The steady-state level of plasma membrane ceramide is regulated by neutral sphingomyelinase 2.

During the last 30 years, an increasing number of cellular functions have been reported to be regulated by the lipid ceramide. The diversity in the ceramide structure, leading to tens of ceramide species and the discrete distribution based on subcellular topology, could explain the wide variety of functions attributed to this bioactive lipid. One of these pools of ceramide resides in the plasma membrane, and several works have suggested that an increase in plasma membrane ceramide (PMCer) in response to stimulation leads to cell death and modulates cell adhesion and migration.

Biased signaling by mutant EGFR underlies dependence on PKCα in lung adenocarcinoma.

Activating mutations in the epidermal growth factor receptor (EGFR) promote ligand-independent signaling; however, the mechanisms involved are poorly defined, and it is unknown whether this generates specific vulnerabilities. We previously observed robust expression of protein kinase Cα (PKCα) in lung adenocarcinoma (LUAD) with mutant EGFR (mEGFR), which, unlike the activation of PKCα, is independent of mEGFR activity. Here, we identify a critical role for PKCα in anchorage-independent growth and survival of lung cancer cells with mEGFR.

Orm proteins control ceramide synthesis and endocytosis via LCB-mediated Ypk1 regulation.

Sphingolipids (SPLs) are major components of cell membranes with significant functions. Their production is a highly-regulated multi-step process with the formation of two major intermediates, long chain bases (LCBs) and ceramides. Homologous Orm proteins in both yeast and mammals negatively regulate LCB production by inhibiting serine palmitoyltransferase (SPT), the first enzyme in SPL de novo synthesis.

TGF-β and TNF-α interaction promotes the expression of MMP-9 through H3K36 dimethylation: implications in breast cancer metastasis.

Increased MMP-9 expression in the tumor microenvironment (TME) plays a crucial role in the extracellular matrix remodeling to facilitate cancer invasion and metastasis. However, the mechanism of MMP-9 upregulation in TME remains elusive. Since TGF-β and TNF-α levels are elevated in TME, we asked whether these two agents interacted to induce/augment MMP-9 expression.

IL-6R (trans-signaling) is a key regulator of reverse cholesterol transport in lipid-laden macrophages.

Atherosclerosis is a cardiovascular disease caused by cholesterol-laden arterial plaques. This study evaluated the correlation between interleukin-6 (IL-6), its receptors (IL6R/CD126), and glycoprotein 130 (gp130) alongside atherosclerosis biomarkers in a cohort of 142 subjects, equally divided between lean and obese individuals. Subsequent analyses used THP-1-derived macrophages to assess the biochemical impact of inhibiting IL-6 receptors.

Enzymes of sphingolipid metabolism as transducers of metabolic inputs.

Sphingolipids (SLs) constitute a discrete subdomain of metabolism, and they display both structural and signaling functions. Accumulating evidence also points to intimate connections between intermediary metabolism and SL metabolism. Given that many SLs exhibit bioactive properties (i.

A comprehensive measure of Golgi sphingolipid flux using NBD C-ceramide: evaluation of sphingolipid inhibitors.

Measurements of sphingolipid metabolism are most accurately performed by LC-MS. However, this technique is expensive, not widely accessible, and without the use of specific probes, it does not provide insight into metabolic flux through the pathway. Employing the fluorescent ceramide analogue NBD-C-ceramide as a tracer in intact cells, we developed a comprehensive HPLC-based method that simultaneously measures the main nodes of ceramide metabolism in the Golgi.

Neutral Sphingomyelinase 2 Inhibition Limits Hepatic Steatosis and Inflammation.

Non-alcoholic fatty liver disease (NAFLD) is manifested by hepatic steatosis, insulin resistance, hepatocyte death, and systemic inflammation. Obesity induces steatosis and chronic inflammation in the liver. However, the precise mechanism underlying hepatic steatosis in the setting of obesity remains unclear.

Expression of Ceramide Synthases in Mice and Their Roles in Regulating Acyl-Chain Sphingolipids: A Framework for Baseline Levels and Future Implications in Aging and Disease.

Sphingolipids are an important class of lipids present in all eukaryotic cells that regulate critical cellular processes. Disturbances in sphingolipid homeostasis have been linked to several diseases in humans. Ceramides are central in sphingolipid metabolism and are largely synthesized by six ceramide synthase (CerS) isoforms (CerS1-6), each with a preference for different fatty acyl chain lengths.

Biological function, topology, and quantification of plasma membrane Ceramide.

Over the past 30 years, a growing body of evidence has revealed the regulatory role of the lipid ceramide in various cellular functions. The structural diversity of ceramide, resulting in numerous species, and its distinct distribution within subcellular compartments may account for its wide range of functions. However, our ability to study the potential role of ceramide in specific subcellular membranes has been limited.

A transcriptional network governing ceramide homeostasis establishes a cytokine-dependent developmental process.

Transcriptional mechanisms controlling developmental processes establish and maintain proteomic networks, which can govern the levels of intracellular small molecules. Although dynamic changes in bioactive small molecules can link transcription factor and genome activity with cell state transitions, many mechanistic questions are unresolved. Using quantitative lipidomics and multiomics, we discover that the hematopoietic transcription factor GATA1 establishes ceramide homeostasis during erythroid differentiation by regulating genes encoding sphingolipid metabolic enzymes.

Targeting sphingosine kinase 1 in p53KO thymic lymphoma.

Sphingosine kinase 1 (SK1) is a key sphingolipid enzyme that is upregulated in several types of cancer, including lymphoma which is a heterogenous group of malignancies. Treatment for lymphoma has improved significantly by the introduction of new therapies; however, subtypes with tumor protein P53 (p53) mutations or deletion have poor prognosis, making it critical to explore new therapeutic strategies in this context. SK1 has been proposed as a therapeutic target in different types of cancer; however, the effect of targeting SK1 in cancers with p53 deletion has not been evaluated yet.

A novel HSPB1 mouse model of Charcot-Marie-Tooth Disease.

Charcot-Marie-Tooth Disease (CMT) is a commonly inherited peripheral polyneuropathy. Clinical manifestations for this disease include symmetrical distal polyneuropathy, altered deep tendon reflexes, distal sensory loss, foot deformities, and gait abnormalities. Genetic mutations in heat shock proteins have been linked to CMT2.

Ceramide as an endothelial cell surface receptor and a lung-specific lipid vascular target for circulating ligands.

The vascular endothelium from individual organs is functionally specialized, and it displays a unique set of accessible molecular targets. These serve as endothelial cell receptors to affinity ligands. To date, all identified vascular receptors have been proteins.

Neutral ceramidase-active site inhibitor chemotypes and binding modes.

Ceramides impact a diverse array of biological functions and have been implicated in disease pathogenesis. The enzyme neutral ceramidase (nCDase) is a zinc-containing hydrolase and mediates the metabolism of ceramide to sphingosine (Sph), both in cells and in the intestinal lumen. nCDase inhibitors based on substrate mimetics, for example C6-urea ceramide, have limited potency, aqueous solubility, and micelle-free fraction.

Dietary choline and sphingomyelin choline moiety intake and risk of colorectal cancer: a case-control study.

Introduction: Phospholipids are possible favorable agents for colorectal cancer (CRC). Choline has been inversely related to CRC risk but findings are inconsistent. We assessed the effect of dietary sphingomyelin (SM) choline moiety and total choline intake on risk of CRC.

ACSL1 is a key regulator of inflammatory and macrophage foaming induced by short-term palmitate exposure or acute high-fat feeding.

Foamy and inflammatory macrophages play pathogenic roles in metabolic disorders. However, the mechanisms that promote foamy and inflammatory macrophage phenotypes under acute-high-fat feeding (AHFF) remain elusive. Herein, we investigated the role of acyl-CoA synthetase-1 (ACSL1) in favoring the foamy/inflammatory phenotype of monocytes/macrophages upon short-term exposure to palmitate or AHFF.

Dietary Choline and Betaine Intake and Risk of Colorectal Cancer in an Iranian Population.

Background: Colorectal cancer (CRC) is increasing in low- and middle-income countries, likely due to changing lifestyle habits, including diet. We aimed to investigate the relationship between dietary betaine, choline, and choline-containing compounds and CRC risk.

Methods: We analyzed data from a case-control study, including 865 CRC cases and 3206 controls from Iran.

Upregulation of sphingosine kinase 1 in response to doxorubicin generates an angiogenic response via stabilization of Snail.

Sphingosine kinase 1 (SK1) converts the pro-death lipid sphingosine to the pro-survival sphingosine-1-phosphate (S1P) and is upregulated in several cancers. DNA damaging agents, such as the chemotherapeutic doxorubicin (Dox), have been shown to degrade SK1 protein in cancer cells, a process dependent on wild-type p53. As mutations in p53 are very common across several types of cancer, we evaluated the effects of Dox on SK1 in p53 mutant cancer cells.

A simple, highly sensitive, and facile method to quantify ceramide at the plasma membrane.

The role of ceramide in biological functions is typically based on the elevation of cellular ceramide, measured by LC-MS in the total cell lysate. However, it has become increasingly appreciated that ceramide in different subcellular organelles regulates specific functions. In the plasma membrane, changes in ceramide levels might represent a small percentage of the total cellular ceramide, evading MS detection but playing a critical role in cell signaling.

Targeting acid ceramidase ameliorates fibrosis in mouse models of non-alcoholic steatohepatitis.

Non-alcoholic fatty liver disease (NAFLD) is a common cause of liver disease worldwide, and is characterized by the accumulation of fat in the liver. Non-alcoholic steatohepatitis (NASH), an advanced form of NAFLD, is a leading cause of liver transplantation. Fibrosis is the histologic feature most associated with liver-related morbidity and mortality in patients with NASH, and treatment options remain limited.

Alkaline ceramidase catalyzes the hydrolysis of ceramides via a catalytic mechanism shared by Zn2+-dependent amidases.

Human alkaline ceramidase 3 (ACER3) is one of three alkaline ceramidases (ACERs) that catalyze the conversion of ceramide to sphingosine. ACERs are members of the CREST superfamily of integral-membrane hydrolases. All CREST members conserve a set of three Histidine, one Aspartate, and one Serine residue.

Neutral ceramidase deficiency protects against cisplatin-induced acute kidney injury.

Cisplatin is a commonly used chemotherapeutic for the treatment of many solid organ cancers; however, its effectiveness is limited by the development of acute kidney injury (AKI) in 30% of patients. AKI is driven by proximal tubule cell death, leading to rapid decline in renal function. It has previously been shown that sphingolipid metabolism plays a role in regulating many of the biological processes involved in cisplatin-induced AKI.