The Intracellular Cholesterol Landscape: Dynamic Integrator of the Immune Response

Fessler, Michael B.

doi:10.1016/j.it.2016.09.001

Cited by 83 publications

(91 citation statements)

References 76 publications

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“…In contrast, activated B cells increase glycolysis and OXPHOS equally. The details of these pathways are beyond the scope of this review and have been extensively described elsewhere [23–29]. …”

Section: Metabolism and Its Regulation In Lymphocytesmentioning

confidence: 99%

Metabolic abnormalities and oxidative stress in lupus

Lightfoot

Blanco

Kaplan

2017

Current Opinion in Rheumatology

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Purpose of review Upon antigen exposure, immune cells rely on cell-specific metabolic pathways to mount an efficient immune response. In autoimmunity, failure in critical metabolic checkpoints may lead to immune cell hyper-activation and tissue damage. Oxidative stress in autoimmune patients can also contribute to immune dysregulation and injury to the host. Recent insights into the immune cell metabolism signatures specifically associated with systemic lupus erythematosus (SLE) and the consequences of heightened oxidative stress in patients are discussed herein. Recent findings Glucose metabolism inhibitors, mTOR pathway modulators, and PPARγ-activating compounds demonstrate therapeutic benefit in experimental models of lupus. Mitochondrial-derived reactive oxygen species (ROS) and molecular modifications induced by oxidative stress appear to be detrimental in lupus. Effective therapies tailored towards the reconfiguration of metabolic imbalances in lupus immune cells and the reduction of mitochondrial ROS production/availability are currently being tested. Summary A paucity of knowledge exists regarding the metabolic needs of a number of immune cells involved in the pathogenesis of SLE, including myeloid cells and B cells. Nonetheless, SLE-specific metabolic signatures have been identified and their specific targeting, along with mitochondrial ROS inhibitors/scavengers, could show therapeutic advantage in lupus patients.

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Section: Metabolism and Its Regulation In Lymphocytesmentioning

confidence: 99%

Metabolic abnormalities and oxidative stress in lupus

Lightfoot

Blanco

Kaplan

2017

Current Opinion in Rheumatology

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“…One potential way for studying the SV ratio would be comparison of polyploid cells obtained through inhibition of cell division to those obtained through cell fusion. Note that statins inhibit an early part in the mevalonate pathway, thus reducing the levels of numerous lipophilic metabolites required for normal mitochondrial function, cell signalling, autophagy and plasma membrane synthesis [10,46,79,86,87]. In contrast, cells that become polyploid and large by normal growth in the absence of cell division should have less surplus membrane (although they may have excess lipids for building membranes) and thus substantially lower SV ratio compared to fused cells.…”

Section: Biophysical Mechanisms Connecting Cell Size To Fitness and Fmentioning

confidence: 99%

“…Note that statins inhibit an early part in the mevalonate pathway, thus reducing the levels of numerous lipophilic metabolites required for normal mitochondrial function, cell signalling, autophagy and plasma membrane synthesis [10,46,79,86,87]. The mevalonate pathway inhibition induces expression of inflammatory cytokines such as interleukin 1 beta (IL-1b) [86,87]. B: Statins influence mitochondrial dynamics in human cells.…”

Section: Biophysical Mechanisms Connecting Cell Size To Fitness and Fmentioning

confidence: 99%

“…It is worth pointing out that high concentrations of statins can severe toxicity, which reduces cell size, and different cell types have vastly different sensitivity to statins [10]. As inflammation can further downregulate the mevalonate pathway [86,87], this may induce a feedback causing further increase in size and enhanced inflammation. Jurkat cell mitochondria (green) were imaged after mevalonate pathway inhibition with statins.…”

Section: Biophysical Mechanisms Connecting Cell Size To Fitness and Fmentioning

confidence: 99%

“…Thus, cell size effects on metabolism and cellular fitness may be useful for understanding certain aspects of these diseases. Increased cell size, such as observed during compensatory growth of pancreatic beta-cells in insulin resistance [85], may be linked to reduction in mevalonate pathway activity [10,67], which induces an inflammatory response [86][87][88] (Fig. Inflammation is a signature of cellular injury and thus a potential indicator of reduced cellular fitness.…”

Section: Emerging Links Between Cell Size and Metabolic Diseasementioning

confidence: 99%

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Cell size control – a mechanism for maintaining fitness and function

et al. 2017

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The maintenance of cell size homeostasis has been studied for years in different cellular systems. With the focus on 'what regulates cell size', the question 'why cell size needs to be maintained' has been largely overlooked. Recent evidence indicates that animal cells exhibit nonlinear cell size dependent growth rates and mitochondrial metabolism, which are maximal in intermediate sized cells within each cell population. Increases in intracellular distances and changes in the relative cell surface area impose biophysical limitations on cells, which can explain why growth and metabolic rates are maximal in a specific cell size range. Consistently, aberrant increases in cell size, for example through polyploidy, are typically disadvantageous to cellular metabolism, fitness and functionality. Accordingly, cellular hypertrophy can potentially predispose to or worsen metabolic diseases. We propose that cell size control may have emerged as a guardian of cellular fitness and metabolic activity.

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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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The Intracellular Cholesterol Landscape: Dynamic Integrator of the Immune Response

Cited by 83 publications

References 76 publications

Metabolic abnormalities and oxidative stress in lupus

Metabolic abnormalities and oxidative stress in lupus

Cell size control – a mechanism for maintaining fitness and function

Lipid Oxidation Derived Aldehydes and Oxysterols Between Health and Disease

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