Oxysterols in Metabolic Syndrome: From Bystander Molecules to Bioactive Lipids

Guillemot-Legris, Owein; Mutemberezi, Valentin; Muccioli, Giulio G.

doi:10.1016/j.molmed.2016.05.006

Cited by 61 publications

(52 citation statements)

References 121 publications

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“…Metabolic syndrome has been associated with oxysterols (Guillemot-Legris et al, 2016). However, the incidence of metabolic syndrome under haloperidol exposure is comparable to, or even lower than with second generation antipsychotic drugs, and some second generation antipsychotic drugs that cause metabolic syndrome did not show elevated 7DHC levels in the blood samples we tested (Kahn et al, 2008).…”

Section: Discussionmentioning

confidence: 99%

“…While its role as a precursor for cholesterol, vitamin D and neurosteroids might be beneficial for brain function, 7DHC and 8DHC are a source of lipid peroxidation and oxysterols (Liu et al, 2013; Xu et al, 2009). Of relevance to treatment with psychotropic drugs, oxysterols have been associated with metabolic syndrome, a side effect of treatment with psychoactive drugs manifested in cardiovascular disease and obesity (Guillemot-Legris et al, 2016). Moreover, cellular stress caused by lipid peroxidation might contribute to the extrapyramidal side effects in the brain caused by treatment.…”

Section: Introductionmentioning

confidence: 99%

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Effect of psychotropic drug treatment on sterol metabolism

Korade¹,

Liu

Warren

et al. 2017

Schizophrenia Research

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Cholesterol metabolism is vital for brain function. Previous work in cultured cells has shown that a number of psychotropic drugs inhibit the activity of 7-dehydrocholesterol reductase (DHCR7), an enzyme that catalyzes the final steps in cholesterol biosynthesis. This leads to the accumulation of 7-dehydrocholesterol (7DHC), a molecule that gives rise to oxysterols, vitamin D, and atypical neurosteroids. We examined levels of cholesterol and the cholesterol precursors desmosterol, lanosterol, 7DHC and its isomer 8-dehydrocholesterol (8DHC), in blood samples of 123 psychiatric patients on various antipsychotic and antidepressant drugs, and 85 healthy controls, to see if the observations in cell lines hold true for patients as well. Three drugs, aripiprazole, haloperidol and trazodone increased circulating 7DHC and 8DHC levels, while five other drugs, clozapine, escitalopram/citalopram, lamotrigine, olanzapine, and risperidone, did not. Studies in rat brain verified that haloperidol dose-dependently increased 7DHC and 8DHC levels, while clozapine had no effect. We conclude that further studies should investigate the role of 7DHC and 8DHC metabolites, such as oxysterols, vitamin D, and atypical neurosteroids, in the deleterious and therapeutic effects of psychotropic drugs. Finally, we recommend that drugs that increase 7DHC levels should not be prescribed during pregnancy, as children born with DHCR7 deficiency have multiple congenital malformations.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Effect of psychotropic drug treatment on sterol metabolism

Korade¹,

Liu

Warren

et al. 2017

Schizophrenia Research

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“…Noticeably, in addition to oxidized fatty acyls, oxysterols play important roles in macrophage and EC biology [70, 71] (Box 1). As the esterified oxidized PUFA decompose to produce so-called oxidation end products, namely, short carbon chain aldehydes and ketones, they become uniformly proinflammatory.…”

Section: Inflammatory Effects Of Lipid Oxidation End Productsmentioning

confidence: 99%

“…Oxysterols, found both intracellularly and in OxLDL, induce a large number of profound cellular responses. For example, 7-ketocholesterol, a product of ROS-mediated cholesterol oxidation in OxLDL, regulates endothelial biomechanics and induces expression of inflammatory genes [70, 71]; enzymatically produced 25-hydroxycholesterol (25-OHC), among other oxysterols, activates the anti-inflammatory liver X receptor and other nuclear receptors and regulates function of insulin-induced gene 1. As is the case with oxidized PUFA products, oxysterols mediate both pro- and anti- inflammatory responses.…”

Section: Inflammatory Effects Of Lipid Oxidation End Productsmentioning

confidence: 99%

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Context-Dependent Role of Oxidized Lipids and Lipoproteins in Inflammation

Miller

Shyy

2017

Trends in Endocrinology & Metabolism

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Oxidized low-density lipoprotein (OxLDL), which contains hundreds of different oxidized lipid molecules, is a hallmark of hyperlipidemia and atherosclerosis. The same oxidized lipids found in OxLDL are also formed in apoptotic cells, and are present in tissues as well as in the circulation under pathological conditions. In many disease contexts, oxidized lipids constitute damage signals, or patterns, that activate pattern-recognition receptors and significantly contribute to inflammation. This article reviews recent discoveries and emerging trends in the field of oxidized lipids and regulation of inflammation, focusing on oxidation products of polyunsaturated fatty acids esterified into cholesteryl esters and phospholipids. The paper highlights context-dependent activation and biased agonism of TLR4 and the NLRP3 inflammasome, among other signaling pathways activated by oxidized lipids.

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Lipid Oxidation Derived Aldehydes and Oxysterols Between Health and Disease

Sottero

Leonarduzzi

Testa

et al. 2018

Euro J Lipid Sci & Tech

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Non‐enzymatic and enzymatic oxidation of lipids has long been a primary issue in human pathophysiology, with special emphasis on diet‐ and nutrition‐related aspects. While there is no doubt that the n‐3 polyunsaturated fatty acids (PUFAs), eicosapentaenoic acid, and docosahexaenoic acid, exert anti‐inflammatory, inflammation resolving, and immunomodulatory effects in different model systems, their non‐enzymatic oxidation during food storage and cooking, as well as during gastrointestinal digestion, can give rise to excessive amounts of quite reactive aldehydic end‐products, in particular 4‐hydroxyhexenal. However, the non‐enzymatic oxidation of n‐6 PUFAs is, in principle, far more harmful, not least because one of its main end‐products, 4‐hydroxynonenal, has been shown to be associated with the progression of a number of human diseases. Several cholesterol oxidation products, known as oxysterols, are also of primary nutritional importance; these can be generated in the human body through both enzymatic and non‐enzymatic reactions, but may also be present in the diet in excessive amounts due to the autoxidation of cholesterol‐containing foods. Their potential contribution to the pathogenesis and progression of human diseases in which hypercholesterolemia is a primary risk factor, such as atheroclerosis, Alzheimer's disease, and some forms of cancers, has been unanimously recognized. Practical Applications: This review highlights the importance of certain lipid oxidation products, namely 4‐hydroxyalkenals and oxysterols, in the modulation of processes fundamental to human health and disease. The observations and facts reviewed here underline the need to carefully consider the pros and cons of the dietary intake and metabolic fate of n‐3 PUFA, n‐6 PUFA, and cholesterol, when producing, storing, and processing lipid‐containing food. Lipid oxidation is a common process that occurs through both enzymatic and non‐enzymatic reactions. It is responsible for the formation of several compounds, including polyunsaturated fatty acid (PUFA)‐derived 4‐hydroxyalkenals and cholesterol oxidation products, namely oxysterols. Depending on their concentrations, these molecules possess physiopathological properties involved in cell viability and function. At high concentrations, such as those resulting from intense oxidative stress or excessive fatty food intake, they are associated to the onset of many diseases. A correct diet regimen, improved food processing and storage, and suitable antioxidant supplementation, should be implemented to counteract promotion of disease development by excess oxidized lipids. (HHE, 4‐hydroxyhexenal; HNE, 4‐hydroxynonenal; ROS, reactive oxygen species).

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Oxysterols in Metabolic Syndrome: From Bystander Molecules to Bioactive Lipids

Cited by 61 publications

References 121 publications

Effect of psychotropic drug treatment on sterol metabolism

Effect of psychotropic drug treatment on sterol metabolism

Context-Dependent Role of Oxidized Lipids and Lipoproteins in Inflammation

Lipid Oxidation Derived Aldehydes and Oxysterols Between Health and Disease

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