Research
The major accomplishment of our laboratory is advancing the idea that sphingolipids (e.g. ceramides) contribute to insulin resistance and metabolic disease. This prior work involving cell culture and rodent model systems has revealed considerable new mechanistic insight into the role of these molecules as central regulators of nutrient homeostasis. This focus on basic science and discovery biology will continue to be a major component of our laboratory. However, we now endeavor to also translate these findings into new clinical procedures or behavioral interventions to improve health.
Major Projects in the Laboratory
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Genetics of Hyperceramidemia
We merge murine and human genetic approaches to identify novel genes involved in lipid homeostasis and novel genetic variants which predispose to cardiometabolic disease
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Role of Ceramides in Hepatic Metabolism
We study the role of ceramides in metabolic diseases such as non-alcoholic fatty liver disease and type 2 diabetes
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Ceramides as Pathogenic Drivers of Kidney Disease
We use gain- and loss-of-ceramide interventions to study the role of ceramides in kidney injury and disease
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Role of Ceramides in the Pancreatic Islets
We are interested in understanding the role Ceramides play in regulating pancreatic physiology, especially in regulating insulin and glucagon secretions
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Sphingolipid metabolism in the intestinal stem cells and gut health
We use human, mice and Drosophila alimentary canal tissues to study the role of sphingolipid metabolism in regulating the GI health and associated diseases
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Ceramides and Cellular Stress
We discern the molecular mechanism that allows ceramides to mediate cellular responses to stress
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Ceramides as Drivers of Heart Failure
We utilize genetic mouse-models to investigate ceramides in the onset and progression of heart failure and how they influence glucose utilization and mitochondrial energetics within the cardiomyocyte
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Ceramides and Inborn Errors of Metabolism
We study the role ceramides play in pathology of rare genetic diseases called inborn errors of metabolism
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Development of Dihydroceramide Desaturase Inhibitors to Treat Metabolic Diseases
We hope to treat metabolic diseases by developing novel dihydroceramide desaturase inhibitors and using them to reduce ceramides.
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Role of FOXN3 in Glucagon Action & Energy Metabolism
We use in-vivo and in-vitro studies to investigate the metabolic role of FOXN3 in energy substrate regulation in states of healthy and metabolic distress
Genetics of Hyperceramidemia
Our understanding of the genetic landscape that favors ceramide formation in response to environmental cues remains limited. The Diversity Outbred (DO) mouse panel, generated from the outbreeding of eight founder strains, offers an ideal discovery platform to identify genetic drivers of ceramides. Lipidomic, genomic, and transcriptomic data from 384 DO mice are enabling us to pinpoint quantitative traits (ceramides) driven by genetic loci. We are pairing the discovery-potential of the DO platform with the power of family-based human genetics—an approach that has allowed us to identify rare and distinct mutations that underlie familial hyperceramidemia. Our data suggest that patients with hyperceramidemia are at high risk for diabetes and diabetic complications. As such, identification of at-risk patients could allow for precise therapeutic interventions with ceramide-lowering medications to improve quality of life.
Role of Ceramides in Hepatic Metabolism
The liver is an essential organ involved in proper whole-body metabolic regulation. Genetic and pharmacological models have revealed an important role of ceramides in the development of hepatic manifestations of metabolic disease including, steatosis, mitochondrial dysfunction, insulin resistance, and fibrosis. We seek to understand the precise mechanism by which ceramides contribute to the development of hepatic pathologies.
Ceramides as Pathogenic Drivers of Kidney Disease
Hallmark molecular drivers of kidney kidney tubule injury include lipotoxicity, mitochondrial dysfunction, and cell death – pathologies sharing an established link to ceramide accumulation. We seek to understand the role of ceramide accrual in kidney injury and disease in vivo with targeted genetic and pharmacological approaches. This work will further our understanding of sphingolipid metabolism in different cell populations of the kidney and may potentially contribute to therapeutic development for kidney disease.
Role of Ceramides in the Pancreatic islets
Ceramides are important sphingolipid species linked to the induction of insulin resistance, dyslipidemia, fibrosis and apoptosis. Remarkably, inhibiting ceramide biosynthesis in rodents ameliorates hypertension, atherosclerosis, lipotoxic cardiomyopathy, and type 2 diabetes. Work in our lab demonstrates that adiponectin dose-dependently lowers ceramide levels. Adiponectin receptors (AdipoR1 & AdipoR2) have intrinsic ceramidase activity and the ceramide-lowering activity of these receptors requires their cognate ligand, adiponectin. Genetic adiponectin insufficiency promotes high ceramides in mice and humans. Research by our group demonstrates that ceramides are necessary and sufficient to trigger glucagon hypersecretion in mouse models of type-2 diabetes. Notably, adiponectin lowers ceramides in the islet and in cultured α-cells. Therefore, our goal is to study the various mechanisms by which increased ceramide accumulation and decreased adiponectin section can affect islet health with the eventual goal of finding effective therapeutic interventions to treat diabetes.
Sphingolipid metabolism in the intestinal stem cells and gut health
Sphingolipid metabolism regulates cellular processes such as proliferation, growth, apoptosis, inflammation, and senescence. Genetic defects in the metabolism of sphingolipids are associated with several metabolic disorders, including colorectal cancer. While high-fat diet and fatty acid oxidation have been known to regulate ISC proliferation, the molecular mechanisms involved in sphingolipid metabolism-mediated intestinal stem cell (ISC) homeostasis and tumorigenesis are poorly understood. We know that some of the intermediate products in the anabolic or catabolic processes of the ceramide have different functions in regulating ISC fates in the adult midgut. To check if any of the sphingolipid metabolic enzymes are involved in the ISC homeostasis or tumorigenesis, we genetically perturb these enzymes in the specific cell types of the ISC lineages and the progenitor cells together, as well as tumor clones. We score the stem cell proliferation, cell morphology, differential potential, tumor growth, interactions with with other signaling pathways, and evaluate their associations with specific sphingolipid metabolic profile to draw conclusions on the role of sphingolipid metabolite(s) in cell determinations.
Ceramides and Cellular Stress
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Ceramides as Drivers of Heart Failure
We utilize genetic mouse-models to investigate ceramides in the onset and progression of heart failure and how they influence glucose utilization and mitochondrial energetics within the cardiomyocyte.
Ceramides and Inborn Errors of Metabolism
While advances in newborn screening and treatment have improved survival in fatty acid oxidation disorders, severe very long-chain acyl-coA dehydrogenase deficiency (VLCADD) continues to cause heart failure and early childhood death. Although energy deficiency resulting from the diminished production of ATP from lipid fuels has been implicated as a driver of VLCADD-associated pathologies, it is unlikely to explain the full spectrum of tissue defects. We hypothesize that the accumulation of ceramides contributes to the cellular dysfunction that drives heart failure. Our preliminary data confirm that ceramides are elevated in both in vitro and in vivo models of VLCADD, that in vitro inhibition of ceramide synthesis improves many lipotoxic and metabolic deficits of VLCADD, and that in vivo inhibition of ceramide synthesis improves cardiac hypertrophy and cardiac function in VLCADD mouse models. This project has a high potential to drastically improve patient care within the next 5 years.
Schematic of abbreviated fatty acid oxidation and de novo ceramide synthesis pathways. DES1, dihydroceramide desaturase; SPT, serine palmitoyl transferase.
Development of Dihydroceramide Desaturase Inhibitors to Treat Metabolic Diseases
Ceramides influence cardiometabolic disease in mice and humans. Most observations have been conclusively demonstrated in rodents and are supported by strong correlational data from humans. The physiological effects of ceramide are therefore strongly preserved between the two organisms. Ceramide effects include induction of insulin resistance, impairment in vascular reactivity, enhancement of triglyceride synthesis, impairment in lipid oxidation, inhibition of insulin gene transcription and stimulation of apoptosis and fibrosis. We hope to treat metabolic diseases by developing novel dihydroceramide desaturase inhibitors and using them to reduce ceramides.
Role of FOXN3 in Glucagon
Action & Energy Metabolism
Diabetes Mellitus (DM) is associated with macro-and microvascular dysfunction, leading to cardiac dysfunction and heart failure (HF). This systemic interdependence of DM and HF is caused by changes in substrate availability and hormonal status, which can alter myocardial substrate selection resulting in impaired energetics and dysfunction via lipo- and glucotoxicity. Although glucagon is beneficial in acute cardiac conditions, continuous glucagon secretion increases the decline of cardiac function and exacerbates diabetes. We seek to understand how glucagon and the transcriptional repressor FOXN3 interact to direct metabolic changes and fluctuating nutrient availability in states of metabolic dysfunction.