Virtual Issue: Solving the enigma of the sphinx, one sphingolipid at a time

Assembled by Rotonya Carr

Rotonya Carr

Rotonya Carr is an assistant professor of medicine at the Hospital of the University of Pennsylvania. Her research efforts include translational and basic science research in non-alcoholic and alcoholic fatty liver disease, focusing on the pathologic role of lipids and lipid associated proteins.

In 1884, the term sphingolipid was coined to reflect the complexity and sphinxlike nature of this lipid class.  Since that time, much progress has been made regarding our understanding of the various types of sphingolipids and their biologic roles in health and disease.  In this virtual issue of JLR, we have an opportunity to reflect on some of the recent advances in the field of sphingolipid biology, and in so doing, continue to solve the enigma of these lipids.  In addition, we would like to highlight both established and new investigators in the field who undoubtedly are the future of sphingolipid research.  These researchers span the spectrum of trainees to faculty at academic institutions and present fresh perspectives on the basic biology, methodologic techniques, pathogenesis, and therapeutic roles of sphingolipid classes.  Here, we reintroduce them to our readers by way of a brief and personal biography and putting a face to the name.

Sphingolipids are lipids with a sphingosine backbone (e.g. ceramides, sphingomyelin, cerebrosides and gangliosides) and are key components of cell membranes and intracellular organelles.  Some sphingolipids have cell signaling capability and thus are important for the cellular regulation of growth, differentiation, inflammation, senescence and energy homeostasis.  Sphingolipids are highly regulated and, increasingly, the sphingolipid ceramide, its derivatives and metabolites are being implicated in diseases as a result of their abnormal accumulation within cellular compartments.  For example, in patients with non-alcoholic steatohepatitis (NASH), C:16 ceramide-rich extracellular vesicles are released into the circulation by hepatocytes and promote macrophage activation.  Recently, this emerging role of ceramides in extracellular vesicles was expertly reviewed by Verderio et al. Ceramides are also implicated in the development of neurodegenerative disease, as ceramide-rich exosomes derived from TNF-alpha and IFN-y exposed cells promote cell death in a human oligodendroglioma cell line.  Conversely, ceramide reduction through deficiency of acid sphingomyelinase mitigates the brain damage observed in traumatic brain injury.  In the future, naturally occurring human mutations in ceramide synthetic genes such as the recently discovered mutation in desaturase DEGS1 and further exploration of how sex differences in ceramide homeostasis arise will give us even more insight into how sphingolipids confer disease susceptibility.

Not surprisingly, given the aforementioned role of sphingolipids in disease, sphingolipid modulation offers a range of therapeutic possibilities.  Here, we highlight two potential therapeutic applications, namely the genetic and pharmacologic inhibition of sphingosine synthesis by acid ceramidase to prevent cancer cell-treatment escape mechanisms and vaccination strategies that capitalize on sphingomyelin hydrolysis to impair cellular viral entry of the West Nile virus.  Further, application of new methodology to more precisely characterize sphingolipid structure and binding sites and to establish how sphingolipids move among cellular compartments to exert their effects will, ultimately, enable investigators to explore the cellular- and organelle-specific effects of these therapies and solve the enigma of the metaphorical sphinx, one sphingolipid at a time.

Cover Image

The cover art features the structures of several sphingolipids being freed as the Sphinx unravels. Concept by Rotonya Carr. Artwork by Luciana Giono.

Featured research articles

Probing compartment-specific sphingolipids with targeted bacterial sphingomyelinases and ceramidases

Wataru Sakamoto, Daniel Canals, Silvia Salamone, Janet Allopenna, Christopher J. Clarke, Justin Snider, Lina M. Obeid and Yusuf A. Hannun
First Published on June 26, 2019

Nicholas Blackburn

Wataru Sakamoto has studied sphingolipids in Yusuf Hannun's lab at Stony Brook University as a visiting researcher, and is currently working at ONO Pharmaceutical Co. Ltd. His focus is on understanding the sphingolipid metabolism related to diseases such as cancer and inflammation and his goal is to make new therapeutic drugs. Every weekend, he enjoys running and watching basketball games.

Rare DEGS1 variant significantly alters de novo ceramide synthesis pathway

Nicholas B. Blackburn, Laura F. Michael, Peter J. Meikle, Juan M. Peralta, Marian Mosior, Scott McAhren, Hai H. Bui, Melissa A. Bellinger, Corey Giles, Satish Kumar, Ana C. Leandro, Marcio Almeida, Jacquelyn M. Weir, Michael C. Mahaney, Thomas D. Dyer, Laura Almasy, John L. VandeBerg, Sarah Williams-Blangero, David C. Glahn, Ravindranath Duggirala, Mark Kowala, John Blangero and Joanne E. Curran
First Published on June 21, 2019

Nicholas Blackburn

Nicholas Blackburn, Ph.D., is an assistant professor in the department of human genetics at the University of Texas Rio Grande Valley’s School of Medicine, in Brownsville, Texas. His research centers around the analysis of whole genome sequence data from multigenerational pedigrees in the ongoing and longitudinal San Antonio Family Heart Study. Blackburn analyzes novel lipidomic datasets and quantitative phenotypes in Mexican American families with the goal of identifying new genetic factors related to cardiovascular disease risk.

Genetic and pharmacological inhibition of acid ceramidase prevents asymmetric cell division by neosis

Shai White-Gilbertson, Ping Lu, James S. Norris and Christina Voelkel-Johnson
First Published on April 15, 2019

Shai White-Gilbertson

Shai White-Gilbertson is a staff scientist at the Medical University of South Carolina. She has primarily focused on mechanisms of therapy evasion in cancer cells. Recent interests include the process of neosis, a form of asymmetric cell division. In addition to her molecular biology pursuits, Shai maintains credentials as an acupuncturist and certified tumor registrar. In her spare time, she and her husband attempt to detangle their fuzzy dog.

Acid sphingomyelinase deficiency protects mitochondria and improves function recovery after brain injury

Sergei A. Novgorodov, Joshua R. Voltin, Wenxue Wang, Stephen Tomlinson, Christopher L. Riley and Tatyana I. Gudz
First Published on January 20, 2019

Sergei Novgorodov

Sergei Novgorodov is an assistant professor at the Medical University of South Carolina. He has spent his career studying mitochondria and the contribution of sphingolipids to mitochondria-mediated cell dysfunction, particularly in the setting of diabetes, stroke and traumatic brain injury. His current work is related to sphingolipid metabolism in Gulf War syndrome—a condition that may be corrected by the FDA approved drugs amitriptyline and zoledronic acid.

Role of sphingolipids in the biogenesis and biological activity of extracellular vesicles

Claudia Verderio, Martina Gabrielli and Paola Giussani
First Published on May 31, 2018

Claudia Verderio

Claudia Verderio is a research director of biological sciences at the National Research Council in Milan Italy. Verderio’s research is oriented towards understanding how innate immune cells in the brain influence synaptic dysfunction and neurodegeneration in later life, with a focus on extracellular vesicles released by glial cells and their role in neuroinflammatory processes of multiple sclerosis and Alzheimer’s disease.

Genetic, dietary, and sex-specific regulation of hepatic ceramides and the relationship between hepatic ceramides and IR

Frode Norheim, Thomas Bjellaas, Simon T. Hui, Karthickeyan Chella Krishnan, Jakleen Lee, Sonul Gupta, Calvin Pan, Yehudit Hasin-Brumshtein, Brian W. Parks, Daniel Y. Li, Hai H. Bui, Marian Mosier, Yuping Wu, Adriana Huertas-Vazquez, Stanley L. Hazen, Thomas E. Gundersen, Margarete Mehrabian, W. H. Wilson Tang, Andrea L. Hevener, Christian A. Drevon and Aldons J. Lusis
First Published on May 8, 2018

Frode Norheim

Frode Norheim is currently working as a researcher at the University of Oslo (UiO). Norheim received his master’s degree and doctorate from UiO. His graduate work was followed by postdoctoral research at UiO and the University of California, Los Angeles. Norheim’s research is focused on genetic regulation of metabolic diseases and on the health benefits of exercise physiology. He has also recently become interested in why the genetic regulation of a variety of metabolic disease varies between the sexes.

An intrinsic lipid-binding interface controls sphingosine kinase 1 function

Michael J. Pulkoski-Gross, Meredith L. Jenkins, Jean-Philip Truman, Mohamed F. Salama, Christopher J. Clarke, John E. Burke, Yusuf A. Hannun and Lina M. Obeid
First Published on January 11, 2018

Pulkoski–Gross

Michael Pulkoski–Gross is a postdoctoral scholar in Ellen Yeh's lab at Stanford University in Stanford, California. His current scientific interests include studying the underlying mechanisms of apicomplexan parasite growth and infection. In his downtime he enjoys hiking and fishing.

Novel function of ceramide for regulation of mitochondrial ATP release in astrocytes

Ji-Na Kong, Zhihui Zhu, Yutaka Itokazu, Guanghu Wang, Michael B. Dinkins, Liansheng Zhong, Hsuan-Pei Lin, Ahmed Elsherbini, Silvia Leanhart, Xue Jiang, Haiyan Qin, Wenbo Zhi, Stefka D. Spassieva and Erhard Bieberich
First Published on January 10, 2018

Ji Na Kong

Ji Na Kong is a postdoctoral associate in the department of biology at Massachusetts Institute of Technology in Cambridge, Massachusetts. Her graduate research focused on the biological function of ceramide, a key sphingolipid, in breast cancer and neurodegenerative diseases. She is currently interested in studying stress biology. Jina enjoys swimming and doing pilates.

Cytokine-induced release of ceramide-enriched exosomes as a mediator of cell death signaling in an oligodendroglioma cell line

Maria Podbielska, Zdzislaw M. Szulc, Ewa Kurowska, Edward L. Hogan, Jacek Bielawski, Alicja Bielawska and Narayan R. Bhat
First Published on September 13, 2016

Maria Podbielska

Maria Podbielska is new faculty at the Ludwik Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences in Wroclaw, Poland. She is a former Fulbright Scholar and a prior research scholar at the Medical University of South Carolina. She studies the role of sphingolipids in autoimmunity, particularly as they relate to multiple sclerosis. Podbielska loves American country music and travelling.

In-depth sphingomyelin characterization using electron impact excitation of ions from organics and mass spectrometry

Takashi Baba, J. Larry Campbell, J. C. Yves Le Blanc and Paul R. S. Baker
First Published on March 22, 2016

Takashi Baba

Takashi Baba is currently a senior research scientist at Sciex in Concord, Canada. His research interest is to establish a mass spectrometry methodology for biomolecule identification using low energy electrons based on novel physical instrumentation and radical chemistry. In addition to structural lipidomics, Baba’s research area covers top down proteomics, glycoproteomics and metabolomics.

Host sphingomyelin increases West Nile virus infection in vivo

Miguel A. Martín-Acebes, Enrique Gabandé-Rodríguez, Ana M. García-Cabrero, Marina P. Sánchez, María Dolores Ledesma, Francisco Sobrino and Juan-Carlos Saiz
First Published on January 13, 2016

Eiji Kakazu

Miguel Martin–Acebes is a principal investigator at the department of biotechnology at the National Institute of Investigation and Agrary Technology and Alimentary in Madrid, Spain. He studies virus–host interactions to identify novel antiviral targets and to improve vaccine strategies, with special focus on the role of lipids during viral infections.

Hepatocytes release ceramide-enriched pro-inflammatory extracellular vesicles in an IRE1a-dependent manner

Eiji Kakazu, Amy S. Mauer, Meng Yin and Harmeet Malhi
First Published on November 30, 2015

Eiji Kakazu

Eiji Kakazu is an assistant professor in the department of gastroenterology at the Tohoku University School of Medicine in Sendai, Japan. His current scientific interests include risk factors for NASH, lipids, lipoproteins and amino acids. Kakazu has very productive days with research and medicine, but during his time off, he enjoys watching movies and cooking with his daughter.