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Lipid droplets (LDs) are organelles of cellular lipid storage with fundamental roles in energy metabolism and cell membrane homeostasis. There has been an explosion of research into the biology of LDs, in part due to their relevance in diseases of lipid storage, such as atherosclerosis, obesity, type 2 diabetes, and hepatic steatosis. Consequently, there is an increasing need for a resource that combines datasets from systematic analyses of LD biology. Here, we integrate high-confidence, systematically generated human, mouse, and fly data from studies on LDs in the framework of an online platform named the "Lipid Droplet Knowledge Portal" (https://lipiddroplet.org/). This scalable and interactive portal includes comprehensive datasets, across a variety of cell types, for LD biology, including transcriptional profiles of induced lipid storage, organellar proteomics, genome-wide screen phenotypes, and ties to human genetics. This resource is a powerful platform that can be utilized to identify determinants of lipid storage.

Haploinsufficiency of GRN causes frontotemporal dementia (FTD). The GRN locus produces progranulin (PGRN), which is cleaved to lysosomal granulin polypeptides. The function of lysosomal granulins and why their absence causes neurodegeneration are unclear. Here we discover that PGRN-deficient human cells and murine brains, as well as human frontal lobes from GRN-mutation FTD patients have increased levels of gangliosides, glycosphingolipids that contain sialic acid. In these cells and tissues, levels of lysosomal enzymes that catabolize gangliosides were normal, but levels of bis(monoacylglycero)phosphates (BMP), lipids required for ganglioside catabolism, were reduced with PGRN deficiency. Our findings indicate that granulins are required to maintain BMP levels to support ganglioside catabolism, and that PGRN deficiency in lysosomes leads to gangliosidosis. Lysosomal ganglioside accumulation may contribute to neuroinflammation and neurodegeneration susceptibility observed in FTD due to PGRN deficiency and other neurodegenerative diseases.

Biomarkers are molecules that can be used to observe changes in an individual's biochemical or medical status and provide information to aid diagnosis or treatment decisions. Dysregulation in lipid metabolism in the brain is a major risk factor for many neurodegenerative disorders, including frontotemporal dementia, Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. Thus, there is a growing interest in using lipids as biomarkers in neurodegenerative diseases, with the anionic phospholipid bis(monoacylglycerol)phosphate and (glyco-)sphingolipids being the most promising lipid classes thus far. In this review, we provide a general overview of lipid biology, provide examples of abnormal lysosomal lipid metabolism in neurodegenerative diseases, and discuss how these insights might offer novel and promising opportunities in biomarker development and therapeutic discovery. Finally, we discuss the challenges and opportunities of lipid biomarkers and biomarker panels in diagnosis, prognosis, and/or treatment response in the clinic. [ABSTRACT FROM AUTHOR]

Abstract Background Burkholderia rhizoxinica is an intracellular symbiont of the phytopathogenic zygomycete Rhizopus microsporus, the causative agent of rice seedling blight. The endosymbiont produces the antimitotic macrolide rhizoxin for its host. It is vertically transmitted within vegetative spores and is essential for spore formation of the fungus. To shed light on the evolution and genetic potential of this model organism, we analysed the whole genome of B. rhizoxinica HKI 0454 - a type strain of endofungal Burkholderia species. Results The genome consists of a structurally conserved chromosome and two plasmids. Compared to free-living Burkholderia species, the genome is smaller in size and harbors less transcriptional regulator genes. Instead, we observed accumulation of transposons over the genome. Prediction of primary metabolic pathways and transporters suggests that endosymbionts consume host metabolites like citrate, but might deliver some amino acids and cofactors to the host. The rhizoxin biosynthesis gene cluster shows evolutionary traces of horizontal gene transfer. Furthermore, we analysed gene clusters coding for nonribosomal peptide synthetases (NRPS). Notably, B. rhizoxinica lacks common genes which are dedicated to quorum sensing systems, but is equipped with a large number of virulence-related factors and putative type III effectors. Conclusions B. rhizoxinica is the first endofungal bacterium, whose genome has been sequenced. Here, we present models of evolution, metabolism and tools for host-symbiont interaction of the endofungal bacterium deduced from whole genome analyses. Genome size and structure suggest that B. rhizoxinica is in an early phase of adaptation to the intracellular lifestyle (genome in transition). By analysis of tranporters and metabolic pathways we predict how metabolites might be exchanged between the symbiont and its host. Gene clusters for biosynthesis of secondary metabolites represent novel targets for genomic mining of cryptic natural products. In silico analyses of virulence-associated genes, secreted proteins and effectors might inspire future studies on molecular mechanisms underlying bacterial-fungal interaction.

APOE4 disrupts lipid homeostasis in glia: APOE4 is a strong genetic risk factor for many diseases, most notably, late-onset Alzheimer's disease. Sienski et al. now show that cultured human glia with an APOE4 genotype accumulated unsaturated triglycerides leading to a lipid imbalance. Using genetic screens in yeast, the authors discovered that promoting phospholipid synthesis through choline supplementation of culture medium restored a normal lipid state in APOE4-expressing yeast cells. The authors then demonstrated that choline supplementation also restored lipid homeostasis in human APOE4 astrocytes. These findings suggest that modulating glial metabolism could help to reduce APOE4-associated disease risk. The E4 allele of the apolipoprotein E gene (APOE) has been established as a genetic risk factor for many diseases including cardiovascular diseases and Alzheimer's disease (AD), yet its mechanism of action remains poorly understood. APOE is a lipid transport protein, and the dysregulation of lipids has recently emerged as a key feature of several neurodegenerative diseases including AD. However, it is unclear how APOE4 perturbs the intracellular lipid state. Here, we report that APOE4, but not APOE3, disrupted the cellular lipidomes of human induced pluripotent stem cell (iPSC)–derived astrocytes generated from fibroblasts of APOE4 or APOE3 carriers, and of yeast expressing human APOE isoforms. We combined lipidomics and unbiased genome-wide screens in yeast with functional and genetic characterization to demonstrate that human APOE4 induced altered lipid homeostasis. These changes resulted in increased unsaturation of fatty acids and accumulation of intracellular lipid droplets both in yeast and in APOE4-expressing human iPSC-derived astrocytes. We then identified genetic and chemical modulators of this lipid disruption. We showed that supplementation of the culture medium with choline (a soluble phospholipid precursor) restored the cellular lipidome to its basal state in APOE4-expressing human iPSC-derived astrocytes and in yeast expressing human APOE4. Our study illuminates key molecular disruptions in lipid metabolism that may contribute to the disease risk linked to the APOE4 genotype. Our study suggests that manipulating lipid metabolism could be a therapeutic approach to help alleviate the consequences of carrying the APOE4 allele. [ABSTRACT FROM AUTHOR]

The free-living soil nematode Caenorhabditis elegans adapts its development to the availability of food. When food is scarce and population density is high, worms enter a developmentally arrested non-feeding diapause stage specialized for long-term survival called the dauer larva. When food becomes available, they exit from the dauer stage, resume growth and reproduction. It has been postulated that compound(s) present in food, referred to as the “food signal”, promote exit from the dauer stage. In this study, we have identified NAD+ as a component of bacterial extract that promotes dauer exit. NAD+, when dissolved in alkaline medium, causes opening of the mouth and ingestion of food. We also show that to initiate exit from the dauer stage in response to NAD+ worms require production of serotonin. Thus, C. elegans can use redox cofactors produced by dietary organisms to sense food. [ABSTRACT FROM AUTHOR]

Proper cholesterol transport is crucial for the functionality of cells. In C. elegans, certain cholesterol derivatives called dafachronic acids (DAs) govern the entry into diapause. In their absence, worms form a developmentally arrested dauer larva. Thus, cholesterol transport to appropriate places for DA biosynthesis warrants the reproductive growth. Recently, we discovered a novel class of glycosphingolipids, PEGCs, required for cholesterol mobilization/transport from internal storage pools. Here, we identify other components involved in this process. We found that strains lacking polyunsaturated fatty acids (PUFAs) undergo increased dauer arrest when grown without cholesterol. This correlates with the depletion of the PUFA-derived endocannabinoids 2-arachidonoyl glycerol and anandamide. Feeding of these endocannabinoids inhibits dauer formation caused by PUFAs deficiency or impaired cholesterol trafficking (e.g. in Niemann-Pick C1 or DAF-7/TGF-β mutants). Moreover, in parallel to PEGCs, endocannabinoids abolish the arrest induced by cholesterol depletion. These findings reveal an unsuspected function of endocannabinoids in cholesterol trafficking regulation.

Background: Persistent chest pain after a normal ischemic evaluation is often a diagnostic dilemma. Although stress-echo, nuclear stress perfusion imaging and invasive coronary arteriography are commonly used for detection of coronary atherosclerosis, they are not well suited for diagnosing inflammatory heart disease. Cardiac MRI (CMR) is uniquely capable of detecting increased myocardial tissue water content (i.e. edema), a hallmark of myocardial inflammation. This study was designed to assess the value of CMR for detecting myocarditis in a cohort of patients with chest pain and a negative ischemic evaluation. Methods: An institutional cardiac imaging database was queried for all patients with chest pain who underwent CMR after a normal ischemic evaluation. Of 3,702 patients in the database, 1,527 patients with chest pain had a normal stress-echo, normal nuclear myocardial perfusion study(MPI), or normal CMR stress perfusion study. CMR findings of myocarditis included myocardial enhancement on T2 weighted imaging, early gadolinium enhancement, increased T1 relaxation time on T1 mapping, increased T2 relaxation time on T2 mapping and gadolinium enhancement on delayed imaging. At least 2 findings were required for a diagnosis of myocarditis. Results: Of 149 patients with a normal stress-echo, 10 (6.8%) had evidence of myocarditis. Of these 10 patients, nine (90%) were female. 29 out of 403 (7.2%) with a normal MPI had myocarditis. 63 of 924 patients (6.8%) with a normal CMR stress perfusion study, also had myocarditis on CMR. Conclusions: This retrospective analysis of a large institutional cardiac imaging database suggests that patients with a clinical presentation of chest pain, followed by a negative ischemic evaluation have a 7% prevalence of underlying myocarditis. Moreover, females with normal stress-echo results are more likely to have an undetected diagnosis of acute myocarditis. These findings stress the value of CMR for diagnosing myocarditis, especially when the more commonly used cardiac imaging modalities have failed to establish the etiology of chest pain. [ABSTRACT FROM AUTHOR]

Massive water loss is a serious challenge for terrestrial animals, which usually has fatal consequences. However, some organisms have developed means to survive this stress by entering an ametabolic state called anhydrobiosis. The molecular and cellular mechanisms underlying this phenomenon are poorly understood. We recently showed that Caenorhabditis elegans dauer larva, an arrested stage specialized for survival in adverse conditions, is resistant to severe desiccation. However, this requires a preconditioning step at a mild desiccative environment to prepare the organism for harsher desiccation conditions. A systems approach was used to identify factors that are activated during this preconditioning. Using microarray analysis, proteomics, and bioinformatics, genes, proteins, and biochemical pathways that are upregulated during this process were identified. These pathways were validated via reverse genetics by testing the desiccation tolerances of mutants. These data show that the desiccation response is activated by hygrosensation (sensing the desiccative environment) via head neurons. This leads to elimination of reactive oxygen species and xenobiotics, expression of heat shock and intrinsically disordered proteins, polyamine utilization, and induction of fatty acid desaturation pathway. Remarkably, this response is specific and involves a small number of functional pathways, which represent the generic toolkit for anhydrobiosis in plants and animals. [ABSTRACT FROM AUTHOR]

Background: Trauma systems save lives by coordinating timely and effective responses to injury. However, trauma system effectiveness varies geographically, with worse outcomes observed in rural settings. Prior data suggest that undertriage may play a role in this disparity. Our aim was to explore potential driving factors for decision making among clinicians for undertriaged trauma patients., Methods: We performed a retrospective analysis of the National Emergency Medical Services Information System database among patients who met physiologic or anatomic national field triage guideline criteria for transport to the highest level of trauma center. Undertriage was defined as transport to a non-level I/II trauma center. Multivariable logistic regression was used to determine demographic, injury, and system characteristics associated with undertriage. Undertriaged patients were then categorized into "recognized" and "unrecognized" groups using the documented reason for transport destination to identify underlying factors associated with undertriage., Results: A total of 36,094 patients were analyzed. Patients in urban areas were more likely to be transported to a destination based on protocol rather than the closest available facility. As expected, patients injured in urban regions were less likely to be undertriaged than their suburban (adjusted odds ratio [aOR], 2.69; 95% confidence interval [95% CI], 2.21-3.31), rural (aOR, 2.71; 95% CI, 2.28-3.21), and wilderness counterparts (aOR, 3.99; 95% CI, 2.93-5.45). The strongest predictor of undertriage was patient/family choice (aOR, 6.29; 5.28-7.50), followed by closest facility (aOR, 5.49; 95% CI, 4.91-6.13) as the reason for hospital selection. Nonurban settings had over twice the odds of recognizing the presence of triage criteria among undertriaged patients (p < 0.05)., Conclusion: Patients with injuries in nonurban settings and those with less apparent causes of severe injury are more likely to experience undertriage. By analyzing how prehospital clinicians choose transport destinations, we identified patient and system factors associated with undertriage. Targeting these at-risk demographics and contributing factors may help alleviate regional disparities in undertriage., Level of Evidence: Diagnostic; Level IV., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)