Abstract
Graphical abstract
Abstract
7-Ketocholesterol (or 7-oxocholesterol) is an oxysterol essentially formed by cholesterol autoxidation. It is often found at enhanced levels in the body fluids and/or target tissues of patients with age-related diseases (cardiovascular, neuronal, and ocular diseases) as well as in subjects concerned with civilization diseases (type 2 diabetes, bowel diseases, and metabolic syndrome). The involvement of increased 7-ketocholesterol levels in the pathophysiology of these diseases is widely suspected. Indeed, 7-ketocholesterol at elevated concentrations is a powerful inducer of oxidative stress, inflammation, and cellular degeneration which are common features of all these diseases. It is important to better know the origin of 7-ketocholesterol (diet, incidence of environmental factors, and endogenous formation (autoxidation and enzymatic synthesis)) and its inactivation mechanisms which include esterification, sulfation, oxidation, and reduction. This knowledge will make it possible to act at different levels to regulate 7-ketocholesterol level and counteract its toxicity in order to limit the incidence of diseases associated with this oxysterol. These different points as well as food and biomedical applications are addressed in this review.
Introduction
7-ketocholesterol (7KC; C27H44O2; PubChem CID 91474; also named 7-oxocholesterol) is a lipid molecule. It is a cholesterol oxide derivative (oxysterol) essentially resulting from the autoxidation of cholesterol which is the most abundant member of a family of polycyclic compounds known as sterols. 7KC was first identified in large quantities in oxidized low-density lipoproteins (LDLox) and in atherosclerotic plaques (Brown & Jessup 1999, Vejux & Lizard 2009). It is also present in high quantities in the retina of patients with age-related macular degeneration (AMD) (Rodríguez & Larrayoz 2010) and in the cortex of Alzheimer’s patients (Testa et al. 2016). The contribution of 7KC to Alzheimer’s disease is well documented (Mahalakshmi et al. 2021). 7KC is also increased in the plasma of sarcopenic patients (Ghzaiel et al. 2021b ). 7KC is also elevated in plasma and tissues of patients with rare diseases such as Smith–Lemli–Opitz syndrome (SLO) (PMID: 26976653), Nieman Pick disease type C (PMID: 29626102), and type B (PMID: 31009661), as well as in patients with severe forms of X-linked adrenoleukodystrophy (X-ALD, PMID: 300100) (Nury et al. 2017). In vitro, 7KC induces oxidative stress, as well as cytokinic and non-cytokinic inflammation, often leading to an apoptotic mode of cell death associated with autophagy criteria. The type of cell death frequently induced by 7KC, as well as by other cytotoxic oxysterols (7β-hydroxycholesterol, 24S-hydroxycholesterol, 25-hydroxycholesterol, 5,6 epoxycholesterol isomers), is defined as oxiapoptophagy (Nury et al. 2021b ) and has been observed on different cell types: human monocytic U397 cells (Monier et al. 2003), human myeloma cells (Jaouadi et al. 2021), nerve cells (158N oligodendrocytes (Nury et al. 2014, 2015), murine microglial BV-2 cells (Nury et al. 2017), murine neuronal N2a-cells (Yammine et al. 2020), human bone marrow mesenchymal stem cells (Paz et al. 2019), and L929 mouse fibroblast cells (You et al. 2021). Currently, due to the ability of 7KC to trigger cytotoxic activities (oxidative stress, inflammation, cell death induction) characterizing frequent age-related diseases (cardiovascular, ocular, and neurodegenerative diseases), the involvement of this oxysterol in the pathophysiology of these illnesses is well accepted (Zarrouk et al. 2014, Samadi et al. 2021). Consequently, to efficiently treat these highly disabling diseases which have a high cost for society, a better knowledge of the production and inactivation of 7KC is required. However, if 7KC is mainly studied for its cytotoxic activities, this should not lead to ignore that this molecule could also have beneficial effects on the immune response, control of infectious diseases, and cell proliferation and differentiation (Lembo et al. 2016, de Freitas et al. 2021, Ghzaiel et al. 2021a ).
Cholesterol and related sterols autoxidation: formation of 7-ketocholesterol
Cholesterol autoxidation falls within the lipid peroxidation field. Cholesterol oxide derivatives (also named oxysterols) are 27 carbons molecules formed by the addition of oxygen to the cholesterol molecule (an overview of oxysterols formation is provided on the LipidWeb website: https://lipidmaps.org/resources/lipidweb/lipidweb_html/lipids/simple/chol-der/index.htm; May 2022). This addition of oxygen to cholesterol can be achieved by non-enzymatic and/or enzymatic reactions (Mutemberezi et al. 2016a , Brown et al. 2021). Electrochemical oxidation of cholesterol-generating numerous oxysterols, including 7KC, in a short time has also been described (Weber et al. 2016). The term autoxidation refers to non-enzymatic oxidation which can be considered as a part of chemical reactions which contribute to produce cholesterol derivatives (Morzycki 2014). For cholesterol, a distinction is made between type I autoxidation induced by reactive oxygen species (ROS such as superoxide anion (O2 ·−) and hydroxyl anion (HO·)), reactive nitrogen species (RNS such as nitric oxide (NO) and peroxynitrite ONOO·), Fenton reaction (H2O2 + Men+ → HO· + OH− + Me(n+1)+ where Me is a transition metal such as copper, iron, or aluminium) or Haber–Weiss reaction (O2 ·− + H2O2 → HO· + HO− + O2)), and type II autoxidation induced by ozone (O3), hypochlorite (HOCl), and singlet oxygen (1ΔgO2) (Iuliano 2011). The preferred site for cholesterol autoxidation is at carbon 7 where the carbon–hydrogen bond is weak (Iuliano 2011). The three oxysterols, 7-ketocholesterol (7KC), 7β-hydroxycholesterol (7β-OHC), and 7α-hydroxycholesterol (7α-OHC), are mainly formed by type I autoxidation and 7KC is the most abundant (Anderson et al. 2020, Nury et al. 2021a ) (Fig. 1A). Hydro-peroxycholesterol C4, C5, and C6 are also produced by type I autoxidation and give 4α-hydroxycholesterol (4α-OHC), 5α- or 5β-hydroxycholesterol (5α-OHC or 5β-OHC: 5α/β-hydroxycholesterol), and 6α- or 6β-hydroxycholesterol (6α-OHC or 6β-OHC: 6α/β-hydroxycholesterol), respectively (Zerbinati & Iuliano 2017) (Fig. 1B). 4β-hydroxycholesterol (4β-OHC) is enzymatically formed by CYP3A4 and CYP3A5 in humans (Diczfalusy et al. 2011, Mutemberezi et al. 2016a ). As for cholesterol epoxides (5α,6α-epoxycholesterol and 5β,6β-epoxycholesterol), which are stable molecules (Paillasse et al. 2012), they can be formed either by type I autoxidation or type II autoxidation (with O3) and can give cholestane 3β,5α,6β-triol (cholestane-triol) (Noguer et al. 2017) which can also be enzymatically formed from 5α,6α-epoxycholesterol by the cholesterol epoxide hydrolase (Ch-EH) (Iuliano 2011, Silvente-Poirot & Poirot 2012, Zerbinati & Iuliano 2017) (Fig. 1B). Noteworthy, whereas the reactions on the cholesterol side chain are mostly enzymatic reactions, 25-hydroxycholesterol (25-OHC) can be formed both by autoxidation as well as enzymatically by the enzyme 25-hydroxylase (cholesterol + AH2 + O2 ↔ 25-hydroxycholesterol + A + H2O) (Lund et al. 1998).
Production of oxysterols, including 7-ketocholesterol, by cholesterol autoxidation. (A) 7-Ketocholesterol can be formed by type I autoxidation as well as Fenton and Haber–Weiss reactions. (B) 4α-Hydroxycholesterol, 5α (or 5β)-hydroxycholesterol (5α/β-hydroxycholesterol), and 6α (or 6β)-hydroxycholesterol (6α/β-hydroxycholesterol) are formed by cholesterol autoxidation involving type I autoxidation (ROS/RNS), whereas 5α,6α-epoxycholesterol and 5β,6β-epoxycholesterol can be formed by type I autoxidation (ROS/RNS) and type II autoxidation (Ozone: O3). Triol is formed from 5α,6α epoxycholesterol or 5β,6β epoxycholesterol in an acidic environment.
Citation: Redox Experimental Medicine 2022, 1; 10.1530/REM-22-0005
Exogenous and endogenous sources of 7-ketocholesterol
Dietary origin of 7-ketocholesterol
Oxysterols formed by autoxidation, such as 7KC, are often present in high amounts in manufactured food products (Yan 1999, Rodriguez-Estrada et al. 2014, Poli et al. 2022). With the following oxysterols (7α-hydroxycholesterol (7α-OHC), 7β-hydroxycholesterol (7β-OHC), 5α,6α-epoxycholesterol (5α,6α-EPOC), 5β,6β-epoxycholesterol (5β,6β-EPOC), cholestane-3β,5α,6β-triol (cholestane-triol), and 25-hydroxycholesterol (25-OHC)), 7KC is one of the oxysterols present in significant quantities in food products of animal origin (Maraschiello et al. 1998, Petrón et al. 2003, Canzoneri et al. 2022). While 7KC is metabolized by the liver (Lyons et al. 1999), the lack of regulation on the content of cytotoxic oxysterols mainly formed by autoxidation (7KC, 7β-OHC, 5β,6β-EPOC, cholestane-triol) and present in manufactured food products constitutes a real public health problem when they are consumed regularly and in large quantities. Thus, 7KC is abundant in industrial foods associated with a complex manufacturing process involving raw materials where cholesterol is present in large quantities (butter, cream, eggs, meat, milk, milk chocolates) (Clariana & García-Regueiro 2011, Risso et al. 2021, 2022). In addition, during the industrial processes, high heating steps and exposure to air favour cholesterol autoxidation (Sabolová et al. 2017). Prolonged storage of butter, pastries, shellfish, and meat also promotes the formation of 7KC (Nielsen et al. 1996, Lee et al. 2001, Mazalli & Bragagnolo 2007, Hernández Becerra et al. 2014). In traditional cuisine, the way of cooking can also lead to more or less important 7KC formation (Echarte et al. 2005, Lee et al. 2006). It is also important to highlight that several oxysterols, including 7KC, have been identified in high quantities in baby’s and children’s foods (Sander et al. 1989, Kilvington et al. 2021). Some data support the serious consequences of oxysterols on the intellectual and physical development of children (Kilvington et al. 2021) and underline that they could promote metabolic syndrome and obesity (Guillemot-Legris et al. 2016, Mutemberezi et al. 2016b ), as well as inflammatory bowel disease (Guina et al. 2015). Therefore, in the food industry, it seems important to take appropriate measures to control and limit oxysterol levels in food. In a first step, oxysterols profile (realized by HPLC-mass spectrometry or gas chromatography-mass spectrometry) could be implemented as a guarantee of quality, safety, and nutritional value in the selection of ingredients but also during processing and storage (van de Bovenkamp et al. 1988, Razzazi-Fazeli et al. 2000, Gorassini et al. 2017). In addition, some oxysterols present in the digestive tract, such as 7KC, can also come from cholesterol-rich foods and can be the consequence of digestion in the stomach. Indeed, the acidic pH of the latter, and the presence of free iron and heme proteins, such as myoglobin provided by red meats, make it a very pro-oxidant medium which can favour cholesterol autoxidation (Kanner & Lapidot 2001, Lapidot et al. 2005). It is suggested that the presence of 7KC in the stomach could destabilize the gastric epithelial cell barrier (Gajewski et al. 2016).
Metabolic origin of 7-ketocholesterol
The production of 7KC by type I autoxidation is the most frequent and it is well established in several age-related diseases (Zarrouk et al. 2014, Zerbinati & Iuliano 2017, Nury et al. 2021a ). However, 7KC can also be obtained enzymatically (Fig. 2). Thus, 7KC can also be formed enzymatically from 7β-OHC by the hydroxysteroid dehydrogenase type 2 (11β-HSD2; HSD11B2 gene, OMIM 614232) which is mainly expressed in the kidney, colon, and placenta (Ferrari 2010). In addition, in patients with cerebrotendinous xanthomatosis or with SLO syndrome, 7KC can be formed from 7-dehydrocholesterol (7DHC, a direct precursor in cholesterol biosynthesis belonging to the Kandutsch–Russel pathway (Petrov et al. 2016)) by the enzyme cholesterol-7α-hydroxylase (CYP7A1) (Liu et al. 2013, Björkhem et al. 2014).
Enzymatic synthesis of 7-ketocholesterol. 7-ketocholesterol can be formed from 7β-hydroxycholesterol by the 11β hydroxysteroid dehydrogenase type 2 (11β-HSD2) and from 7-dehydrocholesterol by cholesterol-7α-hydroxylase (CYP7A1). 7-Ketocholesterol can also give 7β-hydroxycholesterol via the 11β hydroxysteroid dehydrogenase type 1 (11β-HSD1).
Citation: Redox Experimental Medicine 2022, 1; 10.1530/REM-22-0005
Age-related diseases and civilization diseases associated with 7-ketocholesterol
7KC is greatly increased in the tissues (vascular wall, retina, and certain brain regions) of patients with cardiovascular diseases, AMD, Alzheimer’s disease, and Parkinson’s disease (Zarrouk et al. 2014, Pariente et al. 2019), and most likely in X-ALD which is also associated with important oxidative stress (Deon et al. 2016, Nury et al. 2017). It is now well accepted that 7KC, which triggers oxidative stress and inflammation leading to numerous cell damages, plays key roles in the pathophysiology and in the outcome of age-related diseases (Samadi et al. 2021). Several data also support that 7KC can contribute to ageing (de Medina et al. 2022) as well as civilization diseases such as diabetes type 2 (Endo et al. 2008, Samadi et al. 2019), bowel diseases (Poli et al. 2013), metabolic syndrome, and obesity (Murdolo et al. 2016) resulting from life habits (diet, physical activity), environmental pollution (air pollution, endocrine disrupters, and obesogens), and neuroemotional pollution (chronic stress). Currently, different types of relationships have been found between environmental pollution that can promote age-related and civilization diseases and 7KC. Thus, it has been reported that 7KC accumulates in vessels as a result of the stress caused by air pollution (Rao et al. 2014), is an endogenous modulator for the aryl hydrocarbon receptor which interacts with dioxin (Savouret et al. 2001), contributes to cigarette smoke side effects (Steffen et al. 2012), could favour asthma (Zanjani et al. 2022) as well as silicosis (Aksu et al. 2020), and increases the toxicity of nanoparticles (Kahn et al. 2010). In civilization diseases, it is suggested that 7KC, when present at increased levels, may act as an adipokine modulating the adipogenic potential of undifferentiated adipose precursor cells (Murdolo et al. 2016). There are also evidences that dietary 7KC accelerates hepatic steatosis and inflammation in obese mice models (Chang et al. 2020). Currently, several studies also support that 7KC acts on adipogenic differentiation factor (de Freitas et al. 2021). In the context of osteoporosis, it has also been reported that 7KC induces miR107-5p which promotes the differentiation of osteoclasts by downregulating mitogen-activated protein kinase 1 (MKP1) (Li et al. 2022).
Characteristics of 7-ketocholesterol-induced cytotoxic effects
7KC has been shown to accumulate in lipid rafts (Royer et al. 2009, Ragot et al. 2013). 7KC disrupts plasma membrane organization (Kahn et al. 2011, Wnętrzak et al. 2022) and enhances plasma membrane rigidity (Olkkonen & Hynynen 2009, Vejux et al. 2009), as well as permeability (Vejux et al. 2020, Nury et al. 2021a). 7KC is also a strong inducer of oxidative stress and triggers organelles dysfunctions (mitochondria, peroxisome, lysosome, endoplasmic reticulum), inflammation, and cell death (Nury et al. 2021a) (Fig. 3). 7KC activates cell death on different cell types (primary cultures, cell lines) of different species in a concentration range of 25–50 μM after 24–48 h of culture. 7KC-induced cell death can be either a mode of cell death by apoptosis (caspases-dependent cell death) or a caspases-independent cell death process (Fig. 4). 7KC-induced apoptosis has been described on vascular wall cells, monocytes/macrophages, and nerve cells (neurons, glial cells (oligodendrocytes), and microglial cells). On human monocytic THP-1 cells, 7KC-induced cell death is associated with a sustained increase of Ca2+ which elicits the mitochondrial pathway of apoptosis (Berthier et al. 2004). A non-apoptotic mode of cell death, without caspases activation, has been described on human fibroblasts, MCF-7 mammary tumor cells, which are deficient in caspase-3, as well as on C6 rat glioblastoma cells (Vejux et al. 2020), and in some cases on ARPE-19, a human retinal pigment epithelial cell lines with differentiated properties (Dugas et al. 2010). A caspase-independent cell death has also been observed on C2C12 murine myoblasts (Ghzaiel et al. 2021b). In all the cases, whether it is an apoptotic mode of cell death or a caspases-independent cell death process, significant mitochondrial and peroxisomal alterations have been found. Thus, topographical and morphological changes in mitochondria have been observed; these changes were associated with a drop in transmembrane mitochondrial potential (ΔΨm) (Nury et al. 2021a). On A7r5 rat aorta smooth muscle cells, it has been shown that the drop of ΔΨm induced by 7KC precedes the activation of apoptosis associated with a loss of cell adhesion (Zahm et al. 2003). In addition, under treatment with 7KC, the Krebs cycle (also called the citric acid cycle), as well as the oxidative phosphorylation, is also strongly altered leading to lower glycolysis and a decrease in ATP production (Leoni et al. 2017). Overproduction of reactive oxygen species (ROS), especially superoxide anions (O2·−), is also observed at the mitochondrial level (Nury et al. 2021a). Like mitochondria, the peroxisome, which is functionally connected to the mitochondria and vice versa (Lismont et al. 2015, Fransen et al. 2017), is also subject to significant topographical and morphological changes. In addition, a reduction in peroxisomal mass is always observed, as well as a decrease in peroxisomal β-oxidation which results in a cytoplasmic accumulation of very long-chain fatty acids (VLCFA) known for their cytotoxic and pro-oxidant activities (Zarrouk et al. 2012, Nury et al. 2018). This alteration of the peroxisome, in particular, the decrease in the levels of peroxisomal proteins, ATP-binding cassette subfamily D member 1 (ABCD1, involved in the transport of VLCFA from the cytoplasm inside the peroxisome) and acyl-CoA oxidase 1 (ACOX1, the first and rate-limiting enzyme in peroxisomal fatty acid β-oxidation of VLCFA), could contribute to 7KC-induced oxidative stress (Trompier et al. 2014). Indeed, on 158N rat oligodendrocytes, it has been shown that the decreased expression of ABCD1 and ACOX1 induced by RNA silencing triggered a strong overproduction of ROS and reactive nitrogen species (RNS) (Baarine et al. 2012). Thus, regardless of the type of cell death induced by 7KC (caspases-dependent or independent), mitochondrial and peroxisomal dysfunctions could favour oxidative stress. This latter could not only be due to mitochondrial and peroxisomal dysfunctions but also to the activation of NADPH oxidases. In addition, this oxidative stress is associated with a disruption of the RedOx equilibrium which results (i) in changes in the activity of antioxidant enzymes (catalase, superoxide dismutase, glutathione peroxidase) and (ii) in lipid peroxidation leading to the generation of aldehydes such as malondialdehyde (MDA)-promoting protein carbonylation (Vejux et al. 2020, Nury et al. 2021a). Therefore, 7KC-induced oxidative stress appears a major element in cellular dysfunctions leading to caspases-dependent and independent cell death. Moreover, among the events associated with cell death, 7KC also activates an autophagic process considered as survival autophagy (Yammine et al. 2020, Zhang et al. 2020). This latter is observed either during apoptosis or caspases-independent cell death. When autophagy is associated with oxidative stress and apoptosis, the term ‘oxiapoptophagy’ (OXIdation + APOPTOsis + autoPHAGY) is used to define 7KC-induced cell death (Fig. 4) (Nury et al. 2021b). The signalling pathways associated with this type of cell death have been described in the detail by Vejux et al. (2020) and Nury et al. (2021a). In the case of oxiapoptophagy, the autophagy observed (mitophagy, pexophagy, and/or reticulophagy) corresponds to survival autophagy (Yuan et al. 2016). Indeed, when 7KC is combined with 3-methyl adenine (an autophagy inhibitor), cell death increases, while when combined with rapamycin (an autophagy activator), cell death decreases (Yammine et al. 2020). In addition, 7KC also has pro-inflammatory activities. By interacting with the TLR4 receptor (Erridge et al. 2007, Huang et al. 2014), it promotes the production of inflammatory cytokines (Prunet et al. 2006), increases the rate of adhesion molecules (Lemaire et al. 1998, Shimozawa et al. 2004), and promotes the transition of macrophages from the anti-inflammatory M1 phenotype to the pro-inflammatory M2 phenotype (Buttari et al. 2013). On ARPE-19 cells, a link between 7KC-induced autophagy, inflammation, and angiogenesis has been shown: the inhibition of the mammalian target of rapamycin (mTOR) pathway by rapamycin suppresses 7KC-induced IL-6, IL-8, and vascular endothelial growth factor (VEGF) expression by downregulating the mitogen-activated protein kinase (MAPK) pathway (Yang et al. 2022). 7KC also favours non-cytokinic inflammation. Thus, in human mesangial cell, 7KC induces ROS-mediated mRNA expression of 12-lipoxygenase and cyclooxygenase-2 (Watanabe et al. 2018). 7KC-induced oxidative stress also suppresses docosahexaenoic acid (DHA)-derived resolvins like RvD1 which prevents atheromatous plaque instability; it is suggested that 7KC could increase the ratio of (nuclear: non-nuclear lipoxygenase) which would decrease RvD1 (Fredman et al. 2016). 7KC could also be involved in adipogenesis and vascularization (Chang et al. 2020, de Freitas et al. 2021).
Major characteristics of 7-ketocholesterol-associated cytotoxic effects. The main cytotoxic effects of 7-ketocholesterol, which are also hallmarks of age-related diseases and civilization diseases, are oxidative stress and inflammation which can contribute to trigger cell death.
Citation: Redox Experimental Medicine 2022, 1; 10.1530/REM-22-0005
Hypothetical connection between 7-ketocholesterol-induced oxidative stress, inflammation, and cell death. 7-ketocholesterol (also named 7-oxocholesterol) can induce either a caspase-dependent mode of cell death defined as oxiapoptophagy (OXIdative stress + APOPTOsis + autoPHAGY) on different cell types from different species (Nury et al. 2021b) or a caspase-independent mode of cell death (Dugas et al. 2010). These different types of cell death are associated with an important oxidative stress, plasma membrane alterations, and organelles dysfunctions (especially mitochondrial and peroxisomal dyfunctions) leading to cell death. On A7r5 rat smooth muscle cells and 158N oligodendrocytes, an accumulation of 7-ketocholesterol (7KC) in lipid raft has been shown (Royer et al. 2009, Ragot et al. 2013). Detailed signalling pathways associated with 7KC-induced cytotoxicity are described in the reviews by Vejux et al. (2020) and Nury et al. (2021a).
Citation: Redox Experimental Medicine 2022, 1; 10.1530/REM-22-0005
To reduce the cytotoxic activities of 7KC and to prevent and/or cure the diseases of civilizations and age-related diseases associated with increased levels of 7KC, several strategies are possible. In this context, the identification of natural or synthetic molecules allowing to reduce the toxicity of 7KC takes an important place. Among the natural cytoprotective molecules are many nutrients present in the Mediterranean diet: tocopherols, fatty acids, and polyphenols (Nury et al. 2021a). Many Mediterranean oils (argan oil, olive oil, milk thistle seed oil, and Pistacia lentiscus L. seed oil) also reduce the toxicity of this oxysterol (Nury et al. 2021a). Among the synthetic molecules, dimethyl fumarate used in the treatment of multiple sclerosis under the name Tecfidera as well as its major metabolite, monomethyl fumarate, also has powerful cytoprotective activities (Zarrouk et al. 2017). Another strategy, probably more specific, is to promote the catabolism of 7KC to conteract or attenuate its toxicity. This concept was initially validated in vitro by Mathieu et al. under the name of medical bioremediation, by specifically targeting the degradation of 7KC in the lysosome in which this oxysterol accumulates (Mathieu et al. 2008, Schloendorn et al. 2009). Better knowledge of the production of 7KC and on its catabolism will contribute to open innovative and promising therapeutic perspectives.
Inactivation of 7-ketocholesterol
Many of the enzymatic pathways which contribute to metabolize cholesterol are also able to act on oxysterols (Gill et al. 2008). The major oxysterol metabolite routes for oxysterol inactivation are esterification, sulfation, oxidation, and reduction (Brown & Jessup 2009).
Esterification
Both acyl-CoA cholesterol acyl transferase (ACAT), also named sterol-O-acyltransferase (SOAT), and lecithin-cholesterol acyl transferase (LCAT) can esterify oxysterols in cells and plasma, respectively (Szedlacsek et al. 1995, Brown & Jessup 2009, Rogers et al. 2015). Excess cholesterol in the cells is esterified under the action of ACAT, which is a normal cellular mechanism for limiting the level of free cholesterol (unesterified cholesterol) in cell membranes to maintain normal membrane structure (Chang et al. 2006). The esterified cholesterol is stored in lipid droplets (Luo et al. 2020). However, in macrophage foam cells from human atherosclerotic lesions, 7KC levels are the highest in the endosomal and lysosomal compartments (Brown et al. 2000), where it inhibits sphingomyelinase and facilitates the intralysosomal accumulation of both sphingomyelin and cholesterol (Maor et al. 1995), and in 7KC-treated human monocytic U937 cells, an important 7KC-accumulation has been observed in multilamellar structures named myelin figures (Vejux & Lizard 2009). While ACAT is also able to esterify many oxysterols, cholesterol is superior to 7KC or 7α-OHC as an allosteric activator of this enzyme (Zhang et al. 2003). It has also been reported that the esterification of 7KC to fatty acids involves the combined action of cytosolic phospholipase A2 alpha (cPLA2α) and sterol O-acyltransferase (SOAT1) (Lee et al. 2015). Inhibition of either one of these enzymes ablates 7KC-fatty acid ester (7KFAE) formation. The 7KFAEs are not toxic and do not induce inflammatory responses. An additional function of high-density lipoproteins (HDL) would be to favour the elimination of 7KC by returning 7KFAEs to the liver for bile acid formation. However, 7KC could also inactivate 7α-hydroxylase (CYP7A1), a major hepatic enzyme involved in bile acid synthesis (Lyons & Brown 1999, Tempel et al. 2014).
Sulfation
Cytosolic SULT2 family of cytosolic sulfotransferase family 2 (SULT2B1b) shows a particular affinity for cholesterol and for oxysterols (Javitt et al. 2001). SULTs sulfonates at the third position of the ring A of 7KC form 7-ketocholesterol-3- sulphate (7KCS). Sulfation is known to act as a detoxification pathway for the removal of 7KC (Fuda et al. 2007, Sanchez et al. 2021). Previous work demonstrated that human breast cancer MCF-7 cells expressing high levels of SULT2B1b are significantly more resistant to the cytotoxic effect of 7KC than human embryonic kidney 293T cells that do not express this isozyme (Fuda et al. 2007). Over-expressing SULT2B1b in 293T cells increased sterol and 7KC sulfation and decreased the 7KC-mediated toxicity. Since SULTB1b expression is not universal, this detoxification pathway is not present in some important tissues such as retina where 7KC toxic effects are prominent (Rodriguez & Fliesler 2009, Vejux et al. 2011). Expression of SULT2B1b was not observed in neural retinal cells in rats, monkeys, or human (Moreira et al. 2009, Rodriguez & Fliesler 2009, Rodríguez & Larrayoz 2010). However, when added to cultured retinal cells in vitro, 7KCS attenuates cholesterol transporter, ATP-binding cassette transporter ABCA1 (member 1 of human transporter sub-family ABCA), and vascular endothelial growth factor (VEGF) inductions by 7KC (Moreira et al. 2009). Gene transactivation of liver X receptors (LXRs) requires recruitment of co-activators in a ligand-dependent manner and 7KCS inhibited reporter gene activation by LXRα (Song et al. 2001). Despite these early investigations, there is more scope to understand the role of 7KCS on cholesterol homeostasis and pathophysiological consequences.
Oxidation
In humans, the enzyme sterol 27-hydroxylase cytochrome P450 27A1 (CYP27A1) eliminates cholesterol and likely 7KC from the retina and many other tissues (Charvet et al. 2011, Heo et al. 2011). CYP27A1 is a mitochondrial cytochrome P450 enzyme and the first enzyme of the acidic bile acid pathway; CYP27A1 is responsible for the initial metabolism of 7KC by HepG2 cells, a human hepatoblastoma cell line (Lyons & Brown 2001). Thus, via the enzyme CYP27A1, 7KC gives 27-hydroxycholesterol-7-ketocholesterol (27OHC-7KC). The contribution of CYP27A1 in the catabolism of 7KC has also been previously described in the context of the analysis of the cytotoxic effects of 7KC on 158N and BV-2 cells (Bezine et al. 2018). In the insect, the enzyme CYP306A1 has 25-hydroxylase activity and allows the formation of 25-hydroxycholesterol-7-ketocholesterol (25OHC-7KC) from 7KC (Pan et al. 2021).
Reduction
The enzymatic conversion of 7KC to 7β-OHC by hydroxysteroid dehydrogenase 11β-HSD1 (11βHSD1/EC 1.1.1.146 also known as cortisone reductase; HSD11B1 gene, OMIM 600713) can occur in many tissues (Mitić et al. 2013a, b). The conversion of 7KC in 7β-OHC by 11β-HSD1 is well established in the arterial wall (Mitić et al. 2013a). Noteworthy, the activity and reaction direction of adipose 11β-HSD1 are altered in oxysterol excess and could impact the pathophysiology of obesity and its complications (Wamil et al. 2008). The contribution of 11β-HSD1 in the catabolism of 7KC has also been previously described in the context of the analysis of the cytotoxic effects of 7KC on 158N and BV-2 cells (Bezine et al. 2018).
Biodegradation with bacterial enzymes: nutritional and biomedical aspects
The catabolic insufficiency of the human body to inactivate and degrade harmful oxysterols, such as 7KC, leads to their progressive accumulation which can have pathophysiological consequences and trigger the development of diseases. An interesting solution termed ‘Medical Bioremediation’, proposes the use of exogenous enzymes derived from micro-organisms to degrade 7KC either into less toxic metabolites or towards complete mineralization and further explores the delivery of these enzymes in disease conditions. The pioneering works in this field were reported as part of a pilot study funded by the Strategy for Engineered Negligible Senescence(SENS) research foundation (https://www.sens.org/; May 2022) where several bacterial strains such as Psedomonas aeruginosa, Rhodococcus jostii RHA1, Sphingomonas sp. JEM-1, Nocardia nova, and Proteobacterium Y-134 were explored for their 7KC degradation capability (de Grey et al. 2005, Rittmann & Schloendorn 2007, Mathieu et al. 2008, 2009, Schloendorn et al. 2009). Further, genes responsible for 7KC degradation by Rhodococcus RHA1 were studied through transcriptomic studies, and several steroid catabolism gene clusters were found to be expressed, along with enzymes such as dioxygenase (hsaC), 7-keto reductase, and dehydratase (Mathieu et al. 2010). Taking a cue, other researchers reported the high 7KC degradation by Pseudomonas aeruginosa PseA and Rhodococcus erythropolis MTCC 3951, facilitated by the production of the enzymes cholesterol oxidase, lipase, dehydrogenase, and reductase. Some of the identified degradation products were cholesta-3, 5-dien-7-one/cholesta-4, 6-dien-3-one for P. aeruginosa, while in case of R. erythropolis, chol-5-en-3,7-dione and androsta-4-ene-3,7,17-trione were identified (Ghosh & Khare 2016, 2017, Vejux et al. 2020, Ravi et al. 2021). Several other 7KC degrading strains were reported including Thermobifida fusca IP1, Alcanivorax jadensis IP4, Streptomyces auratus IP2, and Serratia marcescens IP3 (Perveen 2016, Perveen et al. 2018). From the above studies, the importance of the first enzyme of the 7KC biodegradation pathway, cholesterol oxidase, cannot be undermined in reducing 7KC cytotoxicity in cells. Thus, a plasmid construct of pEGFP‐N3, containing the Chromobacterium DS-1 cholesterol oxidase gene fused with the signal sequence and transmembrane domain of the lysosomal membrane protein LAMP1, was found to localize into the lysosome, providing the cytoprotective effect in human fibroblast cells treated with 7KC (Mathieu et al. 2012). Cholesterol oxidase immobilized on magnetic iron (II, III) oxide nanoparticles have also been reported to convert cholesterol and 7KC to 4-cholesten-3-one and 4-cholesten-3, 7-dione, respectively, in solution, which find applications as pharmaceutically important steroid precursors (Ghosh et al. 2018a, b). An interesting study to mention is the biosorption of 7KC by the probiotic strain Lactobacillus casei ATCC334 which could be further explored in inhibiting 7KC absorption via intestine (Machorro-Méndez et al. 2013). Thus, the use of bacteria and their degradative enzyme explore a promising route for remediation of 7KC-mediated cytotoxicity which has important applications in food industry and in pharmacology.
Metabolism of 7-ketocholesterol in patients with genetic diseases affecting cholesterol metabolism
The metabolism of 7KC is of interest to limit its accumulation and consequently reduce its side effects. Information on the metabolism of 7KC is often obtained from cell lines (Lyons & Brown 2001, Heo et al. 2011) and from samples of patients where levels of 7KC are particularly high as in patients with Niemann–Pick disease type A, B, C1, and C2 (NPA, NPB, and NPC), lysosomal acid lipase deficiency (LALD) (Griffiths et al. 2019), and SLO syndrome (Björkhem et al. 2014, Griffiths et al. 2017). 7KC could also be used as a biomarker of neonatal cholestasis (López de Frutos et al. 2021). In the catabolism of 7KC, different pathways have been identified (Fig. 5). Numerous enzymes are involved such as the 11β hydroxysteroid dehydrogenase type 1 (11β-HSD1), the 11β hydroxysteroid dehydrogenase type 2 (11β-HSD2), the sterol 27-hydroxylase cytochrome P450 27A1 (CYP27A1), and the cholesterol 25 hydroxylase (CH25H). The following enzymes are also involved in bile acid synthesis: several peroxisomal enzymes (acyl-coenzyme A oxidase 2 (ACOX2), D bifuntional protein (DBP), sterol carrier protein 2 (SCP2)), as well as alpha-methylacyl-CoA-racemase (AMACR), localized in the mitochondria and the peroxisome, and also the bile acyl CoA-synthase (BACS) (Griffiths et al. 2019).
Metabolism of 7-ketocholesterol. The enzymes required for side-chain shortening are presumed to be those utilized in the acidic pathway of bile acid synthesis (Zhou & Hylemon 2014). Reactions catalysed by unknown enzymes are shown by broken arrows. 11β-HSD1, hydroxysteroid dehydrogenase type 1; 11β-HSD2, hydroxysteroid dehydrogenase type 2; CYP27A1, 27-hydroxylase cytochrome P450 27A1. The enzymes involved in bile acid synthesis are peroxisomal enzymes (ACOX2, acyl-coenzyme A oxidase 2; DBP, D bifuntional protein; SCP2, sterol carrier protein 2) and mitochondrial/peroxisomal enzymes (AMACR, alpha-methylacyl-CoA-racemase; BACS, bile acyl CoA-synthase).
Citation: Redox Experimental Medicine 2022, 1; 10.1530/REM-22-0005
Overview and conclusion
7KC is the most frequently formed oxysterol by autoxidation (Anderson et al. 2020, Nury et al. 2021a ). This oxysterol, which is a biomarker of oxidative stress (Iuliano et al. 2003, Seet et al. 2010, Samadi et al. 2019), is present in high amounts in several foods (Canzoneri et al. 2022) and it is formed in the stomach from cholesterol (Kanner & Lapidot 2001). The increase in oxidative stress during ageing and under the influence of environmental factors (lifestyle habits, stress, and pollution) can also, depending on the individual, contribute to a more or less important accumulation of 7KC in different tissues (Zarrouk et al. 2014, de Medina et al. 2022). This last aspect can lead to highly disabling diseases (cardiovascular, neurodegenerative, and ocular diseases, as well as metabolic syndrome) with significant societal consequences. It is therefore essential to better know the metabolism of 7KC in humans, and with appropriate models (Vejux et al. 2020), to identify molecules counteracting 7KC-induced cytotoxicity (Brahmi et al. 2019, Nury et al. 2021a), and to develop new strategies to control the level of this oxysterol in food and in the body in order to avoid its toxic effects: oxidative stress, inflammation, and cell degeneration. Thus, 7KC, which is one of the oldest oxysterols identified, still deserves our full attention.
Declaration of interest
Gérard Lizard and Amira Zarrouk are Editorial Board Members of Redox Experimental Medicine. Gérard Lizard and Amira Zarrouk were not involved in the review or editorial process for this paper, on which they are listed as authors. The other authors have nothing to disclose.
Funding
This work was funded by Université de Bourgogne (Dijon, France), Université Tunis El Manar (Tunis, Tunisia), Université de Monastir (Monastir, Tunisia), and Université Hassan 1er (Settat, Morocco). This work was supported by PHC UTIQUE 2021–2022 (Dr Taoufik Ghrairi, Tunisia and Dr Gérard Lizard, France; code CMCU: 22G0809/Code Campus France: 47608VJ). Imen Ghzaiel also received financial support from ABASIM (Association Bourguignonne pour les Applications des Sciences de l’Information en Médecine ; Dijon, France).
Acknowledgements
The authors acknowledge Mrs Nathalie Bancod for her efficient contribution to iconography. The authors also acknowledge the ENOR network (https://www.oxysterols.net/; May 2022) thanks to which scientific interactions were possible between the authors to optimize the quality of this review.
References
Aksu N, Samadi A, Yalçınkaya A, Çetin T, Eser B, Lay İ, Öziş TN, Öztaş Y & Sabuncuoğlu S 2020 Evaluation of oxysterol levels of patients with silicosis by LC-MS/MS method. Molecular and Cellular Biochemistry 467 117–125. (https://doi.org/10.1007/s11010-020-03706-w)
Anderson A, Campo A, Fulton E, Corwin A, Jerome 3rd WG & O’Connor MS 2020 7-Ketocholesterol in disease and aging. Redox Biology 29 101380.(https://doi.org/10.1016/j.redox.2019.101380)
Baarine M, Andréoletti P, Athias A, Nury T, Zarrouk A, Ragot K, Vejux A, Riedinger JM, Kattan Z & Bessede G et al.2012 Evidence of oxidative stress in very long chain fatty acid – treated oligodendrocytes and potentialization of ROS production using RNA interference-directed knockdown of ABCD1 and ACOX1 peroxisomal proteins. Neuroscience 213 1–18. (https://doi.org/10.1016/j.neuroscience.2012.03.058)
Berthier A, Lemaire-Ewing S, Prunet C, Monier S, Athias A, Bessède G, Pais De Barros JP, Laubriet A, Gambert P & Lizard G et al.2004 Involvement of a calcium-dependent dephosphorylation of BAD associated with the localization of Trpc-1 within lipid rafts in 7-ketocholesterol-induced THP-1 cell apoptosis. Cell Death and Differentiation 11 897–905. (https://doi.org/10.1038/sj.cdd.4401434)
Bezine M, Maatoug S, Ben Khalifa R, Debbabi M, Zarrouk A, Wang Y, Griffiths WJ, Nury T, Samadi M & Vejux A et al.2018 Modulation of Kv3.1b potassium channel level and intracellular potassium concentration in 158N murine oligodendrocytes and BV-2 murine microglial cells treated with 7-ketocholesterol, 24S-hydroxycholesterol or tetracosanoic acid (C24:0). Biochimie 153 56–69. (https://doi.org/10.1016/j.biochi.2018.02.008)
Björkhem I, Diczfalusy U, Lövgren-Sandblom A, Starck L, Jonsson M, Tallman K, Schirmer H, Ousager LB, Crick PJ & Wang Y et al.2014 On the formation of 7-ketocholesterol from 7-dehydrocholesterol in patients with CTX and SLO. Journal of Lipid Research 55 1165–1172. (https://doi.org/10.1194/jlr.P048603)
Brahmi F, Vejux A, Sghaier R, Zarrouk A, Nury T, Meddeb W, Rezig L, Namsi A, Sassi K & Yammine A et al.2019 Prevention of 7-ketocholesterol-induced side effects by natural compounds. Critical Reviews in Food Science and Nutrition 59 3179–3198. (https://doi.org/10.1080/10408398.2018.1491828)
Brown AJ & Jessup W 1999 Oxysterols and atherosclerosis. Atherosclerosis 142 1–28. (https://doi.org/10.1016/s0021-9150(9800196-8)
Brown AJ & Jessup W 2009 Oxysterols: sources, cellular storage and metabolism, and new insights into their roles in cholesterol homeostasis. Molecular Aspects of Medicine 30 111–122. (https://doi.org/10.1016/j.mam.2009.02.005)
Brown AJ, Mander EL, Gelissen IC, Kritharides L, Dean RT & Jessup W 2000 Cholesterol and oxysterol metabolism and subcellular distribution in macrophage foam cells. Accumulation of oxidized esters in lysosomes. Journal of Lipid Research 41 226–237. (https://doi.org/10.1016/S0022-2275(2032056-3)
Brown AJ, Sharpe LJ & Rogers MJ 2021 Oxysterols: from physiological tuners to pharmacological opportunities. British Journal of Pharmacology 178 3089–3103. (https://doi.org/10.1111/bph.15073)
Buttari B, Segoni L, Profumo E, D’Arcangelo D, Rossi S, Facchiano F, Businaro R, Iuliano L & Riganò R 2013 7-Oxo-cholesterol potentiates pro-inflammatory signaling in human M1 and M2 macrophages. Biochemical Pharmacology 86 130–137. (https://doi.org/10.1016/j.bcp.2013.04.008)
Canzoneri F, Leoni V, Rosso G, Risso D, Menta R & Poli G 2022 Oxysterols as reliable markers of quality and safety in cholesterol containing food ingredients and products. Frontiers in Nutrition 9 853460. (https://doi.org/10.3389/fnut.2022.853460)
Chang TY, Chang CC, Ohgami N & Yamauchi Y 2006 Cholesterol sensing, trafficking, and esterification. Annual Review of Cell and Developmental Biology 22 129–157. (https://doi.org/10.1146/annurev.cellbio.22.010305.104656)
Chang J, Koseki M, Saga A, Kanno K, Higo T, Okuzaki D, Okada T, Inui H, Tanaka K & Asaji M et al.2020 Dietary oxysterol, 7-ketocholesterol accelerates hepatic lipid accumulation and macrophage infiltration in obese mice. Frontiers in Endocrinology 11 614692. (https://doi.org/10.3389/fendo.2020.614692)
Charvet C, Liao WL, Heo GY, Laird J, Salomon RG, Turko IV & Pikuleva IA 2011 Isolevuglandins and mitochondrial enzymes in the retina: mass spectrometry detection of post-translational modification of sterol-metabolizing CYP27A1. Journal of Biological Chemistry 286 20413–20422. (https://doi.org/10.1074/jbc.M111.232546)
Clariana M & García-Regueiro JA 2011 Effect of high pressure processing on cholesterol oxidation products in vacuum packaged sliced dry-cured ham. Food and Chemical Toxicology 49 1468–1471. (https://doi.org/10.1016/j.fct.2011.03.027)
de Freitas FA, Levy D, Zarrouk A, Lizard G & Bydlowski SP 2021 Impact of oxysterols on cell death, proliferation, and differentiation induction: current status. Cells 10 2301. (https://doi.org/10.3390/cells10092301)
de Grey AD, Alvarez PJ, Brady RO, Cuervo AM, Jerome WG, Mccarty PL, Nixon RA, Rittmann BE & Sparrow JR 2005 Medical bioremediation: prospects for the application of microbial catabolic diversity to aging and several major age-related diseases. Ageing Research Reviews 4 315–338. (https://doi.org/10.1016/j.arr.2005.03.008)
de Medina P, Silvente-Poirot S & Poirot M 2022 Oxysterols are potential physiological regulators of ageing. Ageing Research Reviews 77 101615. (https://doi.org/10.1016/j.arr.2022.101615)
Deon M, Marchetti DP, Donida B, Wajner M & Vargas C 2016 Oxidative stress in patients with X-linked adrenoleukodystrophy. Cellular and Molecular Neurobiology 36 497–512. (https://doi.org/10.1007/s10571-015-0234-2)
Diczfalusy U, Nylén H, Elander P & Bertilsson L 2011 4β-Hydroxycholesterol, an endogenous marker of CYP3A4/5 activity in humans. British Journal of Clinical Pharmacology 71 183–189. (https://doi.org/10.1111/j.1365-2125.2010.03773.x)
Dugas B, Charbonnier S, Baarine M, Ragot K, Delmas D, Ménétrier F, Lherminier J, Malvitte L, Khalfaoui T & Bron A et al.2010 Effects of oxysterols on cell viability, inflammatory cytokines, VEGF, and reactive oxygen species production on human retinal cells: cytoprotective effects and prevention of VEGF secretion by resveratrol. European Journal of Nutrition 49 435–446. (https://doi.org/10.1007/s00394-010-0102-2)
Echarte M, Conchillo A, Ansoren D & Astiasarán I 2005 Cholesterol oxidation products in fresh and frozen shrimps, raw and grilled. Nutricion Hospitalaria 20 293–296.
Endo K, Oyama T, Saiki A, Ban N, Ohira M, Koide N, Murano T, Watanabe H, Nishii M & Miura M et al.2008 Determination of serum 7-ketocholesterol concentrations and their relationships with coronary multiple risks in diabetes mellitus. Diabetes Research and Clinical Practice 80 63–68. (https://doi.org/10.1016/j.diabres.2007.10.023)
Erridge C, Webb DJ & Spickett CM 2007 25-Hydroxycholesterol, 7beta-hydroxycholesterol and 7-ketocholesterol upregulate interleukin-8 expression independently of toll-like receptor 1, 2, 4 or 6 signalling in human macrophages. Free Radical Research 41 260–266. (https://doi.org/10.1080/10715760601070091)
Ferrari P 2010 The role of 11β-hydroxysteroid dehydrogenase type 2 in human hypertension. Biochimica et Biophysica Acta 1802 1178–1187. (https://doi.org/10.1016/j.bbadis.2009.10.017)
Fransen M, Lismont C & Walton P 2017 The peroxisome-mitochondria connection: how and why? International Journal of Molecular Sciences 18 1126. (https://doi.org/10.3390/ijms18061126)
Fredman G, Hellmann J, Proto JD, Kuriakose G, Colas RA, Dorweiler B, Connolly ES, Solomon R, Jones DM & Heyer EJ et al.2016 An imbalance between specialized pro-resolving lipid mediators and pro-inflammatory leukotrienes promotes instability of atherosclerotic plaques. Nature Communications 7 12859. (https://doi.org/10.1038/ncomms12859)
Fuda H, Javitt NB, Mitamura K, Ikegawa S & Strott CA 2007 Oxysterols are substrates for cholesterol sulfotransferase. Journal of Lipid Research 48 1343–1352. (https://doi.org/10.1194/jlr.M700018-JLR200)
Gajewski A, Mnich E, Szymański K, Hinc K, Obuchowski M, Moran AP & Chmiela M 2016 Helicobacter pylori antigens, acetylsalicylic acid, LDL and 7-ketocholesterol – their potential role in destabilizing the gastric epithelial cell barrier. An in vitro model of Kato III cells. Acta Biochimica Polonica 63 145–152. (https://doi.org/10.18388/abp.2015_1122)
Ghosh S & Khare SK 2016 Biodegradation of cytotoxic 7-ketocholesterol by Pseudomonas aeruginosa PseA. Bioresource Technology 213 44–49. (https://doi.org/10.1016/j.biortech.2016.03.079)
Ghosh S & Khare SK 2017 Biodegradation of 7-ketocholesterol by Rhodococcus erythropolis MTCC 3951: process optimization and enzymatic insights. Chemistry and Physics of Lipids 207 253–259. (https://doi.org/10.1016/j.chemphyslip.2017.05.008)
Ghosh S, Ahmad R, Gautam VK & Khare SK 2018a Cholesterol-oxidase-magnetic nanobioconjugates for the production of 4-cholesten-3-one and 4-cholesten-3,7-dione. Bioresource Technology 254 91–96. (https://doi.org/10.1016/j.biortech.2018.01.030)
Ghosh S, Ahmad R & Khare SK 2018b Immobilization of cholesterol oxidase: an overview. Open Biotechnology Journal 12 176–188. (https://doi.org/10.2174/1874070701812010176)
Ghzaiel I, Sassi K, Zarrouk A, Nury T, Ksila M, Leoni V, Bouhaouala-Zahar B, Hammami S, Hammami M & Mackrill JJ et al.2021a 7-Ketocholesterol: effects on viral infections and hypothetical contribution in COVID-19. Journal of Steroid Biochemistry and Molecular Biology 212 105939. (https://doi.org/10.1016/j.jsbmb.2021.105939)
Ghzaiel I, Zarrouk A, Nury T, Libergoli M, Florio F, Hammouda S, Ménétrier F, Avoscan L, Yammine A & Samadi M et al.2021b Antioxidant properties and cytoprotective effect of Pistacia lentiscus L. seed oil against 7β-hydroxycholesterol-induced toxicity in C2C12 myoblasts: reduction in oxidative stress, mitochondrial and peroxisomal dysfunctions and attenuation of cell death. Antioxidants 10 1772. (https://doi.org/10.3390/antiox10111772)
Gill S, Chow R & Brown AJ 2008 Sterol regulators of cholesterol homeostasis and beyond: the oxysterol hypothesis revisited and revised. Progress in Lipid Research 47 391–404. (https://doi.org/10.1016/j.plipres.2008.04.002)
Gorassini A, Verardo G, Fregolent SC & Bortolomeazzi R 2017 Rapid determination of cholesterol oxidation products in milk powder based products by reversed phase SPE and HPLC-APCI-MS/MS. Food Chemistry 230 604–610. (https://doi.org/10.1016/j.foodchem.2017.03.080)
Griffiths WJ, Abdel-Khalik J, Crick PJ, Ogundare M, Shackleton CH, Tuschl K, Kwok MK, Bigger BW, Morris AA & Honda A et al.2017 Sterols and oxysterols in plasma from Smith-Lemli-Opitz syndrome patients. Journal of Steroid Biochemistry and Molecular Biology 169 77–87. (https://doi.org/10.1016/j.jsbmb.2016.03.018)
Griffiths WJ, Yutuc E, Abdel-Khalik J, Crick PJ, Hearn T, Dickson A, Bigger BW, Hoi-Yee Wu T, Goenka A & Ghosh A et al.2019 Metabolism of non-enzymatically derived oxysterols: clues from sterol metabolic disorders. Free Radical Biology and Medicine 144 124–133. (https://doi.org/10.1016/j.freeradbiomed.2019.04.020)
Guillemot-Legris O, Mutemberezi V, Cani PD & Muccioli GG 2016 Obesity is associated with changes in oxysterol metabolism and levels in mice liver, hypothalamus, adipose tissue and plasma. Scientific Reports 6 19694. (https://doi.org/10.1038/srep19694)
Guina T, Deiana M, Calfapietra S, Cabboi B, Maina M, Tuberoso CI, Leonarduzzi G, Gamba P, Gargiulo S & Testa G et al.2015 The role of p38 MAPK in the induction of intestinal inflammation by dietary oxysterols: modulation by wine phenolics. Food and Function 6 1218–1228. (https://doi.org/10.1039/c4fo01116c)
Heo GY, Bederman I, Mast N, Liao WL, Turko IV & Pikuleva IA 2011 Conversion of 7-ketocholesterol to oxysterol metabolites by recombinant CYP27A1 and retinal pigment epithelial cells. Journal of Lipid Research 52 1117–1127. (https://doi.org/10.1194/jlr.M014217)
Hernández Becerra JA, Ochoa Flores AA, Valerio-Alfaro G, Soto-Rodriguez I, Rodríguez-Estrada MT & García HS 2014 Cholesterol oxidation and astaxanthin degradation in shrimp during sun drying and storage. Food Chemistry 145 832–839. (https://doi.org/10.1016/j.foodchem.2013.08.098)
Huang JD, Amaral J, Lee JW & Rodriguez IR 2014 7-Ketocholesterol-induced inflammation signals mostly through the TLR4 receptor both in vitro and in vivo. PLoS ONE 9 e100985. (https://doi.org/10.1371/journal.pone.0100985)
Iuliano L 2011 Pathways of cholesterol oxidation via non-enzymatic mechanisms. Chemistry and Physics of Lipids 164 457–468. (https://doi.org/10.1016/j.chemphyslip.2011.06.006)
Iuliano L, Micheletta F, Natoli S, Ginanni Corradini S, Iappelli M, Elisei W, Giovannelli L, Violi F & Diczfalusy U 2003 Measurement of oxysterols and alpha-tocopherol in plasma and tissue samples as indices of oxidant stress status. Analytical Biochemistry 312 217–223. (https://doi.org/10.1016/s0003-2697(0200467-0)
Jaouadi O, Limam I, Abdelkarim M, Berred E, Chahbi A, Caillot M, Sola B & Ben Aissa-Fennira F 2021 5,6-Epoxycholesterol isomers induce oxiapoptophagy in myeloma cells. Cancers 13 3747. (https://doi.org/10.3390/cancers13153747)
Javitt NB, Lee YC, Shimizu C, Fuda H & Strott CA 2001 Cholesterol and hydroxycholesterol sulfotransferases: identification, distinction from dehydroepiandrosterone sulfotransferase, and differential tissue expression. Endocrinology 142 2978–2984. (https://doi.org/10.1210/endo.142.7.8244)
Kahn E, Baarine M, Pelloux S, Riedinger JM, Frouin F, Tourneur Y & Lizard G 2010 Iron nanoparticles increase 7-ketocholesterol-induced cell death, inflammation, and oxidation on murine cardiac HL1-NB cells. International Journal of Nanomedicine 5 185–195. (https://doi.org/10.2147/ijn.s8458)
Kahn E, Baarine M, Dauphin A, Ragot K, Tissot N, Seguin A, Ménétrier F, Kattan Z, Bachelet CM & Frouin F et al.2011 Impact of 7-ketocholesterol and very long chain fatty acids on oligodendrocyte lipid membrane organization: evaluation via laurdan and FAMIS spectral image analysis. Cytometry: Part A 79 293–305. (https://doi.org/10.1002/cyto.a.21017)
Kanner J & Lapidot T 2001 The stomach as a bioreactor: dietary lipid peroxidation in the gastric fluid and the effects of plant-derived antioxidants. Free Radical Biology and Medicine 31 1388–1395. (https://doi.org/10.1016/s0891-5849(0100718-3)
Kilvington A, Barnaba C, Rajasekaran S, Laurens Leimanis ML & Medina-Meza IG 2021 Lipid profiling and dietary assessment of infant formulas reveal high intakes of major cholesterol oxidative product (7-ketocholesterol). Food Chemistry 354 129529. (https://doi.org/10.1016/j.foodchem.2021.129529)
Lapidot T, Granit R & Kanner J 2005 Lipid hydroperoxidase activity of myoglobin and phenolic antioxidants in simulated gastric fluid. Journal of Agricultural and Food Chemistry 53 3391–3396. (https://doi.org/10.1021/jf040400w)
Lee JI, Kang S, Ahn DU & Lee M 2001 Formation of cholesterol oxides in irradiated raw and cooked chicken meat during storage. Poultry Science 80 105–108. (https://doi.org/10.1093/ps/80.1.105)
Lee HW, Chien JT & Chen BH 2006 Formation of cholesterol oxidation products in marinated foods during heating. Journal of Agricultural and Food Chemistry 54 4873–4879. (https://doi.org/10.1021/jf060461p)
Lee JW, Huang JD & Rodriguez IR 2015 Extra-hepatic metabolism of 7-ketocholesterol occurs by esterification to fatty acids via cPLA2α and SOAT1 followed by selective efflux to HDL. Biochimica et Biophysica Acta 1851 605–619. (https://doi.org/10.1016/j.bbalip.2015.01.007)
Lemaire S, Lizard G, Monier S, Miguet C, Gueldry S, Volot F, Gambert P & Néel D 1998 Different patterns of IL-1beta secretion, adhesion molecule expression and apoptosis induction in human endothelial cells treated with 7alpha-, 7beta-hydroxycholesterol, or 7-ketocholesterol. FEBS Letters 440 434–439. (https://doi.org/10.1016/s0014-5793(9801496-3)
Lembo D, Cagno V, Civra A & Poli G 2016 Oxysterols: an emerging class of broad spectrum antiviral effectors. Molecular Aspects of Medicine 49 23–30. (https://doi.org/10.1016/j.mam.2016.04.003)
Leoni V, Nury T, Vejux A, Zarrouk A, Caccia C, Debbabi M, Fromont A, Sghaier R, Moreau T & Lizard G 2017 Mitochondrial dysfunctions in 7-ketocholesterol-treated 158N oligodendrocytes without or with α-tocopherol: impacts on the cellular profil of tricarboxylic cycle-associated organic acids, long chain saturated and unsaturated fatty acids, oxysterols, cholesterol and cholesterol precursors. Journal of Steroid Biochemistry and Molecular Biology 169 96–110. (https://doi.org/10.1016/j.jsbmb.2016.03.029)
Li G, Sul OJ, Yu R & Choi HS 2022 7-Ketocholesterol-induced micro-RNA-107-5p increases number and activity of osteoclasts by targeting MKP1. International Journal of Molecular Sciences 23 3697. (https://doi.org/10.3390/ijms23073697)
Lismont C, Nordgren M, Van Veldhoven PP & Fransen M 2015 Redox interplay between mitochondria and peroxisomes. Frontiers in Cell and Developmental Biology 3 35. (https://doi.org/10.3389/fcell.2015.00035)
Liu W, Xu L, Lamberson CR, Merkens LS, Steiner RD, Elias ER, Haas D & Porter NA 2013 Assays of plasma dehydrocholesteryl esters and oxysterols from Smith-Lemli-Opitz syndrome patients. Journal of Lipid Research 54 244–253. (https://doi.org/10.1194/jlr.M031732)
López de Frutos L, Cebolla JJ, De Castro-Orós I, Irún P & Giraldo P 2021 Neonatal cholestasis and Niemann-pick type C disease: a literature review. Clinics and Research in Hepatology and Gastroenterology 45 101757. (https://doi.org/10.1016/j.clinre.2021.101757)
Lund EG, Kerr TA, Sakai J, Li WP & Russell DW 1998 cDNA cloning of mouse and human cholesterol 25-hydroxylases, polytopic membrane proteins that synthesize a potent oxysterol regulator of lipid metabolism. Journal of Biological Chemistry 273 34316–34327. (https://doi.org/10.1074/jbc.273.51.34316)
Luo J, Yang H & Song BL 2020 Mechanisms and regulation of cholesterol homeostasis. Nature Reviews: Molecular Cell Biology 21 225–245. (https://doi.org/10.1038/s41580-019-0190-7)
Lyons MA & Brown AJ 1999 7-Ketocholesterol. International Journal of Biochemistry and Cell Biology 31 369–375. (https://doi.org/10.1016/s1357-2725(9800123-x)
Lyons MA & Brown AJ 2001 Metabolism of an oxysterol, 7-ketocholesterol, by sterol 27-hydroxylase in HepG2 cells. Lipids 36 701–711. (https://doi.org/10.1007/s11745-001-0775-8)
Lyons MA, Samman S, Gatto L & Brown AJ 1999 Rapid hepatic metabolism of 7-ketocholesterol in vivo: implications for dietary oxysterols. Journal of Lipid Research 40 1846–1857. (https://doi.org/10.1016/S0022-2275(2034901-4)
Machorro-Méndez IA, Hernández-Mendoza A, Cardenia V, Rodriguez-Estrada MT, Lercker G, Spinelli F, Cellini A & García HS 2013 Assessment of in vitro removal of cholesterol oxidation products by Lactobacillus casei ATCC334. Letters in Applied Microbiology 57 443–450. (https://doi.org/10.1111/lam.12132)
Mahalakshmi K, Parimalanandhini D, Sangeetha R, Livya Catherene M, Beulaja M, Thiagarajan R, Arumugam M, Janarthanan S & Manikandan R 2021 Influential role of 7-ketocholesterol in the progression of Alzheimer’s disease. Prostaglandins and Other Lipid Mediators 156 106582. (https://doi.org/10.1016/j.prostaglandins.2021.106582)
Maor I, Mandel H & Aviram M 1995 Macrophage uptake of oxidized LDL inhibits lysosomal sphingomyelinase, thus causing the accumulation of unesterified cholesterol-sphingomyelin-rich particles in the lysosomes. A possible role for 7-ketocholesterol. Arteriosclerosis, Thrombosis, and Vascular Biology 15 1378–1387. (https://doi.org/10.1161/01.atv.15.9.1378)
Maraschiello C, Esteve E & García Regueiro JA 1998 Cholesterol oxidation in meat from chickens fed alpha-tocopherol- and beta-carotene-supplemented diets with different unsaturation grades. Lipids 33 705–713. (https://doi.org/10.1007/s11745-998-0260-4)
Mathieu J, Schloendorn J, Rittmann BE & Alvarez PJ 2008 Microbial degradation of 7-ketocholesterol. Biodegradation 19 807–813. (https://doi.org/10.1007/s10532-008-9183-5)
Mathieu JM, Schloendorn J, Rittmann BE & Alvarez PJ 2009 Medical bioremediation of age-related diseases. Microbial Cell Factories 8 21. (https://doi.org/10.1186/1475-2859-8-21)
Mathieu JM, Mohn WW, Eltis LD, Leblanc JC, Stewart GR, Dresen C, Okamoto K & Alvarez PJ 2010 7-Ketocholesterol catabolism by Rhodococcus jostii RHA1. Applied and Environmental Microbiology 76 352–355. (https://doi.org/10.1128/AEM.02538-09)
Mathieu JM, Wang F, Segatori L & Alvarez PJ 2012 Increased resistance to oxysterol cytotoxicity in fibroblasts transfected with a lysosomally targeted Chromobacterium oxidase. Biotechnology and Bioengineering 109 2409–2415. (https://doi.org/10.1002/bit.24506)
Mazalli MR & Bragagnolo N 2007 Effect of storage on cholesterol oxide formation and fatty acid alterations in egg powder. Journal of Agricultural and Food Chemistry 55 2743–2748. (https://doi.org/10.1021/jf063267b)
Mitić T, Andrew R, Walker BR & Hadoke PW 2013a 11β-Hydroxysteroid dehydrogenase type 1 contributes to the regulation of 7-oxysterol levels in the arterial wall through the inter-conversion of 7-ketocholesterol and 7β-hydroxycholesterol. Biochimie 95 548–555. (https://doi.org/10.1016/j.biochi.2012.08.007)
Mitić T, Shave S, Semjonous N, Mcnae I, Cobice DF, Lavery GG, Webster SP, Hadoke PW, Walker BR & Andrew R 2013b 11β-Hydroxysteroid dehydrogenase type 1 contributes to the balance between 7-keto- and 7-hydroxy-oxysterols in vivo. Biochemical Pharmacology 86 146–153. (https://doi.org/10.1016/j.bcp.2013.02.002)
Monier S, Samadi M, Prunet C, Denance M, Laubriet A, Athias A, Berthier A, Steinmetz E, Jürgens G & Nègre-Salvayre A et al.2003 Impairment of the cytotoxic and oxidative activities of 7 beta-hydroxycholesterol and 7-ketocholesterol by esterification with oleate. Biochemical and Biophysical Research Communications 303 814–824. (https://doi.org/10.1016/s0006-291x(0300412-1)
Moreira EF, Larrayoz IM, Lee JW & Rodríguez IR 2009 7-Ketocholesterol is present in lipid deposits in the primate retina: potential implication in the induction of VEGF and CNV formation. Investigative Ophthalmology and Visual Science 50 523–532. (https://doi.org/10.1167/iovs.08-2373)
Morzycki JW 2014 Recent advances in cholesterol chemistry. Steroids 83 62–79. (https://doi.org/10.1016/j.steroids.2014.02.001)
Murdolo G, Piroddi M, Tortoioli C, Bartolini D, Schmelz M, Luchetti F, Canonico B, Papa S, Zerbinati C & Iuliano L et al.2016 Free radical-derived oxysterols: novel adipokines modulating adipogenic differentiation of adipose precursor cells. Journal of Clinical Endocrinology and Metabolism 101 4974–4983. (https://doi.org/10.1210/jc.2016-2918)
Mutemberezi V, Guillemot-Legris O & Muccioli GG 2016a Oxysterols: from cholesterol metabolites to key mediators. Progress in Lipid Research 64 152–169. (https://doi.org/10.1016/j.plipres.2016.09.002)
Mutemberezi V, Masquelier J, Guillemot-Legris O & Muccioli GG 2016b Development and validation of an HPLC-MS method for the simultaneous quantification of key oxysterols, endocannabinoids, and ceramides: variations in metabolic syndrome. Analytical and Bioanalytical Chemistry 408 733–745. (https://doi.org/10.1007/s00216-015-9150-z)
Nielsen JH, Olsen CE, Jensen C & Skibsted LH 1996 Cholesterol oxidation in butter and dairy spread during storage. Journal of Dairy Research 63 159–167. (https://doi.org/10.1017/s0022029900031630)
Noguer E, Soules R, Netter C, Nagarathinam C, Leignadier J, Huc-Claustre E, Serhan N, Rives A, de Medina P & Silvente-Poirot S et al.2017 Quantitative analysis of the tumor suppressor dendrogenin A using liquid chromatography tandem mass spectrometry. Chemistry and Physics of Lipids 207 81–86. (https://doi.org/10.1016/j.chemphyslip.2017.06.010)
Nury T, Zarrouk A, Vejux A, Doria M, Riedinger JM, Delage-Mourroux R & Lizard G 2014 Induction of oxiapoptophagy, a mixed mode of cell death associated with oxidative stress, apoptosis and autophagy, on 7-ketocholesterol-treated 158N murine oligodendrocytes: impairment by α-tocopherol. Biochemical and Biophysical Research Communications 446 714–719. (https://doi.org/10.1016/j.bbrc.2013.11.081)
Nury T, Zarrouk A, Mackrill JJ, Samadi M, Durand P, Riedinger JM, Doria M, Vejux A, Limagne E & Delmas D et al.2015 Induction of oxiapoptophagy on 158N murine oligodendrocytes treated by 7-ketocholesterol-, 7β-hydroxycholesterol-, or 24(S)-hydroxycholesterol: protective effects of α-tocopherol and docosahexaenoic acid (DHA; C22:6 n-3). Steroids 99 194–203. (https://doi.org/10.1016/j.steroids.2015.02.003)
Nury T, Zarrouk A, Ragot K, Debbabi M, Riedinger JM, Vejux A, Aubourg P & Lizard G 2017 7-Ketocholesterol is increased in the plasma of X-ALD patients and induces peroxisomal modifications in microglial cells: potential roles of 7-ketocholesterol in the pathophysiology of X-ALD. Journal of Steroid Biochemistry and Molecular Biology 169 123–136. (https://doi.org/10.1016/j.jsbmb.2016.03.037)
Nury T, Sghaier R, Zarrouk A, Ménétrier F, Uzun T, Leoni V, Caccia C, Meddeb W, Namsi A & Sassi K et al.2018 Induction of peroxisomal changes in oligodendrocytes treated with 7-ketocholesterol: attenuation by α-tocopherol. Biochimie 153 181–202. (https://doi.org/10.1016/j.biochi.2018.07.009)
Nury T, Yammine A, Ghzaiel I, Sassi K, Zarrouk A, Brahmi F, Samadi M, Rup-Jacques S, Vervandier-Fasseur D & Pais De Barros JP et al.2021a Attenuation of 7-ketocholesterol- and 7β-hydroxycholesterol-induced oxiapoptophagy by nutrients, synthetic molecules and oils: potential for the prevention of age-related diseases. Ageing Research Reviews 68 101324. (https://doi.org/10.1016/j.arr.2021.101324)
Nury T, Zarrouk A, Yammine A, Mackrill JJ, Vejux A & Lizard G 2021b Oxiapoptophagy: a type of cell death induced by some oxysterols. British Journal of Pharmacology 178 3115–3123. (https://doi.org/10.1111/bph.15173)
Olkkonen VM & Hynynen R 2009 Interactions of oxysterols with membranes and proteins. Molecular Aspects of Medicine 30 123–133. (https://doi.org/10.1016/j.mam.2009.02.004)
Paillasse MR, Saffon N, Gornitzka H, Silvente-Poirot S, Poirot M & de Medina P 2012 Surprising unreactivity of cholesterol-5,6-epoxides towards nucleophiles. Journal of Lipid Research 53 718–725. (https://doi.org/10.1194/jlr.M023689)
Pan X, Connacher RP & O’Connor MB 2021 Control of the insect metamorphic transition by ecdysteroid production and secretion. Current Opinion in Insect Science 43 11–20. (https://doi.org/10.1016/j.cois.2020.09.004)
Pariente A, Peláez R, Pérez-Sala Á & Larráyoz IM 2019 Inflammatory and cell death mechanisms induced by 7-ketocholesterol in the retina. Implications for age-related macular degeneration. Experimental Eye Research 187 107746. (https://doi.org/10.1016/j.exer.2019.107746)
Paz JL, Levy D, Oliveira BA, De Melo TC, de Freitas FA, Reichert CO, Rodrigues A, Pereira J & Bydlowski SP 2019 7-Ketocholesterol promotes oxiapoptophagy in bone marrow mesenchymal stem cell from patients with acute myeloid leukemia. Cells 8 482. (https://doi.org/10.3390/cells8050482)
Perveen I, SS, Naz I, Raza MA & Jahangir A 2016 Biodegradation of 7-ketocholestrol (7-KC) by Thermobifidafusca IP. International Journal of Biosciences 8 83–93. (https://doi.org/10.12692/ijb/8.4.83-93)
Perveen I, Raza MA, Sehar S, Naz I, Memon MI & Ahmed S 2018 Studies on degradation of 7-ketocholesterol by environmental bacterial isolates. Applied Biochemistry and Microbiology 54 262–268. (https://doi.org/10.1134/S0003683818030110)
Petrón MJ, García-Regueiro JA, Martín L, Muriel E & Antequera T 2003 Identification and quantification of cholesterol and cholesterol oxidation products in different types of Iberian hams. Journal of Agricultural and Food Chemistry 51 5786–5791. (https://doi.org/10.1021/jf034100a)
Petrov AM, Kasimov MR & Zefirov AL 2016 Brain cholesterol metabolism and its defects: linkage to neurodegenerative diseases and synaptic dysfunction. Acta Naturae 8 58–73. (https://doi.org/10.32607/20758251-2016-8-1-58-73)
Poli G, Biasi F & Leonarduzzi G 2013 Oxysterols in the pathogenesis of major chronic diseases. Redox Biology 1 125–130. (https://doi.org/10.1016/j.redox.2012.12.001)
Poli G, Leoni V, Biasi F, Canzoneri F, Risso D & Menta R 2022 Oxysterols: from redox bench to industry. Redox Biology 49 102220. (https://doi.org/10.1016/j.redox.2021.102220)
Prunet C, Montange T, Véjux A, Laubriet A, Rohmer JF, Riedinger JM, Athias A, Lemaire-Ewing S, Néel D & Petit JM et al.2006 Multiplexed flow cytometric analyses of pro- and anti-inflammatory cytokines in the culture media of oxysterol-treated human monocytic cells and in the sera of atherosclerotic patients. Cytometry: Part A 69 359–373. (https://doi.org/10.1002/cyto.a.20272)
Ragot K, Mackrill JJ, Zarrouk A, Nury T, Aires V, Jacquin A, Athias A, Pais De Barros JP, Véjux A & Riedinger JM et al.2013 Absence of correlation between oxysterol accumulation in lipid raft microdomains, calcium increase, and apoptosis induction on 158N murine oligodendrocytes. Biochemical Pharmacology 86 67–79. (https://doi.org/10.1016/j.bcp.2013.02.028)
Rao X, Zhong J, Maiseyeu A, Gopalakrishnan B, Villamena FA, Chen LC, Harkema JR, Sun Q & Rajagopalan S 2014 CD36-dependent 7-ketocholesterol accumulation in macrophages mediates progression of atherosclerosis in response to chronic air pollution exposure. Circulation Research 115 770–780. (https://doi.org/10.1161/CIRCRESAHA.115.304666)
Ravi S, Duraisamy P, Krishnan M, Martin LC, Manikandan B, Raman T, Sundaram J, Arumugam M & Ramar M 2021 An insight on 7- ketocholesterol mediated inflammation in atherosclerosis and potential therapeutics. Steroids 172 108854. (https://doi.org/10.1016/j.steroids.2021.108854)
Razzazi-Fazeli E, Kleineisen S & Luf W 2000 Determination of cholesterol oxides in processed food using high-performance liquid chromatography-mass spectrometry with atmospheric pressure chemical ionisation. Journal of Chromatography: A 896 321–334. (https://doi.org/10.1016/s0021-9673(0000719-6)
Risso D, Leoni V, Fania C, Arveda M, Falchero L, Barattero M, Civra A, Lembo D, Poli G & Menta R 2021 Effect of industrial processing and storage procedures on oxysterols in milk and milk products. Food and Function 12 771–780. (https://doi.org/10.1039/d0fo02462g)
Risso D, Leoni V, Canzoneri F, Arveda M, Zivoli R, Peraino A, Poli G & Menta R 2022 Presence of cholesterol oxides in milk chocolates and their correlation with milk powder freshness. PLoS ONE 17 e0264288. (https://doi.org/10.1371/journal.pone.0264288)
Rittmann BE & Schloendorn J 2007 Engineering away lysosomal junk: medical bioremediation. Rejuvenation Research 10 359–365. (https://doi.org/10.1089/rej.2007.0594)
Rodriguez IR & Fliesler SJ 2009 Photodamage generates 7-keto- and 7-hydroxycholesterol in the rat retina via a free radical-mediated mechanism. Photochemistry and Photobiology 85 1116–1125. (https://doi.org/10.1111/j.1751-1097.2009.00568.x)
Rodríguez IR & Larrayoz IM 2010 Cholesterol oxidation in the retina: implications of 7KCh formation in chronic inflammation and age-related macular degeneration. Journal of Lipid Research 51 2847–2862. (https://doi.org/10.1194/jlr.R004820)
Rodriguez-Estrada MT, Garcia-Llatas G & Lagarda MJ 2014 7-Ketocholesterol as marker of cholesterol oxidation in model and food systems: when and how. Biochemical and Biophysical Research Communications 446 792–797. (https://doi.org/10.1016/j.bbrc.2014.02.098)
Rogers MA, Liu J, Song BL, Li BL, Chang CC & Chang TY 2015 Acyl-CoA:cholesterol acyltransferases (ACATs/SOATs): enzymes with multiple sterols as substrates and as activators. Journal of Steroid Biochemistry and Molecular Biology 151 102–107. (https://doi.org/10.1016/j.jsbmb.2014.09.008)
Royer MC, Lemaire-Ewing S, Desrumaux C, Monier S, Pais De Barros JP, Athias A, Néel D & Lagrost L 2009 7-Ketocholesterol incorporation into sphingolipid/cholesterol-enriched (lipid raft) domains is impaired by vitamin E: a specific role for alpha-tocopherol with consequences on cell death. Journal of Biological Chemistry 284 15826–15834. (https://doi.org/10.1074/jbc.M808641200)
Sabolová M, Pohořelá B, Fišnar J, Kouřimská L, Chrpová D & Pánek J 2017 Formation of oxysterols during thermal processing and frozen storage of cooked minced meat. Journal of the Science of Food and Agriculture 97 5092–5099. (https://doi.org/10.1002/jsfa.8386)
Samadi A, Gurlek A, Sendur SN, Karahan S, Akbiyik F & Lay I 2019 Oxysterol species: reliable markers of oxidative stress in diabetes mellitus. Journal of Endocrinological Investigation 42 7–17. (https://doi.org/10.1007/s40618-018-0873-5)
Samadi A, Sabuncuoglu S, Samadi M, Isikhan SY, Chirumbolo S, Peana M, Lay I, Yalcinkaya A & Bjørklund G 2021 A comprehensive review on oxysterols and related diseases. Current Medicinal Chemistry 28 110–136. (https://doi.org/10.2174/0929867327666200316142659)
Sanchez LD, Pontini L, Marinozzi M, Sanchez-Aranguren LC, Reis A & Dias IHK 2021 Cholesterol and oxysterol sulfates: pathophysiological roles and analytical challenges. British Journal of Pharmacology 178 3327–3341. (https://doi.org/10.1111/bph.15227)
Sander BD, Addis PB, Park SW & Smith DE 1989 Quantification of cholesterol oxidation products in a variety of foods. Journal of Food Protection 52 109–114. (https://doi.org/10.4315/0362-028X-52.2.109)
Savouret JF, Antenos M, Quesne M, Xu J, Milgrom E & Casper RF 2001 7-Ketocholesterol is an endogenous modulator for the arylhydrocarbon receptor. Journal of Biological Chemistry 276 3054–3059. (https://doi.org/10.1074/jbc.M005988200)
Schloendorn J, Webb T, Kemmish K, Hamalainen M, Jackemeyer D, Jiang L, Mathieu J, Rebo J, Sankman J & Sherman L et al.2009 Medical bioremediation: a concept moving toward reality. Rejuvenation Research 12 411–419. (https://doi.org/10.1089/rej.2009.0917)
Seet RC, Lee CY, Lim EC, Tan JJ, Quek AM, Chong WL, Looi WF, Huang SH, Wang H & Chan YH et al.2010 Oxidative damage in Parkinson disease: measurement using accurate biomarkers. Free Radical Biology and Medicine 48 560–566. (https://doi.org/10.1016/j.freeradbiomed.2009.11.026)
Shimozawa M, Naito Y, Manabe H, Uchiyama K, Kuroda M, Katada K, Yoshida N & Yoshikawa T 2004 7-Ketocholesterol enhances the expression of adhesion molecules on human aortic endothelial cells by increasing the production of reactive oxygen species. Redox Report: Communications in Free Radical Research 9 370–375. (https://doi.org/10.1179/135100004225006902)
Silvente-Poirot S & Poirot M 2012 Cholesterol epoxide hydrolase and cancer. Current Opinion in Pharmacology 12 696–703. (https://doi.org/10.1016/j.coph.2012.07.007)
Song C, Hiipakka RA & Liao S 2001 Auto-oxidized cholesterol sulfates are antagonistic ligands of liver X receptors: implications for the development and treatment of atherosclerosis. Steroids 66 473–479. (https://doi.org/10.1016/s0039-128x(0000239-7)
Steffen Y, Vuillaume G, Stolle K, Roewer K, Lietz M, Schueller J, Lebrun S & Wallerath T 2012 Cigarette smoke and LDL cooperate in reducing nitric oxide bioavailability in endothelial cells via effects on both eNOS and NADPH oxidase. Nitric Oxide: Biology and Chemistry 27 176–184. (https://doi.org/10.1016/j.niox.2012.06.006)
Szedlacsek SE, Wasowicz E, Hulea SA, Nishida HI, Kummerow FA & Nishida T 1995 Esterification of oxysterols by human plasma lecithin-cholesterol acyltransferase. Journal of Biological Chemistry 270 11812–11819. (https://doi.org/10.1074/jbc.270.20.11812)
Tempel W, Grabovec I, Mackenzie F, Dichenko YV, Usanov SA, Gilep AA, Park HW & Strushkevich N 2014 Structural characterization of human cholesterol 7α-hydroxylase. Journal of Lipid Research 55 1925–1932. (https://doi.org/10.1194/jlr.M050765)
Testa G, Staurenghi E, Zerbinati C, Gargiulo S, Iuliano L, Giaccone G, Fantò F, Poli G, Leonarduzzi G & Gamba P 2016 Changes in brain oxysterols at different stages of Alzheimer’s disease: their involvement in neuroinflammation. Redox Biology 10 24–33. (https://doi.org/10.1016/j.redox.2016.09.001)
Trompier D, Vejux A, Zarrouk A, Gondcaille C, Geillon F, Nury T, Savary S & Lizard G 2014 Brain peroxisomes. Biochimie 98 102–110. (https://doi.org/10.1016/j.biochi.2013.09.009)
van de Bovenkamp P, Kosmeijer-Schuil TG & Katan MB 1988 Quantification of oxysterols in Dutch foods: egg products and mixed diets. Lipids 23 1079–1085. (https://doi.org/10.1007/BF02535656)
Vejux A & Lizard G 2009 Cytotoxic effects of oxysterols associated with human diseases: induction of cell death (apoptosis and/or oncosis), oxidative and inflammatory activities, and phospholipidosis. Molecular Aspects of Medicine 30 153–170. (https://doi.org/10.1016/j.mam.2009.02.006)
Vejux A, Guyot S, Montange T, Riedinger JM, Kahn E & Lizard G 2009 Phospholipidosis and down-regulation of the PI3-K/PDK-1/Akt signalling pathway are vitamin E inhibitable events associated with 7-ketocholesterol-induced apoptosis. Journal of Nutritional Biochemistry 20 45–61. (https://doi.org/10.1016/j.jnutbio.2007.12.001)
Vejux A, Samadi M & Lizard G 2011 Contribution of cholesterol and oxysterols in the physiopathology of cataract: implication for the development of pharmacological treatments. Journal of Ophthalmology 2011 471947. (https://doi.org/10.1155/2011/471947)
Vejux A, Abed-Vieillard D, Hajji K, Zarrouk A, Mackrill JJ, Ghosh S, Nury T, Yammine A, Zaibi M & Mihoubi W et al.2020 7-Ketocholesterol and 7β-hydroxycholesterol: in vitro and animal models used to characterize their activities and to identify molecules preventing their toxicity. Biochemical Pharmacology 173 113648. (https://doi.org/10.1016/j.bcp.2019.113648)
Wamil M, Andrew R, Chapman KE, Street J, Morton NM & Seckl JR 2008 7-oxysterols modulate glucocorticoid activity in adipocytes through competition for 11beta-hydroxysteroid dehydrogenase type. Endocrinology 149 5909–5918. (https://doi.org/10.1210/en.2008-0420)
Watanabe Y, Yamaguchi T, Ishihara N, Nakamura S, Tanaka S, Oka R, Imamura H, Sato Y, Ban N & Kawana H et al.2018 7-Ketocholesterol induces ROS-mediated mRNA expression of 12-lipoxygenase, cyclooxygenase-2 and pro-inflammatory cytokines in human mesangial cells: potential role in diabetic nephropathy. Prostaglandins and Other Lipid Mediators 134 16–23. (https://doi.org/10.1016/j.prostaglandins.2017.11.002)
Weber D, Ni Z, Vetter D, Hoffmann R & Fedorova M 2016 Electrochemical oxidation of cholesterol: an easy way to generate numerous oxysterols in short reaction times. European Journal of Lipid Science and Technology 118 325–331. (https://doi.org/10.1002/ejlt.201500101)
Wnętrzak A, Chachaj-Brekiesz A, Stępniak A, Kobierski J & Dynarowicz-Latka P 2022 Different effects of oxysterols on a model lipid raft – langmuir monolayer study complemented with theoretical calculations. Chemistry and Physics of Lipids 244 105182. (https://doi.org/10.1016/j.chemphyslip.2022.105182)
Yammine A, Zarrouk A, Nury T, Vejux A, Latruffe N, Vervandier-Fasseur D, Samadi M, Mackrill JJ, Greige-Gerges H & Auezova L et al.2020 Prevention by dietary polyphenols (resveratrol, quercetin, apigenin) against 7-ketocholesterol-induced oxiapoptophagy in neuronal N2a cells: potential interest for the treatment of neurodegenerative and age-related diseases. Cells 9 2346. (https://doi.org/10.3390/cells9112346)
Yan PS 1999 Cholesterol oxidation products. Their occurrence and detection in our foodstuffs. Advances in Experimental Medicine and Biology 459 79–98. (https://doi.org/10.1007/978-1-4615-4853-9_6)
Yang L, Yu P, Chen M & Lei B 2022 Mammalian target of rapamycin inhibitor rapamycin alleviates 7-ketocholesterol induced inflammatory responses and vascular endothelial growth factor elevation by regulating MAPK pathway in human retinal pigment epithelium cells. Journal of Ocular Pharmacology and Therapeutics 38 189–200. (https://doi.org/10.1089/jop.2021.0082)
You JS, Lim H, Seo JY, Kang KR, Kim DK, Oh JS, Seo YS, Lee GJ, Kim JS & Kim HJ et al.2021 25-Hydroxycholesterol-induced oxiapoptophagy in L929 mouse fibroblast cell line. Molecules 27 199. (https://doi.org/10.3390/molecules27010199)
Yuan XM, Sultana N, Siraj N, Ward LJ, Ghafouri B & Li W 2016 Autophagy induction protects against 7-oxysterol-induced cell death via lysosomal pathway and oxidative stress. Journal of Cell Death 9 1–7. (https://doi.org/10.4137/JCD.S37841)
Zahm JM, Baconnais S, Monier S, Bonnet N, Bessède G, Gambert P, Puchelle E & Lizard G 2003 Chronology of cellular alterations during 7-ketocholesterol-induced cell death on A7R5 rat smooth muscle cells: analysis by time lapse-video microscopy and conventional fluorescence microscopy. Cytometry: Part A 52 57–69. (https://doi.org/10.1002/cyto.a.10027)
Zanjani BN, Samadi A, Isikhan SY, Lay I, Beyaz S, Gelincik A, Buyukozturk S & Arda N 2022 Plasma levels of oxysterols 7-ketocholesterol and cholestane-3β, 5α, 6β-triol in patients with allergic asthma. Journal of Asthma 2022 1–10. (https://doi.org/10.1080/02770903.2022.2045310)
Zarrouk A, Vejux A, Nury T, El Hajj HI, Haddad M, Cherkaoui-Malki M, Riedinger JM, Hammami M & Lizard G 2012 Induction of mitochondrial changes associated with oxidative stress on very long chain fatty acids (C22:0, C24:0, or C26:0)-treated human neuronal cells (SK-NB-E). Oxidative Medicine and Cellular Longevity 2012 623257. (https://doi.org/10.1155/2012/623257)
Zarrouk A, Vejux A, Mackrill J, O’Callaghan Y, Hammami M, O’Brien N & Lizard G 2014 Involvement of oxysterols in age-related diseases and ageing processes. Ageing Research Reviews 18 148–162. (https://doi.org/10.1016/j.arr.2014.09.006)
Zarrouk A, Nury T, Karym EM, Vejux A, Sghaier R, Gondcaille C, Andreoletti P, Trompier D, Savary S & Cherkaoui-Malki M et al.2017 Attenuation of 7-ketocholesterol-induced overproduction of reactive oxygen species, apoptosis, and autophagy by dimethyl fumarate on 158N murine oligodendrocytes. Journal of Steroid Biochemistry and Molecular Biology 169 29–38. (https://doi.org/10.1016/j.jsbmb.2016.02.024)
Zerbinati C & Iuliano L 2017 Cholesterol and related sterols autoxidation. Free Radical Biology and Medicine 111 151–155. (https://doi.org/10.1016/j.freeradbiomed.2017.04.013)
Zhang Y, Yu C, Liu J, Spencer TA, Chang CC & Chang TY 2003 Cholesterol is superior to 7-ketocholesterol or 7 alpha-hydroxycholesterol as an allosteric activator for acyl-coenzyme A:cholesterol acyltransferase 1. Journal of Biological Chemistry 278 11642–11647. (https://doi.org/10.1074/jbc.M211559200)
Zhang YY, Shi YN, Zhu N, Wang W, Deng CF, Xie XJ, Liao DF & Qin L 2020 Autophagy: a killer or guardian of vascular smooth muscle cells. Journal of Drug Targeting 28 449–455. (https://doi.org/10.1080/1061186X.2019.1705312)
Zhou H & Hylemon PB 2014 Bile acids are nutrient signaling hormones. Steroids 86 62–68. (https://doi.org/10.1016/j.steroids.2014.04.016)