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.

Our research has previously focused on increasing deleterious ceramides in beta cells using the CERS6 enzyme to investigate whether elevated ceramide levels could lead to beta cell death and to elucidate the mechanisms involved. Building on this work, we are now examining the effects of overexpressing fSPT, the first enzyme complex in the ceramide synthesis pathway, specifically in beta cells. This current study aims to increase the overall production of various ceramide species, allowing us to explore the broader impacts of enhanced ceramide biosynthesis on beta cell health, functionality, and survival. Through these ongoing investigations, we aim to better understand the role of ceramide metabolism in beta-cell pathology and identify potential therapeutic strategies for preserving beta-cell function in 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

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.

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.