Research Highlights

How accumulation of one lipid disrupts turnover of another

July 2019 | One puzzling feature of gangliosidoses is that often, secondary complex lipids will accumulate even in the absence of  mutations to their turnover pathways. A study from the Sandhoff lab at Bonn University, led by Susi Anheuser, sheds light onto the mechanism for secondary accumulation. Lysosomal lipid degradation enzymes’ activity is affected by the surface charge of lysosomal intraluminal vesicles, and primary lipid-turnover disorders can affect that surface charge. The study appears in the Journal of Lipid Research; read a summary in ASBMB Today.

Ceramide desaturase drives insulin resistance 

July 2019 | Researchers led by Scott Summers report in Science that knocking down the ceramide desaturase DES1 in mice on a high-fat diet improves insulin resistance. The enzyme converts dihydroceramide, which has a saturated side chain, to ceramide, which is unsaturated. Read the article here.

Harmonizing lipidomics

May 2019 | Lipid researchers take center stage in a feature in the May issue of ASBMB Today that explores the history of lipidomics and the challenge of establishing reproducible methods and reference measurements to enable discovery and use of lipid biomarkers. Read the article here.

Blocking lipogenesis, blocking zits

May 2019 | Esler and colleagues from Pfizer’s cardiovascular research unit and the University of California show that, unlike model organisms used to study sebum production, humans generate more than 80% of the lipids in this waxy skin secretion through de novo lipogenesis. Sebum production is higher in people with severe acne. By targeting acetyl-CoA carboxylase, or ACC, with an orally available inhibitor, the researchers reduced participants’ sebum excretion by half. The authors propose that ACC may be a promising therapeutic target to combat acne. (Pfizer is also developing an ACC inhibitor to treat nonalcoholic steatohepatosis.) The work appears in Science Translational Medicine.

Lipid transport: all it takes to reprogram neutrophils

April 2019 | Immune dysregulation is an important part of the cancer landscape: better evasion or dampening of immune responses leads to worse clincal outcomes. Veglia et al. report that pathologically activated neutrophils in cancer overexpress fatty acid transport protein 2, or FATP2. The protein, expressed in response to a growth factor, enables the neutrophils to take up more arachidonic acid and produce more prostaglandin. Pharmacological inhibition or genetic deletion of FATP2 in these cells slowed tumor progression in mice. The study appears in Nature.

Bacteria fight back against an antimicrobial fatty acid

April 2019 | One weapon in the skin’s arsenal against invaders is an unsaturated 16-carbon fatty acid called palmitoleic acid. Subramanian et al., investigating a Staphylococcus aureus fatty acid desaturase called OhyA, discovered that the protein is used to detoxify sebum lipids. Read more. 

Systems genetics of mouse lipid metabolism

March 2019 | Researchers using the hybrid mouse diversity panel developed in LRD member Jake Lusis’s lab to understand how lipid dysregulation leads to liver dysfunction found that lipid abundance appears to correlate with certain proteasomal proteins. Read more.

A novel sphingolipid flippase

February 2019 | Transport of glucosylceramide (GlcCer) from its synthesis site in the cytoplasmic leaflet of the Golgi membrane into the Golgi lumen, where it can be modified into some 200 glycosphingolipids, has been mysterious. Using  a fluorescence-labeled GlcCer molecule, researchers at Kyoto University and Vanderbilt University showed that yeast P4-ATPases thought to be specific for glycerophospholipids can also flip GlcCer. The yeast ATPase is related to human genes ATP10A and ATP10D, both of which have been linked to diabetes, obesity and heart disease in human genome-wide association studies.

Find out more in this Editor’s Pick from the Journal of Biological Chemistry.

A missing mitochondrial link in lysosomal storage disorders

February 2019 | For reasons that have remained unclear, genetic disorders caused by mutation to lipid turnover enzymes in the lysosome can also affect mitochondrial function. By examining brain and liver tissue from NPC1 knockout mice, and fibroblasts from patients with two lysosomal storage disorders, researchers in Finland and Germany found that transcription of mitochondrial genes was downregulated in disease, impairing oxidative respiration. Blocking expression of the transcription factors Etv1 or Klf2 partly or completely rescued various measures of mitochondrial function. Intriguingly, Klf2 expression may depend on sphingosine-1-phosphate signaling, suggesting a link to the impaired sphingolipid processing for which the disease is better known. Read the article, which appeared in eLife, here.

LIPID MAPS serves the next generation of lipid researchers

January 2019 | You may know the LIPID MAPS project, a source for data and protocols in lipidomics, from its years based at the University of California, San Diego. But a recent move to the U.K. and a new website mark a new phase for LIPID MAPS, which the project’s principal investigators explain in Science Signaling.

An autoinhibitory domain in PC synthesis

January 2019 | Phosphatidylcholine is the most abundant lipid in many membranes. In a biophysical study that appeared in the Journal of Biological Chemistry, Ramezanpour et al. used molecular dynamics to show that the PC synthetic enzyme CCT uses the same domain to bind cell membranes and to compete with its substrate. Read a news story on the study in ASBMB Today.

The many roles of ceramide-1-phosphate transfer proteins

December 2018 | Ceramide-1-phosphate transfer protein, or CPTP, is linked to inflammation and to diseases such as age-related macular degeneration. Rhoderick Brown surveys five years of CPTP studies in an informal essay in ASBMB Today.

Membrane desaturation linked to Parkinson’s protein aggregation

December 2018 | Working in yeast and cultured neurons, a team of researchers has shown that inhibiting stearoyl-CoA desaturases can reduce toxic aggregation of alpha-synuclein, the lipid-binding protein that accumulates in Parkinson’s disease. Read the work here.

Ancient sterols give lineage clues on an animal fossil  

October 2018 | You’ve heard of paleogenomics, and maybe paleoproteomics; now, researchers from around the world have used mass spectrometric analysis of lipid biomarkers fossilized in an Ediacaran fossil to establish its phylogeny. Their paper appeared in Science in September.

Sphingosine kinase 1 and tamoxifen resistance in breast cancer

October 2018 | A team led by Sarah Spiegel at VCU Health found that tamoxifen resistance correlates with increased SphK1 and ERα36 expression in tamoxifen-resistant breast cancer cells, in patient-derived xenografts, and in endocrine resistant breast cancer patients. They also say their data indicate that “targeting this ERα36 and SphK1 axis may be a therapeutic option to circumvent endocrine resistance and improve patient outcome.” Read the article in the Journal of Lipid Research.

Lipids linked to longevity 

September 2018 | Researchers led by Jan Gruber at Yale-NUS College found synergy in drug combinations aimed at aging-related genes through SREBP signaling. The changes affected lipid metabolism, especially monounsaturated fatty acids production. Read their paper in the journal Developmental Cell.

‘Converting transient to sustained signaling’

September 2018 | Fibroblast growth factor receptors can activate the kinase Erk in both short bursts and more sustained pulses. Researchers at Masaryk University in the Czech Republic found that inositol phosphatase SHIP2, better known for controlling PI(4,5)P2 in the plasma membrane, acts as a scaffold to recruit downstream kinases to the FGF receptor. Read their paper in the journal Science Signaling.

Structure and synthesis of a key tear film lipid

August 2018 | The August cover article of the Journal of Lipid Research features a newly-reported, ultra-long-chain hydroxy fatty acid that occurs naturally in the lipid layer of human tears. Prior experiments in Langmuir troughs have demonstrated that ultra-long-chain lipids, known as OAHFAs, are required to keep the lipid layer optically clear. Hancock and colleagues characterized the 50-carbon lipid, OAHFA 50:2, and developed a synthesis strategy. Read more.

Myelin regeneration through cholesterol synthesis

July 2018 | Molecules to promote myelin synthesis are a hot therapeutic target for multiple sclerosis and other neurological diseases. High-throughput chemical screens have revealed a number of small molecules, many with known targets, that promote oligodendrocyte maturation in vitro. In a recent analysis of many such molecules, scientists at Case Western University showed that many act on oligodendrocytes not through their known targets, but through a cytochrome and a few other enzymes in the cholesterol biosynthesis pathway. “This is a remarkable study, presenting a  unifying mechanism for the many pro-remyelination small molecules that have emerged recently,” said Cornell lipid biologist Jeremy Baskin in a tweet. The article was published in Nature.

A synthetic, turbo-charged membrane flippase

June 2018 | Researchers have engineered a membrane-embedded DNA nanostructure that functions as a lipid flippase. The pore, constructed from eight strands of DNA, can dismantle the asymmetry of a lipid bilayer at rates an order of magnitude higher than flippase proteins. Read more about the invention in Nature Communications.

Mysterious enzyme activity traced to a familiar protein

June 2018 | Plasmalogens are unusual phospholipids, characterized by an ether next to an alkene, a group known as a vinyl ester, that links the head group and one fatty acid tail. Degradation of plasmalogens can produce arachidonic acid, an important precursor to the eicosanoid family of signaling molecules; but how plasmalogens are cleaved was unknown.

Researchers in Richard Gross’s lab at Washington University in St. Louis recently found that mitochondrial protein cytochrome C can cleave the vinyl ester. Because the cytochrome’s plasmalogenase activity is activated by oxidative stress, the finding hints at a link between mitochondrial oxidative stress and inflammation in conditions like ischemia and amyloidosis. Read the original JBC article here, or a Research Highlight here.

Novel sources for lipid droplets

June 2018 | Scientists in Alwin Köhler’s group at the Max F. Perutz Laboratories in Vienna report the finding that in yeast the inner nuclear membrane, which is contiguous with the outer membrane and the endoplasmic reticulum, can also be a site of lipid storage and lipid droplet formation. Access the Cell article here.

Selenoprotein 1 plays an unexpected role in plasmalogen synthesis

May 2018 | By conducting whole-exome sequencing on a patient with an undiagnosed developmental disorder, researchers in Israel found that a SNP affecting splicing of EPT1, or selenoprotein1, disrupted the protein’s stability. Lipidomic analysis of the patient’s cells revealed that EPT1 was crucial for production of plasmalogens. Read the JLR article here, or read a narrative describing the unusual genesis of an international collaboration here.

Identifying the lipids bound to membrane proteins

April 2018 | Researchers at the University of Oxford report on a new method for identification of lipids in complex with an integral membrane protein by mass spectrometry. The paper was published in Nature Protocols.

Ceramide synthesis demystified

April 2018 | Recent research from Tony Futerman’s lab at the Weizmann Institute of Life Sciences in Rehovot, Israel, in collaboration with Alfred Merrill’s lab at Georgia Tech, has identified a short loop in a family of ceramide synthases that drive substrate selection. The loop of 11 amino acids, which sticks into the ER lumen, determines the enzymes’ specificity for the long-chain fatty acids they couple to sphinganine. This work helps explain how the many distinct sphingolipids arise. Read the JBC article here.

Toward a harmonized field of lipidomics

December 2017 | John Bowden of the National Institute of Standards and Technology talks about a recent paper reporting an exercise to measure the reproducibility of lipidomics analyses across 31 labs in the U.S. and abroad. Read the Q&A with Bowden in ASBMB Today.

Ken Hsu and Caroline Franks discuss diacylglycerol kinase work

August 2017 | Ken Hsu, assistant professor of chemistry at the University of Virginia, and Caroline Franks, a graduate student in the Hsu lab, discuss their research on diacylglycerol kinases (DGKs). Franks is the first author on the paper “The Ligand Binding Landscape of Diacylglycerol Kinases.” Read the paper in the journal Cell Chemical Biology.

Kyle Korshavn discusses how bilayer thickness regulates Aβ aggregation

June 2017 | Kyle Korshavn, a postdoctoral researcher in Ayyalusamy Ramamoorthy’s lab at the University of Michigan, was first author on a paper reporting how pathologically thin lipid bilayers affect amyloid-β aggregation and how pathological lipid oxidation may contribute to Aβ cytotoxicity. Read Korshavn’s paper in the Journal of Biological Chemistry. Watch a video of Korshavn talking about his work.

Visualization technique reveals unusual shape of VLDL

June 2017 | Yu et al. developed a 3-D technique called individual particle electron tomography, allowing them to visualize the carriers of cholesterol. The research reveals a unique polyhedral shape to very low-density lipoproteins (VLDL), which are implicated in the development of cardiovascular disease. This discovery could direct future studies into how flat faces and sharp edges of these molecules affect cholesterol transport and lead to disease. Read the paper in the Journal of Lipid Research.

Understanding phospholipid function: Why are there so many lipids?

May 2017 | In a scientific memoir, Bill Dowhan describes the arc of his career and how the study of lipids has progressed. Once considered that annoying grease that was disposed of while purifying proteins, lipids, we now know, come in a dazzling array and do much for the cell. The memoir is an inspiring must-read for lipidologists at all stages of their careers by one of the true greats in lipid research. Read Dowhan’s “Reflections” article in the Journal of Biological Chemistry.

Friction mediates scission of tubular membranes scaffolded by BAR proteins

May 2017 | We’re used to there being friction between the lipid world and the protein world; little did we know that this friction is an important component of membrane remodeling. Simunovic et al. report that the dynamin-independent scission of endocytic vesicles is driven by the friction generated by the interaction of lipids and BAR-domain proteins. Read the paper in the journal Cell.

ApoE and lipid homeostasis in Alzheimer’s disease: a thematic review series

May 2017 | Besides aging, the most significant known risk factor for Alzheimer’s disease is the ApoE4 allele. ApoE is the major apolipoprotein in the brain, and E4 is a rare variant. This series of eight thematically linked reviews explores the isoform-specific roles ApoE plays in healthy and diseased brain states. Read the introduction by Ta-Yuan Chang and Catherine Chang in the Journal of Biological Chemistry.

Lipid sensing by mTOR complexes via de novo synthesis of phosphatidic acid

April 2017 | Menon et al. report that mTORC1 and mTORC2 are activated in response to exogenously supplied fatty acids via the de novo synthesis of phosphatidic acid, a central metabolite for membrane phospholipid biosynthesis. They show the impact of exogenously supplied fatty acids on mTOR in KRas-driven cancer cells, which are programmed to utilize exogenous lipids. Read the paper in the Journal of Biological Chemistry.

PI-PLC β1 in differentiation and disease

March 2017 | Evidence from several laboratories has highlighted the presence of autonomous nuclear inositol lipid metabolism. The evidence suggests that lipid molecules are important components of signaling pathways operating within the nucleus. The findings are important, given the fact that nuclear signaling activity controls cell growth and differentiation. Read the rest of this “Lipid News” article by Lucio Cocco in ASBMB Today.

Proteins and lipids — a complicated relationship?

January 2017 | Researchers have been discussing for many years the role of the lipid matrix in regulating the activity and the organization of membrane proteins. A variety of effects have been singled out and studied qualitatively and quantitatively in model systems. However, the applicability of those results to living cells is — in many cases — unsatisfactory. Read the rest of this “Lipid News” article by Eva Sevcsik and Gerhard J. Schütz in ASBMB Today.