Lauren Ashley Cowart

• Ph.D.
• Professor at Virginia Commonwealth University

The metazoan lifespan is determined in part by a complex signaling network that regulates energy metabolism and stress responses. Key signaling hubs in this network include insulin/IGF‐1, AMPK, mTOR, and sirtuins. The Hippo/Mammalian Ste20‐like Kinase1 (MST1) pathway has been reported to maintain lifespan in Caenorhabditis elegans, but its role has...

The importance of MCL-1 in leukemogenesis has prompted development of MCL-1 antagonists e.g., S63845, MIK665. However, their effectiveness in acute myeloid leukemia (AML) is limited by compensatory MCL-1 accumulation via the ubiquitin proteasome system. Here, we investigated mechanisms by which kinase inhibitors with Src inhibitory activity e.g., b...

Circadian rhythms align biological functions with the 24-hour day-night cycle, but modern artificial light disrupts these patterns, contributing to health issues like obesity and cardiovascular disease. The circadian clock operates through a transcriptional-translational feedback loop involving core components such as BMAL1 and CLOCK. Recent resear...

Sphingosine kinase 1 (SphK1) plays a crucial role in regulating metabolic pathways within adipocytes and is elevated in the adipose tissue of obese mice. While previous studies have reported both pro- and inhibitory effects of SphK1 and its product, sphingosine-1-phosphate (S1P), on adipogenesis, the precise mechanisms remain unclear. This study ex...

Background: Transition from fatty acid oxidation to glycolysis is linked to oncometabolism and cardiac hypertrophy. We hypothesize that such a metabolic shift is pivotal in driving HFpEF in 3 murine models. The citric acid cycle (CAC) enzyme αKGDH is dysregulated in HFpEF patient biopsies and Alport hearts. Therefore, we also hypothesize more gener...

Introduction: The prevalence of metabolic cardiomyopathy in the absence of hypertension is on the rise. Ceramide Synthase 5 (CerS5) has been implicated in the pathophysiology of this cardiomyopathy. Hypothesis: Depletion of cardiomyocyte CerS5 protects against metabolic cardiomyopathy. Methods: Inducible cardiomyocyte-specific CerS5 knockout (CerS5...

Pulmonary fibrosis is an interstitial scarring disease of the lung characterized by poor prognosis and limited treatment options. Tissue transglutaminase 2 (TG2) is believed to promote lung fibrosis by crosslinking extracellular matrix components and activating latent TGFβ. This study assessed physiologic pulmonary function and metabolic alteration...

Lactic acid (lactate) is elevated in patients with idiopathic (IPF) and radiation-induced lung fibrosis (RILF). Lactate is generated from pyruvate via aerobic glycolysis. We recently published that the exhaled breath of RILF patients had significantly altered metabolomic profiles beyond changes in glycolysis. To expand our understanding of these me...

BACKGROUND Dysregulated metabolism of bioactive sphingolipids, including ceramides and sphingosine-1-phosphate, has been implicated in cardiovascular disease, although the specific species, disease contexts, and cellular roles are not completely understood. Sphingolipids are produced by the serine palmitoyltransferase enzyme, canonically composed o...

Liver failure secondary to metabolic dysfunction-associated steatotic liver disease (MASLD) has become the most common cause for liver transplantation in many parts of the world. Moreover, the prevalence of MASLD not only increases the demand for liver transplantation, but also limits the supply of suitable donor organs because steatosis predispose...

Sphingolipids are not only structural components of cellular membranes but also play vital roles in cell signaling and modulation of cellular processes. Within mitochondria, sphingolipids exert diverse effects on mitochondrial dynamics, energy metabolism, oxidative stress, and cell death pathways. In this review, we summarize literature addressing...

Farnesoid X receptor (FXR) activation reduces renal inflammation, but the underlying mechanisms remain elusive. Neutrophil extracellular traps (NETs) are webs of DNA formed when neutrophils undergo specialized programmed cell death (NETosis). The signaling lipid sphingosine-1-phosphate (S1P) stimulates NETosis via its receptor on neutrophils. Here,...

The endoplasmic reticulum (ER) plays a key role in the regulation of protein folding, lipid synthesis, calcium homeostasis, and serves as a primary site of sphingolipid biosynthesis. ER stress (ER dysfunction) participates in the development of mitochondrial dysfunction during aging. Mitochondria are in close contact with the ER through shared mito...

Lack of significant advancements in early detection and treatment of heart failure have precipitated the need for discovery of novel biomarkers and therapeutic targets. Over the past decade, circulating sphingolipids have elicited promising results as biomarkers that premonish adverse cardiac events. Additionally, compelling evidence directly ties...

Radiation-induced lung injury is a consequence of therapeutic irradiation (TR) for thoracic cancers. Studies report that up to 80% of patients who undergo TR will have CT-detectable interstitial lung abnormalities, and strategies to limit the risk of RILI may make radiotherapy less effective at treating cancer. Our lab and others have reported that...

Background Activation of the farnesoid X receptor (FXR) reduces renal inflammation, but the underlying mechanisms remain elusive. Neutrophil extracellular traps (NETs) are webs of DNA formed when neutrophils undergo specialized programmed cell death (NETosis). Sphingosine-1-phosphate (S1P) is a signaling lipid that stimulates NETosis via its recept...

Apolipoprotein M (ApoM) binds sphingosine-1-phosphate (S1P) and is inversely associated with mortality in human heart failure (HF). Here, we show that anthracyclines such as doxorubicin (Dox) reduce circulating ApoM in mice and humans, that ApoM is inversely associated with mortality in patients with anthracycline-induced heart failure, and ApoM he...

Liver failure secondary to nonalcoholic fatty liver disease (NAFLD) has become the most common cause for liver transplantation in many parts of the world. Moreover, the prevalence of NAFLD not only increases the demand for liver transplantation, but also limits the supply of suitable donor organs because steatosis predisposes grafts to ischemia-rep...

MYCN is amplified in 20% to 25% of neuroblastoma, and MYCN-amplified neuroblastoma contributes to a large percent of pediatric cancer-related deaths. Therapy improvements for this subtype of cancer are a high priority. Ferroptosis is an iron-dependent, oxidative form of cell death that is counteracted mainly by the production of Glutathione Peroxid...

Objective Men with non-alcoholic fatty liver disease (NAFLD) are more likely to progress to nonalcoholic steatohepatitis (NASH) and liver fibrosis than women. However, the underlying molecular mechanisms of this dimorphism is unclear. We have previously shown that mice with global deletion of SphK1, the enzyme that produces the bioactive sphingolip...

Relaxin is a pleiotropic hormone demonstrated to confer cardioprotection in animal models of myocardial infarction and ischemic heart failure by modulating inflammation, fibrosis and arrhythmogenesis. Several of these pathways in the ischemic myocardium are intricately tied with the downstream signaling of bioactive sphingolipids, which play an act...

Obesity research has shifted in recent years to address not only the total amount of adipose tissue present in an individual but also to include adipose tissue functions such as endocrine function and thermogenesis. Data suggest that sphingolipids are critical regulators of metabolic homeostasis, and that disruption of their levels is associated wi...

The relationship between sphingolipid levels and NAFLD pathology has been recognized for some time. Numerous studies using pharmacological and genetic approaches in vitro and in animal models of NAFLD have demonstrated that modifications to sphingolipid metabolism can attenuate various facets of NAFLD pathology. However, a more precise understandin...

Ferroptosis is an iron-dependent, oxidative form of cell death that is countered mainly by glutathione peroxidase 4 (GPX4) and the production of glutathione (GSH), which is formed from cysteine. The identification of the cancers that may benefit from pharmacological ferroptotic induction is just emerging. We recently demonstrated that inducing ferr...

Background: The miR-17-92 cluster is indispensable for normal cardiac development and its deletion leads to cardiovascular disease. Aberrancies in bioactive sphingolipid metabolism, specifically ceramide (CER), contribute to diabetic cardiomyopathy, where induction of ceramide synthases (CerS) predicts elevated risk of cardiovascular complications....

Traumatic brain injury (TBI) causes neuroinflammation and neurodegeneration leading to various pathological complications such as motor and sensory (visual) deficits, cognitive impairment, and depression. N-3 polyunsaturated fatty acid (n-3 PUFA) containing lipids are known to be anti-inflammatory, whereas the sphingolipid, ceramide (Cer), is an in...

The bioactive sphingolipid metabolites ceramide and sphingosine-1-phosphate (S1P) are a recent addition to the lipids accumulated in obesity and have emerged as important molecular players in metabolic diseases. Here we summarize evidence that dysregulation of sphingolipid metabolism correlates with pathogenesis of metabolic diseases in humans. Thi...

Objectives Determine the role of apolipoprotein M (ApoM) in anthracycline (Dox) cardiotoxicity. Background ApoM binds the cardioprotective sphingolipid sphingosine-1-phosphate (S1P). Circulating ApoM is inversely associated with mortality in human heart failure (HF). Methods In the Penn HF Study (PHFS), we tested the relationship between ApoM and...

Introduction: Mitochondrial function is impaired in aged hearts. Increased endoplasm reticulum (ER) stress contributes to the mitochondrial dysfunction observed during aging. Ceramides (CRMD) are sphingolipid metabolites that contribute key roles in cell signaling. Increased CRMD can lead to ER stress. Ceramide synthase enzymes (CerS) generate chai...

Cardiovascular diseases are the leading cause of mortality worldwide and this has largely been driven by the increase in metabolic disease in recent decades. Metabolic disease alters metabolism, distribution, and profiles of sphingolipids in multiple organs and tissues; as such, sphingolipid metabolism and signaling have been vigorously studied as...

Sphingolipids have become established participants in the pathogenesis of obesity and associated maladies. Sphingosine kinase 1 (SPHK1), which generates sphingosine-1-phosphate, has been shown to increase in liver and adipose of obese humans and mice and to regulate inflammation in hepatocytes and adipose tissue, insulin resistance, and systemic in...

In non-alcoholic steatohepatitis (NASH), many lines of investigation have reported a dysregulation in lipid homeostasis, leading to intrahepatic lipid accumulation. Recently, the role of dysfunctional sphingolipid metabolism has also been proposed. Human and animal models of NASH have been associated with elevated levels of long chain ceramides and...

Saturated fatty acids (SFA) have been known to trigger inflammatory signaling in metabolic tissues; however, the effects of specific SFAs in the intestinal epithelium have not been well studied. Several previous studies have implicated disruption in sphingolipid metabolism by oversupply of SFAs could affect the inflammatory process. Also, our previ...

Cardiomyopathy is the leading cause of mortality worldwide. While the causes of cardiomyopathy continue to be elucidated, current evidence suggests that aberrant bioactive lipid signaling plays a crucial role as a component of cardiac pathophysiology. Sphingolipids have been implicated in the pathophysiology of cardiovascular disease, as they regul...

Rationale: Heart failure caused by ischemic cardiomyopathy is the leading cause of death and disability in the USA and world, accounting for 10 million deaths in 2016. Sphingolipids including ceramides and sphingosine-1-phosphate have been demonstrated to play roles in myocardial injury. In general, these lipids are synthesized from serine palmitoy...

Nonalcoholic fatty liver disease (NAFLD), a leading cause of liver dysfunction, is a metabolic disease that begins with steatosis. Sphingolipid metabolites, particularly ceramide and sphingosine-1-phosphate (S1P), have recently received attention for their potential roles in insulin resistance and hepatic steatosis. FTY720/fingolimod, a prodrug for...

Adipose tissue lies at the heart of obesity, mediating its many effects upon the rest of the body, with its unique capacity to expand and regenerate, throughout the lifespan of the organism. Adipose is appreciated as an endocrine organ, with its myriad adipokines that elicit both physiological and pathological outcomes. Sphingolipids, bioactive sig...

Non-alcoholic fatty liver disease (NAFLD) is a major clinical concern and its treatment consumes abundant resources. While accumulation of lipids in hepatocytes initiates the disease, this in itself is not necessarily harmful; rather, initiation of inflammation and subsequent fibrosis and cirrhosis are critical steps in NAFLD pathology. Mechanisms...

Saturated fatty acids (SFAs) have been shown to induce endoplasmic reticulum (ER) stress and chronic inflammatory responses, as well as alter sphingolipid metabolism. Disruptions in ER stress and sphingolipid metabolism have also been implicated in intestinal inflammation. Therefore, to elucidate the roles of SFAs in ER stress and inflammation in i...

It is well known that saturated fatty acids (SFAs) and unsaturated fatty acid, in particular omega-3 polyunsaturated fatty acids (n-3 PUFAs), have different effects on inflammatory signaling: SFAs are pro-inflammatory but n-3 PUFAs have strong anti-inflammatory properties. We have reported that palmitic acid (PA), a saturated fatty acid, robustly a...

Obesity, type 2 diabetes, and metabolic syndrome induce dyslipidemia resulting in inundation of peripheral organs with fatty acids. These not only serve as substrates for energy production, but also contribute to aberrant production of bioactive lipids. Moreover, lipid metabolism is affected in many cardiac disorders including heart failure, ischem...

Accumulating data support a role for bioactive lipids as mediators of lipotixicity in cardiomyocytes. One class of these, the ceramides, constitutes a family of molecules that differ in structure and are synthesized by distinct enzymes, ceramide synthase (CerS)1-CerS6. Data support that specific ceramides and the enzymes that catalyze their formati...

Bipolar disorder (BD) is a severe psychiatric illness affecting ~2% of the world population. Valproate (VPA) and lithium, though widely used for the treatment of BD, are not universally effective. These drugs have been shown to cause inositol depletion, but translating this observation to a specific therapeutic mechanism has been difficult, hamperi...

Adipocytes, apart from their critical role as the energy storage depots, contribute to the composition of the tumor microenvironment. Our previous studies based on a single hematopoietic stem cell (HSC) transplantation model, have revealed a novel source of adipocytes from HSCs via monocyte/macrophage progenitors. Herein, we extend these studies to...

Bipolar disorder (BD), which is characterized by depression and mania, affects 1-2% of the world population. Current treatments are effective in only 40-60% of cases and cause severe side effects. Valproate (VPA) is one of the most widely used drugs for the treatment of BD, but the therapeutic mechanism of action of this drug is not understood. Thi...

Bipolar disorder (BD), which is characterized by depression and mania, affects about 1% of the world population. Current treatments are effective in only 40–60% of cases and cause severe side effects. Valproic acid (VPA), a branched short‐chain fatty acid, is one of the most widely used drugs for the treatment BD. Although many hypotheses have been...

Non‐alcoholic fatty liver disease (NAFLD) is a rampant health problem, but mechanisms underlying its progression are not completely understood. Because targeting pathways that mediate inflammation and fibrosis in NAFLD could serve as novel therapeutic strategies, research in this area is of major clinical interest. NAFLD occurs in the context of me...

In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring au...

In 2008, we published the first set of guidelines for standardizing research in autophagy. Since then, this topic has received increasing attention, and many scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Thus, it is important to formulate on a regular basis updated guidelines for monit...

Background: Nonalcoholic steatohepatitis (NASH) is currently the third most common cause of end stage liver disease necessitating transplantation. The question remains how inflammation and NASH develop in the setting of nonalcoholic fatty liver disease (NAFLD) and steatosis. Aim: Understand the roles of toll-like receptor 4 (TLR4) and dietary fa...

Introduction: Diabetic cardiomyopathy (DbCM) contributes to the high risk of heart failure (HF) in diabetics, but mechanisms underlying DbCM remain unclear. We previously showed that highly saturated fat feeding in mice altered cardiomyocyte sphingolipid profiles leading to DbCM and that some of these maladaptations were dependent on autophagy and...

Steatohepatitis occurs in up to 20% of patients with fatty liver disease and leads to its primary disease outcomes including fibrosis, cirrhosis, and increased risk of hepatocellular carcinoma. Mechanisms that mediate this inflammation are of major interest. We previously showed that overload of saturated fatty acids, such as that which occurs with...

Both high sugar and fat diets can induce prosteatotic genes, leading to obesity and obesity-associated diseases, including hepatic steatosis. Unsaturated fat/fatty acid (USFA) reduces high sugar-induced hepatic steatosis by inhibiting the induced prosteatotic genes. In contrast, it is still unclear how USFA ameliorates saturated fat/fatty acid (SFA...

ATP-binding cassette transporters Pdr5 and Yor1 from Saccharomyces cerevisiae control the asymmetric distribution of phospholipids across the plasma membrane as well as serving as ATP-dependent drug efflux pumps. Mutant strains lacking these transporter proteins were found to exhibit very different resistant phenotypes to two inhibitors of sphingol...

Autophagy is a catabolic process involved in maintaining energy and organelle homeostasis. The relationship between obesity and the regulation of autophagy is cell type specific. Despite adverse consequences of obesity on cardiac structure and function, the contribution of altered cardiac autophagy in response to fatty acid overload is incompletely...

gp96, or grp94, is an endoplasmic reticulum (ER) heat shock protein 90 paralog which acts as a protein chaperone and plays an important role in ER homeostasis. Previous work has demonstrated its role in ER stress, Wnt and integrin signaling, calcium homeostasis and others, which are vital processes in oncogenesis. However, the cancer-intrinsic func...

Climbing obesity rates have contributed to worldwide increases in obesity-associated diseases, including the metabolic syndrome and Type 2 diabetes mellitus (T2DM). Sphingolipids, an important class of structural and signaling lipids, have emerged as key players in the development and pathogenesis of insulin resistance and T2DM. More specifically,...

Non‐alcoholic fatty liver disease (NAFLD) comprises hepatic steatosis that often progresses to inflammation and ultimately cirrhosis, hepatocellular carcinoma, and subsequent need for transplant. Mechanisms mediating the NAFLD are of major clinical interest. Epidemiological studies in humans have linked consumption of dietary saturated fat to NAFLD...

Previous studies have shown that saturated fatty acids cause insulin resistance (IR) that is prevented by unsaturated fatty acids. Tribbles homologue 3 (TRIB3) is a putative endogenous inhibitor of insulin signalling, but its role in insulin signalling is controversial. This study aimed to determine whether fatty acids regulate IR via TRIB3. We tre...

We previously demonstrated that sphingosine kinase 1 (Sphk1) expression and activity are up-regulated by exogenous palmitate (PAL) in a skeletal muscle model system and in diet-induced obesity in mice; however, potential functions and in vivo relevance of this have not been addressed. Here, we aimed to determine the mechanism by which PAL regulates...

Genetic and pharmacological perturbation experiments, such as deleting a gene and monitoring gene expression responses, are powerful tools for studying cellular signal transduction pathways. However, it remains a challenge to automatically derive knowledge of a cellular signaling system at a conceptual level from systematic perturbation-response da...

Metabolic disease, including obesity and type 2 diabetes, constitutes a major emerging health crisis in Western nations. Although the symptoms and clinical pathology and physiology of these conditions are well understood, the molecular mechanisms underlying the disease process have largely remained obscure. Sphingolipids, a lipid class with both si...

The oxysterol binding protein family are amphitropic proteins that bind oxysterols, sterols, and possibly phosphoinositides, in a conserved binding pocket. The Saccharomyces cerevisiae oxysterol binding protein family member Kes1 (also known as Osh4) also binds phosphoinositides on a distinct surface of the protein from the conserved binding pocket...

Plasma fatty acids increase in obesity and diabetes; subsequent lipid overload to cells and tissues mediates numerous pathological processes. This is due in part to aberrant synthesis of bioactive lipids. We previously demonstrated that palmitate (PAL) increased sphingosine‐1‐phosphate through regulation of sphingosine kinase 1 (SphK1); however, po...

Obesity‐associated nonalcoholic fatty liver disease (NAFLD) is characterized by a continuum of pathological changes in the liver. Although progression from simple steatosis to the inflammatory stage of NAFLD (i.e. nonalcoholic steatohepatitis/NASH) represents a critical switch from a benign to a harmful status in the progression of NAFLD, the mecha...

Previously, our laboratory demonstrated that sphingolipids (SL) mediated diet‐induced diabetic cardiomyopathy in mice (Russo et al. 2012. J Clin Invest). Intriguingly, affected hearts displayed accumulation of a novel pool of myristate‐derived d16:0 SL. However, the metabolism and biological functions of these lipids have yet to be defined. The pre...

Obesity is associated with type 2 diabetes, non‐alcoholic fatty liver disease, and cardiovascular disease, but mechanisms by which obesity may promote these disease states are not fully understood. We demonstrate that in obesity, dietary fat composition is reflected in plasma lipid profiles, and differential lipid supply to cells profoundly impacts...

The enzyme serine palmitoyltransferase (SPT) catalyzes the formation of the sphingoid base “backbone” from which all sphingolipids are derived. Previous studies have shown that inhibition of SPT ameliorates pathological cardiac outcomes in models of lipid overload, but the metabolites responsible for these phenotypes remain unidentified. Recent in...

Background Contemporary high-throughput analyses often produce lengthy lists of genes or proteins. It is desirable to divide the genes into functionally coherent subsets for further investigation, by integrating heterogeneous information regarding the genes. Here we report a principled approach for managing and integrating multiple data sources wit...

A PDF file contains supplementary methods and results.

Diabetic cardiomyopathy (DbCM), which consists of cardiac hypertrophy and failure in the absence of traditional risk factors, is a major contributor to increased heart failure risk in type 2 diabetes patients. In rodent models of DbCM, cardiac hypertrophy and dysfunction have been shown to depend upon saturated fatty acid (SFA) oversupply and de no...

Targets of bioactive sphingolipids in Saccharomyces cerevisiae were previously identified using microarray experiments focused on sphingolipid-dependent responses to heat stress. One of these heat-induced genes is the serine deamidase/dehydratase Cha1 known to be regulated by increased serine availability. This study investigated the hypothesis tha...

Much data implicate saturated fatty acids in deleterious processes associated with obesity, diabetes, and the metabolic syndrome. Many of these changes may be due to aberrant generation of bioactive lipids when saturated fatty acid availability to tissues is increased. On the other hand, studies are emerging that implicate the monounsaturated fatty...

Much data implicate saturated fatty acids in deleterious processes associated with obesity, diabetes, and the metabolic syndrome. Many of these changes may be due to aberrant generation of bioactive lipids when saturated fatty acid availability to tissues is increased. On the other hand, studies are emerging that implicate the monounsaturated fatty...

Sphingolipids are an important class of structural and signaling molecules within the cell. As sphingolipids have been implicated in the development and pathogenesis of insulin resistance and the metabolic syndrome, it is important to understand their regulation and metabolism. Although these lipids are initially produced through a common pathway,...

Ceramide is produced by the condensation of a long chain base with a very long chain fatty acid. In Saccharomyces cerevisiae, one of the two major long chain bases is called phytosphingosine (PHS). PHS has been shown to cause toxicity in tryptophan auxotrophic strains of yeast because this bioactive ceramide precursor causes diversion of the high a...

Recent work, especially in the yeast Saccharomyces cerevisiae, has demonstrated that mRNA movement from active translation to cytoplasmic granules, termed mRNA'p-bodies' (processing bodies), occurs in concert with the regulation of translation during cell stress. However, the signals regulating p-body formation are poorly defined. Recent results ha...

sphingolipids are a chemically diverse group of biological lipids typified by a sphingoid base backbone derived from condensation of a fatty acyl-CoA to an amino acid (typically, but not always, serine) ([24][1], [27][2]). These lipids occur throughout eukaryotic species, thus reflecting their

The results of initial analyses for many high-throughput technologies commonly take the form of gene or protein sets, and one of the ensuing tasks is to evaluate the functional coherence of these sets. The study of gene set function most commonly makes use of controlled vocabulary in the form of ontology annotations. For a given gene set, the stati...

A comma separated value (CSV) file contains the lipid measurements. The file contains the numeric values of lipids corresponding to Figure 3B.

A CSV file contains the numeric values for the heatmap of Figure 3C

Supplementary materials, methods and results.

Dataset