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Nature Reviews. Cardiology Oct 2021Increases in calorie consumption and sedentary lifestyles are fuelling a global pandemic of cardiometabolic diseases, including coronary artery disease, diabetes... (Review)
Review
Increases in calorie consumption and sedentary lifestyles are fuelling a global pandemic of cardiometabolic diseases, including coronary artery disease, diabetes mellitus, cardiomyopathy and heart failure. These lifestyle factors, when combined with genetic predispositions, increase the levels of circulating lipids, which can accumulate in non-adipose tissues, including blood vessel walls and the heart. The metabolism of these lipids produces bioactive intermediates that disrupt cellular function and survival. A compelling body of evidence suggests that sphingolipids, such as ceramides, account for much of the tissue damage in these cardiometabolic diseases. In humans, serum ceramide levels are proving to be accurate biomarkers of adverse cardiovascular disease outcomes. In mice and rats, pharmacological inhibition or depletion of enzymes driving de novo ceramide synthesis prevents the development of diabetes, atherosclerosis, hypertension and heart failure. In cultured cells and isolated tissues, ceramides perturb mitochondrial function, block fuel usage, disrupt vasodilatation and promote apoptosis. In this Review, we discuss the body of literature suggesting that ceramides are drivers - and not merely passengers - on the road to cardiovascular disease. Moreover, we explore the feasibility of therapeutic strategies to lower ceramide levels to improve cardiovascular health.
Topics: Animals; Cardiovascular Diseases; Ceramides; Mice; Rats; Sphingolipids
PubMed: 33772258
DOI: 10.1038/s41569-021-00536-1 -
Chemistry and Physics of Lipids Nov 2018In the last 30 years, ceramides have been found to mediate a myriad of biological processes. Ceramides have been recognized as bioactive molecules and their metabolizing... (Review)
Review
In the last 30 years, ceramides have been found to mediate a myriad of biological processes. Ceramides have been recognized as bioactive molecules and their metabolizing enzymes are attractive targets in cancer therapy and other diseases. The molecular mechanism of action of cellular ceramides are still not fully established, with insights into roles through modification of lipid rafts, creation of ceramide platforms, ceramide channels, or through regulation of direct protein effectors such as protein phosphatases and kinases. Recently, the 'Many Ceramides' hypothesis focuses on distinct pools of subcellular ceramides and ceramide species as potential defined bioactive entities. Traditional methods that measure changes in ceramide levels in the whole cell, such as mass spectrometry, fluorescent ceramide analogues, and ceramide antibodies, fail to differentiate specific bioactive species at the subcellular level. However, a few ceramide binding proteins have been reported, and a smaller subgroup within these, have been shown to translocate to ceramide-enriched membranes, revealing these localized pools of bioactive ceramides. In this review we want to discuss and consolidate these works and explore the possibility of defining these binding proteins as new tools are emerging to visualize bioactive ceramides in cells. Our goal is to encourage the scientific community to explore these ceramide partners, to improve techniques to refine the list of these binding partners, making possible the identification of specific domains that recognize and bind ceramides to be used to visualize the 'Many Ceramides' in the cell.
Topics: Animals; Ceramides; Humans
PubMed: 30266560
DOI: 10.1016/j.chemphyslip.2018.09.013 -
Seminars in Nephrology May 2022Altered lipid metabolism is a characteristic feature and potential driving factor of acute kidney injury (AKI). Of the lipids that accumulate in injured renal tissues,... (Review)
Review
Altered lipid metabolism is a characteristic feature and potential driving factor of acute kidney injury (AKI). Of the lipids that accumulate in injured renal tissues, ceramides are potent regulators of metabolism and cell fate. Up-regulation of ceramide synthesis is a common feature shared across several AKI etiologies in vitro and in vivo. Furthermore, ceramide accumulation is an early event in the natural history of AKI that precedes cell death and organ dysfunction. Emerging evidence suggests that inhibition of ceramide accumulation may improve renal outcomes in several models of AKI. This review examines the landscape of ceramide metabolism and regulation in the healthy and injured kidney. Furthermore, we discuss the body of literature regarding ceramides as therapeutic targets for AKI and consider potential mechanisms by which ceramides drive kidney pathogenesis.
Topics: Humans; Ceramides; Acute Kidney Injury; Kidney; Lipid Metabolism
PubMed: 36404212
DOI: 10.1016/j.semnephrol.2022.10.007 -
Biochemical and Biophysical Research... Dec 2022Sphingomyelin has been considered as a merely structural lipid for many years. However, this organelle-specific lipid has many other roles, including increasing membrane... (Review)
Review
Sphingomyelin has been considered as a merely structural lipid for many years. However, this organelle-specific lipid has many other roles, including increasing membrane molecular order, acting as a source of ceramide in cell signaling and apoptosis, and forming clusters/nanodomains with cholesterol and ceramide. This contribution is dedicated to Professor E. Carafoli, on occasion of his 90th anniversary.
Topics: Sphingomyelins; Ceramides; Cholesterol; Apoptosis; Sphingomyelin Phosphodiesterase
PubMed: 36344153
DOI: 10.1016/j.bbrc.2022.08.074 -
The Journal of Biological Chemistry Aug 2011Intensive research over the past 2 decades has implicated ceramide in the regulation of several cell responses. However, emerging evidence points to dramatic... (Review)
Review
Intensive research over the past 2 decades has implicated ceramide in the regulation of several cell responses. However, emerging evidence points to dramatic complexities in ceramide metabolism and structure that defy the prevailing unifying hypothesis on ceramide function that is based on the understanding of ceramide as a single entity. Here, we develop the concept that "ceramide" constitutes a family of closely related molecules, subject to metabolism by >28 enzymes and with >200 structurally distinct mammalian ceramides distinguished by specific structural modifications. These ceramides are synthesized in a combinatorial fashion with distinct enzymes responsible for the specific modifications. These multiple pathways of ceramide generation led to the hypothesis that individual ceramide molecular species are regulated by specific biochemical pathways in distinct subcellular compartments and execute distinct functions. In this minireview, we describe the "many ceramides" paradigm, along with the rationale, supporting evidence, and implications for our understanding of bioactive sphingolipids and approaches for unraveling these pathways.
Topics: Animals; Ceramides; Humans; Lipid Metabolism; Molecular Structure
PubMed: 21693702
DOI: 10.1074/jbc.R111.254359 -
Biomolecules Jun 2021Ceramide is a bioactive sphingolipid involved in numerous cellular processes. In addition to being the precursor of complex sphingolipids, ceramides can act as second... (Review)
Review
Ceramide is a bioactive sphingolipid involved in numerous cellular processes. In addition to being the precursor of complex sphingolipids, ceramides can act as second messengers, especially when they are generated at the plasma membrane of cells. Its metabolic dysfunction may lead to or be a consequence of an underlying disease. Recent reports on transcriptomics and electrospray ionization mass spectrometry analysis have demonstrated the variation of specific levels of sphingolipids and enzymes involved in their metabolism in different neurodegenerative diseases. In the present review, we highlight the most relevant discoveries related to ceramide and neurodegeneration, with a special focus on Parkinson's disease.
Topics: Animals; Antiparkinson Agents; Ceramides; Drug Delivery Systems; Humans; Lipid Metabolism; Oxidoreductases; Parkinson Disease; Sphingolipids
PubMed: 34202192
DOI: 10.3390/biom11070945 -
Advances in Cancer Research 2018Ceramides, important players in signal transduction, interact with multiple cellular pathways, including p53 pathways. However, the relationship between ceramide and p53... (Review)
Review
Ceramides, important players in signal transduction, interact with multiple cellular pathways, including p53 pathways. However, the relationship between ceramide and p53 is very complex, and mechanisms underlying their coregulation are diverse and not fully characterized. The role of p53, an important cellular regulator and a transcription factor, is linked to its tumor suppressor function. Ceramides are involved in the regulation of fundamental processes in cancer cells including cell death, proliferation, autophagy, and drug resistance. This regulation, however, can be pro-death or pro-survival depending on cancer type, the balance between ceramide species, the rate of their synthesis and utilization, and the availability of a specific array of downstream targets. This chapter highlights the central role of ceramide in sphingolipid metabolism, its role in cancer, specific effectors in ceramide pathways controlled by p53, and coregulation of ceramide and p53 signaling. We discuss the recent studies, which underscore the function of p53 in the regulation of ceramide pathways and the reciprocal regulation of p53 by ceramide. This complex relationship is based on several molecular mechanisms including the p53-dependent transcriptional regulation of enzymes in sphingolipid pathways, the activation of mutant p53 through ceramide-mediated alternative splicing, as well as modulation of the p53 function through direct and indirect effects on p53 coregulators and downstream targets. Further insight into the connections between ceramide and p53 will allow simultaneous targeting of the two pathways with a potential to yield more efficient anticancer therapeutics.
Topics: Animals; Apoptosis; Autophagy; Ceramides; Humans; Neoplasms; Signal Transduction; Tumor Suppressor Protein p53
PubMed: 30060809
DOI: 10.1016/bs.acr.2018.04.011 -
International Journal of Molecular... Jan 2019In addition to playing a role as a structural component of cellular membranes, ceramide is now clearly recognized as a bioactive lipid implicated in a variety of... (Review)
Review
In addition to playing a role as a structural component of cellular membranes, ceramide is now clearly recognized as a bioactive lipid implicated in a variety of physiological functions. This review aims to provide updated information on the role of ceramide in the regulation of vascular tone. Ceramide may induce vasodilator or vasoconstrictor effects by interacting with several signaling pathways in endothelial and smooth muscle cells. There is a clear, albeit complex, interaction between ceramide and redox signaling. In fact, reactive oxygen species (ROS) activate different ceramide generating pathways and, conversely, ceramide is known to increase ROS production. In recent years, ceramide has emerged as a novel key player in oxygen sensing in vascular cells and mediating vascular responses of crucial physiological relevance such as hypoxic pulmonary vasoconstriction (HPV) or normoxic ductus arteriosus constriction. Likewise, a growing body of evidence over the last years suggests that exaggerated production of vascular ceramide may have detrimental effects in a number of pathological processes including cardiovascular and lung diseases.
Topics: Animals; Biomarkers; Blood Vessels; Ceramides; Disease Susceptibility; Endothelium, Vascular; Energy Metabolism; Humans; Mechanotransduction, Cellular; Metabolic Networks and Pathways; Oxidation-Reduction; Oxygen; Reactive Oxygen Species; Signal Transduction; Vasomotor System
PubMed: 30669371
DOI: 10.3390/ijms20020411 -
Nature Metabolism Nov 2019Ceramides are products of metabolism that accumulate in individuals with obesity or dyslipidaemia and alter cellular processes in response to fuel surplus. Their... (Review)
Review
Ceramides are products of metabolism that accumulate in individuals with obesity or dyslipidaemia and alter cellular processes in response to fuel surplus. Their actions, when prolonged, elicit the tissue dysfunction that underlies diabetes and heart disease. Here, we review the history of research on these enigmatic molecules, exploring their discovery and mechanisms of action, the evolutionary pressures that have given them their unique attributes and the potential of ceramide-reduction therapies as treatments for cardiometabolic disease.
Topics: Animals; Ceramides; Dyslipidemias; Humans; Insulin Resistance; Obesity; Severity of Illness Index; Signal Transduction
PubMed: 32694860
DOI: 10.1038/s42255-019-0134-8 -
European Journal of Cell Biology Sep 2023Different studies corroborate a role for ceramide synthases and their downstream products, ceramides, in modulation of apoptosis and autophagy in the context of cancer.... (Review)
Review
Different studies corroborate a role for ceramide synthases and their downstream products, ceramides, in modulation of apoptosis and autophagy in the context of cancer. These mechanisms of regulation, however, appear to be context dependent in terms of ceramides' fatty acid chain length, subcellular localization, and the presence or absence of their downstream targets. Our current understanding of the role of ceramide synthases and ceramides in regulation of apoptosis and autophagy could be harnessed to pioneer the development of new treatments to activate or inhibit a single type of ceramide synthase, thereby regulating the apoptosis induction or cross talk of apoptosis and autophagy in cancer cells. Moreover, the apoptotic function of ceramide suggests that ceramide analogues can pave the way for the development of novel cancer treatments. Therefore, in the current review paper we discuss the impact of ceramide synthases and ceramides in regulation of apoptosis and autophagy in context of different types of cancers. We also briefly introduce the latest information on ceramide synthase inhibitors, their application in diseases including cancer therapy, and discuss approaches for drug discovery in the field of ceramide synthase inhibitors. We finally discussed strategies for developing strategies to use lipids and ceramides analysis in biological fluids for developing early biomarkers for cancer.
Topics: Humans; Ceramides; Neoplasms; Apoptosis; Autophagy
PubMed: 37392580
DOI: 10.1016/j.ejcb.2023.151337