Sphingolipids in metabolic disease: The good, the bad, and the unknown

Green, Christopher D.; Maceyka, Michael; Cowart, L. Ashley; Spiegel, Sarah

doi:10.1016/j.cmet.2021.06.006

Cited by 128 publications

(129 citation statements)

References 125 publications

(154 reference statements)

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“…De novo sphingolipid synthesis requires several enzymatic steps performed by enzymes such as ceramide synthases (CerS), serine palmitoyl-CoA transferase (SPT), 3-ketosphinganine reductase (KSR) and dihydroceramide desaturase (DES), which are continuously explored for their pharmacological potential as targets in certain metabolic diseases [13]. The ceramide biosynthesis pathway starts with the condensation of palmitoyl-CoA and serine, to produce 3-ketosphinganine, a reaction that is catalyzed by SPT [14]. 3-ketosphinganine is then reduced to sphinganine via KSR.…”

Section: Ceramidesmentioning

confidence: 99%

Involvement of Ceramides in Non-Alcoholic Fatty Liver Disease (NAFLD) Atherosclerosis (ATS) Development: Mechanisms and Therapeutic Targets

et al. 2021

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Non-alcoholic fatty liver disease (NAFLD) and atherosclerosis (ATS) are worldwide known diseases with increased incidence and prevalence. These two are driven and are interconnected by multiple oxidative and metabolic functions such as lipotoxicity. A gamut of evidence suggests that sphingolipids (SL), such as ceramides, account for much of the tissue damage. Although in humans they are proving to be accurate biomarkers of adverse cardiovascular disease outcomes and NAFLD progression, in rodents, pharmacological inhibition or depletion of enzymes driving de novo ceramide synthesis prevents the development of metabolic driven diseases such as diabetes, ATS, and hepatic steatosis. In this narrative review, we discuss the pathways which generate the ceramide synthesis, the potential use of circulating ceramides as novel biomarkers in the development and progression of ATS and related diseases, and their potential use as therapeutic targets in NAFDL-ATS development which can further provide new clues in this field.

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Section: Ceramidesmentioning

confidence: 99%

Involvement of Ceramides in Non-Alcoholic Fatty Liver Disease (NAFLD) Atherosclerosis (ATS) Development: Mechanisms and Therapeutic Targets

et al. 2021

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“…They are also part of cell membrane, where they influence vesicular transport, membrane receptors, and exosome secretion [29]. Thus, ceramides are implicated in both intracellular and cell-to-cell signaling [31]. Ceramides synthesis and accumulation are influenced by multiple factors, which include excessive supply of substrates, systemic inflammation, oxidative stress and the microbiome [31].…”

Section: Ceramides In Cardiometabolic Health and Diseasesmentioning

confidence: 99%

“…Thus, ceramides are implicated in both intracellular and cell-to-cell signaling [31]. Ceramides synthesis and accumulation are influenced by multiple factors, which include excessive supply of substrates, systemic inflammation, oxidative stress and the microbiome [31]. In obesity, levels of Tumor Necrosis Factor-Alpha (TNF-α) are elevated, and Toll-like receptors (TLRs) are stimulated by excess of fatty acids [32].…”

Section: Ceramides In Cardiometabolic Health and Diseasesmentioning

confidence: 99%

“…Thoracic adipose tissue of obese individuals secretes a particular ceramide species, named Cer (18:1;2/16:0), which acts on endothelial cells to reduce vasodilatation, induce inflammation, oxidative stress, and finally increase risk of cardiovascular death [55]. Again, circulating long-chain ceramides, such as Cer (18:1;2/16:0), Cer (18:1;2/18:0) and Cer (18:1;2/24:1), seem to be the species most frequently associated with cardiovascular morbidity and mortality [10,31,56]. Statin therapy showed conflicting results on ceramide levels.…”

Section: Ceramides In Cardiometabolic Health and Diseasesmentioning

confidence: 99%

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How Ceramides Orchestrate Cardiometabolic Health—An Ode to Physically Active Living

et al. 2021

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Cardiometabolic diseases (CMD) represent a growing socioeconomic burden and concern for healthcare systems worldwide. Improving patients’ metabolic phenotyping in clinical practice will enable clinicians to better tailor prevention and treatment strategy to individual needs. Recently, elevated levels of specific lipid species, known as ceramides, were shown to predict cardiometabolic outcomes beyond traditional biomarkers such as cholesterol. Preliminary data showed that physical activity, a potent, low-cost, and patient-empowering means to reduce CMD-related burden, influences ceramide levels. While a single bout of physical exercise increases circulating and muscular ceramide levels, regular exercise reduces ceramide content. Additionally, several ceramide species have been reported to be negatively associated with cardiorespiratory fitness, which is a potent health marker reflecting training level. Thus, regular exercise could optimize cardiometabolic health, partly by reversing altered ceramide profiles. This short review provides an overview of ceramide metabolism and its role in cardiometabolic health and diseases, before presenting the effects of exercise on ceramides in humans.

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“…Conditional DAMPs include lysophospholipids, hyperhomocysteinemia (14)(15)(16)(17)(28)(29)(30), and succinate (27) among others. Lysophospholipids are a group of bioactive lipids; some of which are pro-inflammatory molecules (31,32), such as lysophosphatidylcholines (LPCs, lysoPC) (23,33,34), lysophosphatidic acid (LPA) (34)(35)(36), lysophosphatidylinositols (LPIs, lysoPIs) (19), and sphingosine-1-phosphate (37). LPA, LPCs, and LPIs are the characteristics of atherosclerotic aorta plaque in apolipoprotein E deficient (ApoE −/− ) and low-density lipoprotein receptor (LDLR −/− ) mice.…”

Section: Introductionmentioning

confidence: 99%

Novel Knowledge-Based Transcriptomic Profiling of Lipid Lysophosphatidylinositol-Induced Endothelial Cell Activation

Xu¹,

Shao²,

Saaoud³

et al. 2021

Front. Cardiovasc. Med.

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To determine whether pro-inflammatory lipid lysophosphatidylinositols (LPIs) upregulate the expressions of membrane proteins for adhesion/signaling and secretory proteins in human aortic endothelial cell (HAEC) activation, we developed an EC biology knowledge-based transcriptomic formula to profile RNA-Seq data panoramically. We made the following primary findings: first, G protein-coupled receptor 55 (GPR55), the LPI receptor, is expressed in the endothelium of both human and mouse aortas, and is significantly upregulated in hyperlipidemia; second, LPIs upregulate 43 clusters of differentiation (CD) in HAECs, promoting EC activation, innate immune trans-differentiation, and immune/inflammatory responses; 72.1% of LPI-upregulated CDs are not induced in influenza virus-, MERS-CoV virus- and herpes virus-infected human endothelial cells, which hinted the specificity of LPIs in HAEC activation; third, LPIs upregulate six types of 640 secretomic genes (SGs), namely, 216 canonical SGs, 60 caspase-1-gasdermin D (GSDMD) SGs, 117 caspase-4/11-GSDMD SGs, 40 exosome SGs, 179 Human Protein Atlas (HPA)-cytokines, and 28 HPA-chemokines, which make HAECs a large secretory organ for inflammation/immune responses and other functions; fourth, LPIs activate transcriptomic remodeling by upregulating 172 transcription factors (TFs), namely, pro-inflammatory factors NR4A3, FOS, KLF3, and HIF1A; fifth, LPIs upregulate 152 nuclear DNA-encoded mitochondrial (mitoCarta) genes, which alter mitochondrial mechanisms and functions, such as mitochondrial organization, respiration, translation, and transport; sixth, LPIs activate reactive oxygen species (ROS) mechanism by upregulating 18 ROS regulators; finally, utilizing the Cytoscape software, we found that three mechanisms, namely, LPI-upregulated TFs, mitoCarta genes, and ROS regulators, are integrated to promote HAEC activation. Our results provide novel insights into aortic EC activation, formulate an EC biology knowledge-based transcriptomic profile strategy, and identify new targets for the development of therapeutics for cardiovascular diseases, inflammatory conditions, immune diseases, organ transplantation, aging, and cancers.

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Sphingolipids in metabolic disease: The good, the bad, and the unknown

Cited by 128 publications

References 125 publications

Involvement of Ceramides in Non-Alcoholic Fatty Liver Disease (NAFLD) Atherosclerosis (ATS) Development: Mechanisms and Therapeutic Targets

Involvement of Ceramides in Non-Alcoholic Fatty Liver Disease (NAFLD) Atherosclerosis (ATS) Development: Mechanisms and Therapeutic Targets

How Ceramides Orchestrate Cardiometabolic Health—An Ode to Physically Active Living

Novel Knowledge-Based Transcriptomic Profiling of Lipid Lysophosphatidylinositol-Induced Endothelial Cell Activation

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