipine, indicating that the influx of Ca(2+) occurred through L-type channels. However, following long-term incubation with 7beta-OH, elevated levels of cytoplasmic Ca(2+) were not maintained and nifedipine did not provide protection against apoptotic cell death. Our results indicate that the increase in Ca(2+) may be an initial trigger of 7beta-OH-induced apoptosis, but following chronic exposure to the oxysterol, the influence of Ca(2+) on apoptotic cell death appears to be less significant. In contrast, Ca(2+) did not appear to be involved in beta-epoxide-induced apoptosis.

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Increased plasma levels of oxysterols, in vivo markers of oxidative stress, in patients with familial combined hyperlipidemia: Reduction during atorvastatin and fenofibrate therapy

Cited by 76 publications

References 47 publications

7‐ketocholesterol and 5,6‐secosterol modulate differently the stress‐activated mitogen‐activated protein kinases (MAPKs) in liver cells

7‐ketocholesterol and 5,6‐secosterol modulate differently the stress‐activated mitogen‐activated protein kinases (MAPKs) in liver cells

Oxysterols: A world to explore

The role of calcium in apoptosis induced by 7β‐hydroxycholesterol and cholesterol‐5β,6β‐epoxide

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