Lipid Loss Research Articles

Extrusion-controlled lipid retention and distribution of wheat germ and its application combining exogenous starch

Wheat germ is an agricultural but low-economic by-product for animal feed or waste due to its susceptibility of hydrolytic/oxidative rancidities. Here, we use controllable extrusion to treat wheat germ, and with assistance of exogenous starch as lipid protective factor at different ratios (0:10 2:8, 3:7, 4:6). Oxidation of optimized germ extrudate was slowed down during storage, with total lipid retention rate reach up to ∼88.3%. Extrusion dynamic analysis showed that relatively high screw speed (100–150 rpm) significantly shortened mean residence time, increased axial diffusion velocity and reduced the loss of free and bound lipid. Type Ⅱ starch-lipid complex was changed to type Ⅰ during extrusion, with thermal transition peak declined. Wheat germ lipid was most evenly distributed under 100 rpm extrusion. The hydrogen bonding interaction between exogenous starch and lipids in wheat germ was strengthened, with significant modification in water absorption, water solubility, expansion and textual indexes.

Impact of Lipid Composition on Vesicle Protein Adsorption: A BSA Case Study.

Investigating the interaction between liposomes and proteins is of paramount importance in the development of liposomal formulations with real potential for bench-to-bedside transfer. Upon entering the body, proteins are immediately adsorbed on the liposomal surface, changing the nanovehicles' biological identity, which has a significant impact on their biodistribution and pharmacokinetics and ultimately on their therapeutic effect. Albumin is the most abundant plasma protein and thus usually adsorbs immediately on the liposomal surface. We herein report a comprehensive investigation on the adsorption of model protein bovine serum albumin (BSA) onto liposomal vesicles containing the zwitterionic lipid 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC), in combination with either cholesterol (CHOL) or the cationic lipid 1,2-dioleoyl-3-trimethylammoniumpropane (DOTAP). While many studies regarding protein adsorption on the surface of liposomes with different compositions have been performed, to the best of our knowledge, the differential responses of CHOL and DOTAP upon albumin adsorption on vesicles have not yet been investigated. UV-vis spectroscopy and sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) revealed a strong influence of the phospholipid membrane composition on protein adsorption. Hence, it was found that DOTAP-containing vesicles adsorb proteins more robustly but also aggregate in the presence of BSA, as confirmed by DLS and TEM. Separation of liposome-protein complexes from unadsorbed proteins performed by means of centrifugation and size exclusion chromatography (SEC) was also investigated. Our results show that neither method can be regarded as a golden experimental setup to study the protein corona of liposomes. Yet, SEC proved to be more successful in the separation of unbound proteins, although the amount of lipid loss upon liposome elution was higher than expected. In addition, coarse-grained molecular dynamics simulations were employed to ascertain key membrane parameters, such as the membrane thickness and area per lipid. Overall, this study highlights the importance of surface charge and membrane fluidity in influencing the extent of protein adsorption. We hope that our investigation will be a valuable contribution to better understanding protein-vesicle interactions for improved nanocarrier design.

Tissue fibrosis associated depletion of lipid-filled cells.

Fibrosis is primarily described as the deposition of excessive extracellular matrix, but in many tissues it also involves a loss of lipid or lipid-filled cells. Lipid-filled cells are critical to tissue function and integrity in many tissues including the skin and lungs. Thus, loss or depletion of lipid-filled cells during fibrogenesis, has implications for tissue function. In some contexts, lipid-filled cells can impact ECM composition and stability, highlighting their importance in fibrotic transformation. Recent papers in fibrosis address this newly recognized fibrotic lipodystrophy phenomenon. Even in disparate tissues, common mechanisms are emerging to explain fibrotic lipodystrophy. These findings have implications for fibrosis in tissues composed of fibroblast and lipid-filled cell populations such as skin, lung, and liver. In this review, we will discuss the roles of lipid-containing cells, their reduction/loss during fibrotic transformation, and the mechanisms of that loss in the skin and lungs.

Thymic stromal lymphopoietin induces IL-4/IL-13 from T cells to promote sebum secretion and adipose loss

BackgroundThe cytokine thymic stromal lymphopoietin (TSLP) promotes type 2 immune responses and can induce adipose loss by stimulating lipid loss from the skin through sebum secretion by sebaceous glands, which enhances the skin barrier. However, the mechanism by which TSLP upregulates sebaceous gland function is unknown. ObjectiveHere, we investigated the mechanism by which TSLP stimulates sebum secretion and adipose loss. MethodsRNA sequencing analysis was performed on sebaceous glands isolated by laser capture microdissection and single cell RNA sequencing analysis was performed on sorted skin T cells. Sebocyte function was analyzed by histological analysis and sebum secretion in vivo and by measuring lipogenesis and proliferation in vitro. ResultsWe found that TSLP sequentially stimulated the expression of lipogenesis genes followed by cell death genes in sebaceous glands to induce holocrine secretion of sebum. TSLP did not affect sebaceous gland activity directly. Rather, single cell RNA sequencing revealed that TSLP recruited distinct T cell clusters that produce IL-4 and IL-13, which were necessary for TSLP-induced adipose loss and sebum secretion. Moreover, IL-13 was sufficient to cause sebum secretion and adipose loss in vivo and to induce lipogenesis and proliferation of a human sebocyte cell line in vitro. ConclusionWe propose that TSLP stimulates T cells to deliver IL-4 and IL-13 to sebaceous glands, which enhances sebaceous gland function, turnover, and subsequent adipose loss. Clinical ImplicationThus, beyond causing skin inflammation, IL-4 and IL-13 can also promote sebum secretion, which is an important component of the skin barrier.

Divergence in aerobic capacity influences hepatic and systemic metabolic adaptations to bile acid sequestrant and short-term high-fat/sucrose feeding in rats.

High versus low aerobic capacity significantly impacts the risk for metabolic diseases. Rats selectively bred for high or low intrinsic aerobic capacity differently modify hepatic bile acid metabolism in response to high-fat diets (HFDs). Here we tested if a bile acid sequestrant would alter hepatic and whole body metabolism differently in rats with high and low aerobic capacity fed a 1-wk HFD. Male rats (8 mo of age) that were artificially selected to be high (HCR) and low-capacity runners (LCR) with divergent intrinsic aerobic capacities were transitioned from a low-fat diet (LFD, 10% fat) to an HFD (45% fat) with or without a bile acid sequestrant (BA-Seq, 2% cholestyramine resin) for 7 days while maintained in an indirect calorimetry system. HFD + BA-Seq increased fecal excretion of lipids and bile acids and prevented weight and fat mass gain in both strains. Interestingly, HCR rats had increased adaptability to enhance fecal bile acid and lipid loss, resulting in more significant energy loss than their LCR counterpart. In addition, BA-Seq induced a greater expression of hepatic CYP7A1 gene expression, the rate-limiting enzyme of bile acid synthesis in HCR rats both on HFD and HFD + BA-Seq diets. HCR displayed a more significant reduction of RQ in response to HFD than LCR, but HFD + BA-Seq lowered RQ in both groups compared with HFD alone, demonstrating a pronounced impact on metabolic flexibility. In conclusion, BA-Seq provides uniform metabolic benefits for metabolic flexibility and adiposity, but rats with higher aerobic capacity display adaptability for hepatic bile acid metabolism.NEW & NOTEWORTHY The administration of bile acid sequestrant (BA-Seq) has uniform metabolic benefits in terms of metabolic flexibility and adiposity in rats with high and low aerobic capacity. However, rats with higher aerobic capacity demonstrate greater adaptability in hepatic bile acid metabolism, resulting in increased fecal bile acid and lipid loss, as well as enhanced fecal energy loss.

Effects of taro [Colocasia esculenta (L.) Schott] slices on nutritional quality, sensory quality, and shelf life of Chinese pickled and steamed pork belly.

This study aimed to investigate the influence of different ratios of taro slices (TS) on the nutritional quality, sensory quality, and shelf life of Chinese pickled and steamed pork belly (CPSPB). The study examined various aspects of CPSPB, including its proximate components, fat oxidation, fatty acid composition, protein hydrolysis, oxidation reaction, and induction period (IP). Additionally, the sensory quality and texture analysis were compared simultaneously. The results showed that the addition of TS to CPSPB significantly improved water and lipid loss (p < 0.05), increased the unsaturated/saturated ratio of fatty acids, and reduced lipid and protein oxidation. Additionally, the incorporation of TS extended the IP and enhanced the shelf life of CPSPB. Particularly, the addition of a specific amount of TS (60%) to CPSPB resulted in the highest organoleptic quality. Therefore, these results emphasize the positive impact of TS on the overall quality of CPSPB, highlighting its potential to enhance the nutritional value, sensory attributes, and shelf life.

Toward Precision Weight-Loss Dietary Interventions: Findings from the POUNDS Lost Trial.

The POUNDS Lost trial is a 2-year clinical trial testing the effects of dietary interventions on weight loss. This study included 811 adults with overweight or obesity who were randomized to one of four diets that contained either 15% or 25% protein and 20% or 40% fat in a 2 × 2 factorial design. By 2 years, participants on average lost from 2.9 to 3.6 kg in body weight in the four intervention arms, while no significant difference was observed across the intervention arms. In POUNDS Lost, we performed a series of ancillary studies to detect intrinsic factors particular to genomic, epigenomic, and metabolomic markers that may modulate changes in weight and other cardiometabolic traits in response to the weight-loss dietary interventions. Genomic variants identified from genome-wide association studies (GWASs) on obesity, type 2 diabetes, glucose and lipid metabolisms, gut microbiome, and dietary intakes have been found to interact with dietary macronutrients (fat, protein, and carbohydrates) in relation to weight loss and changes of body composition and cardiometabolic traits. In addition, we recently investigated epigenomic modifications, particularly blood DNA methylation and circulating microRNAs (miRNAs). We reported DNA methylation levels at NFATC2IP, CPT1A, TXNIP, and LINC00319 were related to weight loss or changes of glucose, lipids, and blood pressure; we also reported thrifty miRNA expression as a significant epigenomic marker related to changes in insulin sensitivity and adiposity. Our studies have also highlighted the importance of temporal changes in novel metabolomic signatures for gut microbiota, bile acids, and amino acids as predictors for achievement of successful weight loss outcomes. Moreover, our studies indicate that biochemical, behavioral, and psychosocial factors such as physical activity, sleep disturbance, and appetite may also modulate metabolic changes during dietary interventions. This review summarized our major findings in the POUNDS Lost trial, which provided preliminary evidence supporting the development of precision diet interventions for obesity management.

Altered structure indicating reduced barrier function of lesional compared to non-lesional psoriatic skin-A non-invasive in vivo study of the human stratum corneum with confocal Raman micro-spectroscopy.

Psoriasis, one of the most common skin diseases affecting roughly 2%-3% of the world population, is associated with a reduced skin barrier function (SBF) that might play an important role in its pathophysiology. The SBF is provided primarily by the stratum corneum (SC) of the skin. Previous studies have revealed a higher trans-epidermal water loss, lower hydration, abnormal concentration and composition of intercellular lipids, as well as alterations in secondary keratin structure in the psoriatic SC. We compared on molecular level lesional psoriatic skin (LPS) with non-lesional psoriatic skin (nLPS) from 19 patients non-invasively in vivo, using confocal Raman micro-spectroscopy. By analysing the corresponding Raman spectra, we determined SBF-defining parameters of the SC depth-dependently. Our results revealed a lower total lipid concentration, a shift of lamellar lipid organisation towards more gauche-conformers and an increase of the less dense hexagonal lateral packing of the intercellular lipids in LPS. Furthermore, we observed lower natural moisturising factor concentration, lower total water as well as a strong tendency towards less strongly bound and more weakly bound water molecules in LPS. Finally, we detected a less stable secondary keratin structure with increased β-sheets, in contrast to the tertiary structure, showing a higher degree of folded keratin in LPS. These findings clearly suggest structural differences indicating a reduced SBF in LPS, and are discussed in juxtaposition to preceding outcomes for psoriatic and healthy skin. Understanding the alterations of the psoriatic SC provides insights into the exact pathophysiology of psoriasis and paves the way for optimal future treatments.

The mechanism of the phage-encoded protein antibiotic from ΦX174.

The historically important phage ΦX174 kills its host bacteria by encoding a 91-residue protein antibiotic called protein E. Using single-particle electron cryo-microscopy, we demonstrate that protein E bridges two bacterial proteins to form the transmembrane YES complex [MraY, protein E, sensitivity to lysis D (SlyD)]. Protein E inhibits peptidoglycan biosynthesis by obstructing the MraY active site leading to loss of lipid I production. We experimentally validate this result for two different viral species, providing a clear model for bacterial lysis and unifying previous experimental data. Additionally, we characterize the Escherichia coli MraY structure-revealing features of this essential enzyme-and the structure of the chaperone SlyD bound to a protein. Our structures provide insights into the mechanism of phage-mediated lysis and for structure-based design of phage therapeutics.

Effect of the Waveform of the Pulsed Electric Field on the Cylindrical Deformation of Uncharged Giant Unilamellar Vesicles.

High-speed imaging of giant unilamellar vesicles (GUVs) in recent years has shown significant shape deformation of these vesicles under electroporating direct current (DC) pulsed electric fields, possibly altering the surface distribution of transmembrane potential (TMP) and, thereby, the location and extent of electroporation on the bilayer membrane. The development of TMP, the corresponding shape deformation, and the extent of electroporation depend upon the waveform of the applied electric field. In this work, the deformation of vesicles was carried out under a high-intensity, single cycle of a sinusoidal pulsed electric field (SSPEF) and a square wave pulsed electric field (SWPEF). The cylindrical shape deformations of vesicles were observed for both SSPEF and SWPEF and were dependent upon the ratio of conductivity of the inner medium to the outer medium, α. For α = 1 and α > 1, the vesicles deformed into prolate cylinders as a result of Maxwell stress, whereas they were compressed into oblate cylinders for α < 1. Vesicles subjected to a SSPEF relaxed following either the pore closure dominated t2 or the efflux and lipid loss dominated, slow t3 mechanism depending upon the value of α. For α = 1 and α < 1, the relaxation of the vesicles was found to be predominantly dependent upon pore closure. On the other hand, a majority of vesicles gained excess area during poration when α > 1, which can be attributed to a higher TMP and faster charging of the membrane. The predictions of the approximate model for the deformation of vesicles agreed with the experiment, with deviations between the two as a result of the simplicity of the model. Moreover, the degree of deformation of vesicles [measured by the aspect ratio (AR)] and shape deformations of vesicles were found to be dependent upon the pulse width (TP) and amplitude (E0) of the SSPEF. The specific temporal variation of pore-forming tendencies of SSPEF and SWPEF, with their associated peculiarities, can be judiciously used for controlling electroporation in cells and vesicles.

Proteomic analysis of the small extracellular vesicles and soluble secretory proteins from cachexia inducing and non-inducing cancer cells.

Cancer cachexia is a wasting syndrome characterised by the loss of fat and/or muscle mass in advanced cancer patients. It has been well-established that cancer cells themselves can induce cachexia via the release of several pro-cachectic and pro-inflammatory factors. However, it is unclear how this process is regulated and the key cachexins that are involved. In this study, we validated C26 and EL4 as cachexic and non-cachexic cell models, respectively. Treatment of adipocytes and myotubes with C26 conditioned medium induced lipolysis and atrophy, respectively. We profiled soluble secreted proteins (secretome) as well as small extracellular vesicles (sEVs) released from cachexia-inducing (C26) and non-inducing (EL4) cancer cells by label-free quantitative proteomics. A total of 1268 and 1022 proteins were identified in the secretome of C26 and EL4, respectively. Furthermore, proteomic analysis of sEVs derived from C26 and EL4 cancer cells revealed a distinct difference in the protein cargo. Functional enrichment analysis using FunRich highlighted the enrichment of proteins that are implicated in biological processes such as muscle atrophy, lipolysis, and inflammation in both the secretome and sEVs derived from C26 cancer cells. Overall, our characterisation of the proteomic profiles of the secretory factors and sEVs from cachexia-inducing and non-inducing cancer cells provides insights into tumour factors that promote weight loss by mediating protein and lipid loss in various organs and tissues. Further investigation of these proteins may assist in highlighting potential therapeutic targets and biomarkers of cancer cachexia.

Gut AstA mediates sleep deprivation-induced energy wasting in Drosophila

Severe sleep deprivation (SD) has been highly associated with systemic energy wasting, such as lipid loss and glycogen depletion. Despite immune dysregulation and neurotoxicity observed in SD animals, whether and how the gut-secreted hormones participate in SD-induced disruption of energy homeostasis remains largely unknown. Using Drosophila as a conserved model organism, we characterize that production of intestinal Allatostatin A (AstA), a major gut-peptide hormone, is robustly increased in adult flies bearing severe SD. Interestingly, the removal of AstA production in the gut using specific drivers significantly improves lipid loss and glycogen depletion in SD flies without affecting sleep homeostasis. We reveal the molecular mechanisms whereby gut AstA promotes the release of an adipokinetic hormone (Akh), an insulin counter-regulatory hormone functionally equivalent to mammalian glucagon, to mobilize systemic energy reserves by remotely targeting its receptor AstA-R2 in Akh-producing cells. Similar regulation of glucagon secretion and energy wasting by AstA/galanin is also observed in SD mice. Further, integrating single-cell RNA sequencing and genetic validation, we uncover that severe SD results in ROS accumulation in the gut to augment AstA production via TrpA1. Altogether, our results demonstrate the essential roles of the gut-peptide hormone AstA in mediating SD-associated energy wasting.

MANAGEMEN FISIOTERAPI PADA KASUS XEROSIS EC MORBUS HANSEN MULTI BASILLER DI RS KUSTA KELET DONOROJO (STUDI KASUS)

Introduction: Xerosis is a term for dry skin that often occurs on the lower limbs, heels, elbows, and fingers. Xerosis is caused by reduced moisture due to loss of lipids and natural moisturizing factors in the Stratum Corneum. The purpose of this study is to determine the implementation of physiotherapy in reducing xerosis in both lower limbs and maintaining skin elasticity with. Methods: patients are given oiling treatment, ankle pumping, bridging exercise, balance exercise and sensory stimulus exercises on the feet for 4 weeks which are carried out 3x/week. Results: evaluation was carried out using Range Of Motion (ROM), Manual Muscle Testing, Anthropometry, ODSS (Overall Dry Skin Score). Conclusion: there is an increase in ROM, MMT, ODSS (Overall Dry Skin Score) and a decrease in Anthropometry after being given Exercise therapy for 4 weeks.

Impact of (intestinal) LAL deficiency on lipid metabolism and macrophage infiltration

ObjectiveTo date, the only enzyme known to be responsible for the hydrolysis of cholesteryl esters and triacylglycerols in the lysosome at acidic pH is lysosomal acid lipase (LAL). Lipid malabsorption in the small intestine (SI), accompanied by macrophage infiltration, is one of the most common pathological features of LAL deficiency. However, the exact role of LAL in intestinal lipid metabolism is still unknown. MethodsWe collected three parts of the SI (duodenum, jejunum, ileum) from mice with a global (LAL KO) or intestine-specific deletion of LAL (iLAL KO) and corresponding controls. ResultsWe observed infiltration of lipid-associated macrophages into the lamina propria, where neutral lipids accumulate massively in the SI of LAL KO mice. In addition, LAL KO mice absorb less dietary lipids but have accelerated basolateral lipid uptake, secrete fewer chylomicrons, and have increased fecal lipid loss. Inflammatory markers and genes involved in lipid metabolism were overexpressed in the duodenum of old but not in younger LAL KO mice. Despite the significant reduction of LAL activity in enterocytes of enterocyte-specific (iLAL) KO mice, villous morphology, intestinal lipid concentrations, expression of lipid transporters and inflammatory genes, as well as lipoprotein secretion were comparable to control mice. ConclusionsWe conclude that loss of LAL only in enterocytes is insufficient to cause lipid deposition in the SI, suggesting that infiltrating macrophages are the key players in this process.

Turnover of non-polymeric leaf lipids in a loamy grassland soil

BackgroundLeaves constitute a large input of lipids to soil, yet comparatively little is known about the fate of leaf lipids in soil. Our aim was to explore the initial stages of degradation of leaf lipids, both the loss of intact lipid and subsequent mineralisation. We focussed on intracellular lipids – triacylglycerols implicated in storage, membrane lipids such as phospholipids and galactolipids, and pigments – because they collectively constitute more than 1% of leaf mass.MethodsA mixture of U-13C lipids was extracted from leaves of wheat grown with 13CO2. The lipid mixture included the range of plant lipids soluble in organic solvent (e.g. free fatty acids, acylglycerols, pigments) but not polymeric lipids such as cutin and suberin. Mineralisation was deduced from 13CO2 efflux, while LC–MS examined degradation of intact 13C lipids.ResultsThere was no delay before lipids were mineralised. Instead, mineralisation was significant within minutes and reached a maximum within three hours. There was rapid loss (i.e. degradation) of a broad range of intact lipids including phospholipids, galactolipids, pigments (chlorophylls), and triacylglycerols. Around two-thirds of added lipid-C was respired over the course of 15 days, with one-third of lipid-C persisting in soil.ConclusionsOur study indicates that non-polymeric leaf lipids degrade quickly in soil, yet a fraction of lipid-C likely persisted in degradation products and/or microbial biomass. Persistence of lipid-C probably also reflected the presence of lipids that are more resistant to degradation (e.g. phaeophytins), and a fraction of added lipid being protected (e.g. by interaction with clays).Graphical abstract

Differential distribution of surface proteins/lipids between wheat A- and B-starch granule contributes to their difference in pasting and rheological properties

The distribution of surface proteins/lipids and their effect on physicochemical properties of wheat A- and B-starch were investigated. Small B-starch with higher surface protein (~1.8 %) and lipid (~0.4 %) contents did not differ significantly from specific surface area of large A-starch (~0.2 % protein and ~0.1 % lipid), indicating surface lipids/proteins for starch are characteristic of their biological origin, not directly related to granule size. The surface of A-starch granule was an integrated membrane structure (lipids covered by proteins). B-starch showed a greater decrease in peak and trough viscosity (130 and 82 cP) than A-starch (99 and 52 cP) after removing surface proteins, perhaps because the presence of residual surface lipid as a membrane protected the rigidity of A-starch granule. B-starch showed a greater increase in consistency coefficient (K) (47.01 Pa·sn) than A-starch (20.33 Pa·sn) after removing surface lipids, possibly because the greater loss of surface lipid as complex with amylose in B-starch retarded retrogradation and reduced K. These results show that different distributions and contents of surface proteins/lipids between wheat A- and B-starch granule contribute to the pasting and rheological properties.

IGFBP-3 promotes cachexia-associated lipid loss by suppressing insulin-like growth factor/insulin signaling.

Progressive lipid loss of adipose tissue is a major feature of cancer-associated cachexia. In addition to systemic immune/inflammatory effects in response to tumor progression, tumor-secreted cachectic ligands also play essential roles in tumor-induced lipid loss. However, the mechanisms of tumor-adipose tissue interaction in lipid homeostasis are not fully understood. The yki -gut tumors were induced in fruit flies. Lipid metabolic assays were performed to investigate the lipolysis level of different types of insulin-like growth factor binding protein-3 (IGFBP-3) treated cells. Immunoblotting was used to display phenotypes of tumor cells and adipocytes. Quantitative polymerase chain reaction (qPCR) analysis was carried out to examine the gene expression levels such as Acc1 , Acly , and Fasn et al . In this study, it was revealed that tumor-derived IGFBP-3 was an important ligand directly causing lipid loss in matured adipocytes. IGFBP-3, which is highly expressed in cachectic tumor cells, antagonized insulin/IGF-like signaling (IIS) and impaired the balance between lipolysis and lipogenesis in 3T3-L1 adipocytes. Conditioned medium from cachectic tumor cells, such as Capan-1 and C26 cells, contained excessive IGFBP-3 that potently induced lipolysis in adipocytes. Notably, neutralization of IGFBP-3 by neutralizing antibody in the conditioned medium of cachectic tumor cells significantly alleviated the lipolytic effect and restored lipid storage in adipocytes. Furthermore, cachectic tumor cells were resistant to IGFBP-3 inhibition of IIS, ensuring their escape from IGFBP-3-associated growth suppression. Finally, cachectic tumor-derived ImpL2, the IGFBP-3 homolog, also impaired lipid homeostasis of host cells in an established cancer-cachexia model in Drosophila . Most importantly, IGFBP-3 was highly expressed in cancer tissues in pancreatic and colorectal cancer patients, especially higher in the sera of cachectic cancer patients than non-cachexia cancer patients. Our study demonstrates that tumor-derived IGFBP-3 plays a critical role in cachexia-associated lipid loss and could be a biomarker for diagnosis of cachexia in cancer patients.

Accelerated abdominal lipid depletion from pesticide treatment alters honey bee pollen foraging strategy, but not onset, in worker honey bees.

Honey bee abdominal lipids decline with age, a change thought to be associated with the onset of foraging behavior. Stressors, such as pesticides, may accelerate this decline by mobilizing internal lipid to facilitate the stress response. Whether bees with stressor-induced accelerated lipid loss vary from controls in both the onset of foraging and nutritional quality of collected pollen is not fully understood. We asked whether stressors affect foraging behavior through the depletion of abdominal lipid, and whether stress-induced lipid depletion causes bees to forage earlier and for fattier pollen. We tested this by treating newly emerged bees with one of two pesticides, pyriproxyfen (a juvenile hormone analog) and spirodiclofen (a fatty acid synthesis disruptor), that may affect energy homeostasis in non-target insects. Bees fed these pesticides were returned to hives to observe the onset of foraging behavior. We also sampled foraging bees to assay both abdominal lipids and dietary lipid content of their corbicular pollen. Initially, spirodiclofen-treated bees had significantly more abdominal lipids, but these declined faster compared with controls. These bees also collected less, yet more lipid-rich, pollen. Our results suggest that bees with accelerated lipid decline rely on dietary lipid content and must collect fattier pollen to compensate. Pyriproxyfen treatment reduced the age at first forage but did not affect abdominal or collected pollen lipid levels, suggesting that accelerated fat body depletion is not a prerequisite for precocious foraging.

Interplay of lipid head group and packing defects in driving amyloid-beta–mediated myelin-like model membrane deformation

Accumulating evidence suggests that amyloid plaque associated myelin lipid loss as a result of elevated amyloid burden might also contribute to Alzheimer's disease. The amyloid fibrils though closely associated with lipids under physiological conditions, however, the progression of membrane remodeling events leading to lipid-fibril assembly remains unknown. Here we first reconstitute the interaction of Aβ-40 with myelin-like model membrane and show that the binding of Aβ-40 induces extensive tubulation. To look into the mechanism of membrane tubulation we chose a set of membrane conditions varying in lipid packing density and net charge that allows us to dissect the contribution of lipid specificity of Aβ-40 binding, aggregation kinetics, and subsequent changes in membrane parameters such as fluidity, diffusion, and compressibility modulus. We show that the binding of Aβ-40 depends predominantly on the lipid packing defect densities and electrostatic interactions and results in rigidification of the myelin-like model membrane during the early phase of amyloid aggregation. Furthermore, elongation of Aβ-40 into higher oligomeric and fibrillar species leads to eventual fluidization of the model membrane followed by extensive lipid membrane tubulation observed in the late phase. Taken together, our results capture mechanistic insights into snapshots of temporal dynamics of Aβ-40 - myelin-like model membrane interaction and demonstrate how short timescale, local phenomena of binding, and fibril-mediated load generation results in the consequent association of lipids with growing amyloid fibrils.

Disrupted myelin lipid metabolism differentiates frontotemporal dementia caused by GRN and C9orf72 gene mutations

Heterozygous mutations in the GRN gene and hexanucleotide repeat expansions in C9orf72 are the two most common genetic causes of Frontotemporal Dementia (FTD) with TDP-43 protein inclusions. The triggers for neurodegeneration in FTD with GRN (FTD-GRN) or C9orf72 (FTD-C9orf72) gene abnormalities are unknown, although evidence from mouse and cell culture models suggests that GRN mutations disrupt lysosomal lipid catabolism. To determine how brain lipid metabolism is affected in familial FTD with TDP-43 inclusions, and how this is related to myelin and lysosomal markers, we undertook comprehensive lipidomic analysis, enzyme activity assays, and western blotting on grey and white matter samples from the heavily-affected frontal lobe and less-affected parietal lobe of FTD-GRN cases, FTD-C9orf72 cases, and age-matched neurologically-normal controls. Substantial loss of myelin-enriched sphingolipids (sulfatide, galactosylceramide, sphingomyelin) and myelin proteins was observed in frontal white matter of FTD-GRN cases. A less-pronounced, yet statistically significant, loss of sphingolipids was also observed in FTD-C9orf72. FTD-GRN was distinguished from FTD-C9orf72 and control cases by increased acylcarnitines in frontal grey matter and marked accumulation of cholesterol esters in both frontal and parietal white matter, indicative of myelin break-down. Both FTD-GRN and FTD-C9orf72 cases showed significantly increased lysosomal and phagocytic protein markers, however galactocerebrosidase activity, required for lysosomal catabolism of galactosylceramide and sulfatide, was selectively increased in FTD-GRN. We conclude that both C9orf72 and GRN mutations are associated with disrupted lysosomal homeostasis and white matter lipid loss, but GRN mutations cause a more pronounced disruption to myelin lipid metabolism. Our findings support the hypothesis that hyperactive myelin lipid catabolism is a driver of gliosis and neurodegeneration in FTD-GRN. Since FTD-GRN is associated with white matter hyperintensities by MRI, our data provides important biochemical evidence supporting the use of MRI measures of white matter integrity in the diagnosis and management of FTD.