Search

Infection by bacteria leads to tissue damage and inflammation, which need to be tightly controlled by host mechanisms to avoid deleterious consequences. It is previously reported that TMEM16F, a calcium‐activated lipid scramblase expressed in various immune cell types including T cells and neutrophils, is critical for the control of infection by bacterium Listeria monocytogenes (Lm) in vivo. This function correlated with the capacity of TMEM16F to repair the plasma membrane (PM) damage induced in T cells in vitro, by the Lm toxin listeriolysin O (LLO). However, whether the protective effect of TMEM16F on Lm infection in vivo is mediated by an impact in T cells, or in other cell types, is not determined. Herein, the immune cell types and mechanisms implicated in the protective effect of TMEM16F against Lm in vivo are elucidated. Cellular protective effects of TMEM16F correlated with its capacity of lipid scrambling and augment PM fluidity. Using cell type‐specific TMEM16F‐deficient mice, the indication is obtained that TMEM16F expressed in liver Kupffer cells (KCs), but not in T cells or B cells, is key for protection against Listeria in vivo. In the absence of TMEM16F, Listeria induced PM rupture and fragmentation of KCs in vivo. KC death associated with greater liver damage, inflammatory changes, and dysregulated liver metabolism. Overall, the results uncovered that TMEM16F expressed in Kupffer cells is crucial to protect the host against Listeria infection. This influence is associated with the capacity of Kupffer cell‐expressed TMEM16F to prevent excessive inflammation and abnormal liver metabolism. [ABSTRACT FROM AUTHOR]

Ferroptosis, a form of cell death driven by iron‐dependent lipid peroxidation, is emerging as a promising target in cancer therapy. It is regulated by a network of molecules and pathways that modulate lipid metabolism, iron homeostasis and redox balance, and related processes. However, there are still numerous regulatory molecules intricately involved in ferroptosis that remain to be identified. Here, we indicated that suppression of Golgi protein acyl‐coenzyme A binding domain A containing 3 (ACBD3) increased the sensitivity of Henrieta Lacks and PANC1 cells to ferroptosis. ACBD3 knockdown increases labile iron levels by promoting ferritinophagy. This increase in free iron, coupled with reduced levels of glutathione peroxidase 4 due to ACBD3 knockdown, leads to the accumulation of reactive oxygen species and lipid peroxides. Moreover, ACBD3 knockdown also results in elevated levels of polyunsaturated fatty acid‐containing glycerophospholipids through mechanisms that remain to be elucidated. Furthermore, inhibition of ferrtinophagy in ACBD3 downregulated cells by knocking down the nuclear receptor co‐activator 4 or Bafilomycin A1 treatment impeded ferroptosis. Collectively, our findings highlight the pivotal role of ACBD3 in governing cellular resistance to ferroptosis and suggest that pharmacological manipulation of ACBD3 levels is a promising strategy for cancer therapy. [ABSTRACT FROM AUTHOR]

Early life nutrition can reprogram development and exert long‐term consequences on body weight regulation. In mice, maternal high‐fat diet (HFD) during lactation predisposed male but not female offspring to diet‐induced obesity when adult. Molecular and cellular changes in the hypothalamus at important time points are examined in the early postnatal life in relation to maternal diet and demonstrated sex‐differential hypothalamic reprogramming. Maternal HFD in lactation decreased the neurotropic development of neurons formed at the embryo stage (e12.5) and impaired early postnatal neurogenesis in the hypothalamic regions of both males and females. Males show a larger increased ratio of Neuropeptide Y (NPY) to Pro‐opiomelanocortin (POMC) neurons in early postnatal neurogenesis, in response to maternal HFD, setting an obese tone for male offspring. These data provide insights into the mechanisms by which hypothalamic reprograming by early life overnutrition contributes to the sex‐dependent susceptibility to obesity in adult life in mice. [ABSTRACT FROM AUTHOR]

Mass spectrometry‐based metabolomics has emerged as a powerful technique for biomedical research, although technical issues with its analytical precision and structural characterization remain. Herein, a robust non‐targeted strategy for accurate quantitation and precise profiling of metabolomes is developed and applied to investigate plasma metabolic features associated with human aging. A comprehensive set of isotope‐labeled standards (ISs) covering major metabolic pathways is incorporated to quantify polar metabolites. Matching rules to select ISs for calibration follow a primary criterion of minimal coefficients of variations (COVs). If minimal COVs between specific ISs for a particular metabolite fall within 5% window, a further selection of ISs is conducted based on structural similarities and proximity in retention time. The introduction and refined selection of appropriate ISs for quantitation reduces the COVs of 480 identified metabolites in quality control samples from 14.3% to 9.8% and facilitates identification of additional metabolite. Finally, the precise metabolomics approach reveals perturbations in a diverse array of metabolic pathways across aging that principally implicate steroid metabolism, amino acid metabolism, lipid metabolism, and purine metabolism, which allows the authors to draw correlates to the pathology of various age‐related diseases. These findings provide clues for the prevention and treatment of these age‐related diseases. [ABSTRACT FROM AUTHOR]

Objective: This study investigated the effects of constant light exposure on polycystic ovary syndrome (PCOS)‐like endocrine and metabolic changes in high‐fat diet (HFD)‐fed rats and to elucidate the related microbiotic mechanisms. Methods: A total of 32 female Sprague‐Dawley rats were divided into four groups (n = 8 each): rats on a normal chow diet with standard light‐dark cycle, rats on a normal chow diet with constant light exposure, rats on an HFD with standard light‐dark cycle, and rats on an HFD with constant light exposure. After 16 weeks of treatment, changes in anthropometric parameters, estrous cycle, hormone profiles, ovarian pathology, and gut microbiota and short‐/medium‐chain fatty acids in colon contents were assessed. Results: Constant light exposure aggravated PCOS‐like phenotypes in HFD‐fed rats, such as hyperandrogenism, disrupted estrous cycle, and polycystic ovaries. Additionally, constant light exposure and an HFD synergized to decrease α‐diversity of gut microbiota, create a reduced abundance of Ruminococcus genus, and create an increased abundance of Firmicutes and the Firmicutes/Bacteroidetes ratio. In HFD‐fed rats, the group with constant light exposure had an increase in propionate acid and a decrease in total medium‐chain fatty acids in colon contents compared with the standard light‐dark cycle group. Conclusions: Constant light exposure causes gut dysbiosis, alters production of short‐ and medium‐chain fatty acids, and aggravates PCOS‐like traits in HFD‐fed rats. [ABSTRACT FROM AUTHOR]

Given the functional correlation between the loss of CerS2 expression and abnormal polyploidy of liver chromosomes, we performed proteomics analysis on 1-month-old WT and CerS2-depleted liver tissues. Next, flow-cytometric analyses on cell cycle profiles demonstrated that the CerS2-depleted hepatocytes displayed a significantly higher proportion of octoploid or hexadecploid hepatocytes and fewer diploid hepatocytes than the WT controls (Figure 2C). Cytokinesis failure is the primary cause of hepatocyte polyploidization.1 However, there are few studies on ceramide synthase and polyploidy. Hepatic loss of CerS2 induces cell division defects via a mad2-mediated pathway. [Extracted from the article]

Summary: Maize kernel weight is influenced by the unloading of nutrients from the maternal placenta and their passage through the transfer tissue of the basal endosperm transfer layer (BETL) and the basal intermediate zone (BIZ) to the upper part of the endosperm.Here, we show that Small kernel 10 (Smk10) encodes a choline transporter‐like protein 1 (ZmCTLP1) that facilitates choline uptake and is located in the trans‐Golgi network (TGN). Its loss of function results in reduced choline content, leading to smaller kernels with a lower starch content.Mutation of ZmCTLP1 disrupts membrane lipid homeostasis and the normal development of wall in‐growths. Expression levels of Mn1 and ZmSWEET4c, two kernel filling‐related genes, are downregulated in the smk10, which is likely to be one of the major causes of incompletely differentiated transfer cells. Mutation of ZmCTLP1 also reduces the number of plasmodesmata (PD) in transfer cells, indicating that the smk10 mutant is impaired in PD formation. Intriguingly, we also observed premature cell death in the BETL and BIZ of the smk10 mutant.Together, our results suggest that ZmCTLP1‐mediated choline transport affects kernel development, highlighting its important role in lipid homeostasis, wall in‐growth formation and PD development in transfer cells. [ABSTRACT FROM AUTHOR]

Summary: The improvement of cold adaptation has contributed to the increased growing area of rice. Standing variation and de novo mutation are distinct natural sources of beneficial alleles in plant adaptation. However, the genetic mechanisms and evolutionary patterns underlying these sources in a single population during crop domestication remain elusive.Here we cloned the CTB2 gene, encoding a UDP‐glucose sterol glucosyltransferase, for cold tolerance in rice at the booting stage. A single standing variation (I408V) in the conserved UDPGT domain of CTB2 originated from Chinese Oryza rufipogon and contributed to the cold adaptation of Oryzasativa ssp. japonica.CTB2 is located in a 56.8 kb region, including the previously reported gene CTB4a in which de novo mutation arose c. 3200 yr BP in Yunnan province, China, conferring cold tolerance. Standing variation of CTB2 and de novo mutation of CTB4a underwent stepwise selection to facilitate cold adaptation to expand rice cultivation from high‐altitude to high‐latitude regions.These results provide an example of stepwise selection on two kinds of variation and describe a new molecular mechanism of cold adaptation in japonica rice. [ABSTRACT FROM AUTHOR]

Summary: Phosphoinositides play important roles in plant growth and development. Several SAC domain phosphoinositide phosphatases have been reported to be important for plant development.Here, we show functional analysis of SUPPRESSOR OF ACTIN 6 (SAC6) to SAC8 in Arabidopsis, a subfamily of phosphoinositide phosphatases containing SAC‐domain and two transmembrane motifs.We isolated an Arabidopsis mutant ncp2 that lacked cotyledons in seedling and embryo in pid, a background defective in auxin signaling and transport. NCP2 encodes RHD4/SAC7 phosphoinositide phosphatase. SAC6, SAC7 and SAC8 exhibit overlapping and specific expression patterns in seedling and embryo. The sac6 sac7 embryos either fail to develop into seeds, or have three or four cotyledons. The embryo development of sac7 sac8 and sac6 sac7 sac8 mutants is significantly delayed or lethal, and the seedlings are arrested at early stages. Auxin maxima are decreased in double and triple sac mutants. The contents of PtdIns4P and PtdIns(4,5)P2 in sac6 sac7 and sac7 sac8 mutants are dramatically increased. Protein trafficking of the plasma membrane (PM)‐localized protein PIN1 and PIN2 from trans‐Golgi network/early endosome back to PM is delayed in sac7 sac8 mutants.These results indicate that SAC6–SAC8 are essential for maintaining homeostasis of PtdIns4P and PtdIns(4,5)P2, and auxin‐mediated development in Arabidopsis. [ABSTRACT FROM AUTHOR]

Lipid droplets (LDs) are dynamic cytoplasmic organelles present in most eukaryotic cells. The appearance of LDs in neurons is not usually observed under physiological conditions, but is associated with neural diseases. It remains unclear how LD dynamics is regulated in neurons and how the appearance of LDs affects neuronal functions. We discovered that mutations of two key lipolysis genes atgl‐1 and lid‐1 lead to LD appearance in neurons of Caenorhabditis elegans. This neuronal lipid accumulation protects neurons from hyperactivation‐triggered neurodegeneration, with a mild decrease in touch sensation. We also discovered that reduced biosynthesis of polyunsaturated fatty acids (PUFAs) causes similar effects and synergizes with decreased lipolysis. Furthermore, we demonstrated that these changes in lipolysis and PUFA biosynthesis increase PUFA partitioning toward triacylglycerol, and reduced incorporation of PUFAs into phospholipids increases neuronal protection. Together, these results suggest the crucial role of neuronal lipolysis in cell‐autonomous regulation of neural functions and neurodegeneration. Synopsis: This study reveals the role of neuronal lipolysis in cell‐autonomous regulation of neural functions and neurodegeneration. Neuronal lipolysis prevents LD accumulation in neurons.Blocking neuronal lipolysis alleviates neurodegeneration.Neuronal lipolysis and de novo PUFA biosynthesis synergistically promote neurodegeneration.The incorporation of PUFAs into phospholipids promotes neurodegeneration. [ABSTRACT FROM AUTHOR]

Background and Aim: Non‐alcoholic fatty liver disease (NAFLD) is a growing public health concern worldwide. With the progression of urbanization, light pollution is becoming an inevitable risk factor for NAFLD. However, the role of light pollution on NAFLD is insufficiently understood, and the underlying mechanism remains unclear. The present study explored effects of constant light exposure on NAFLD and elucidated its related mechanisms. Methods: Thirty‐two male Sprague Dawley rats were divided into four groups (n = 8 each): (i) rats on a normal diet exposed to standard light–dark cycle (ND‐LD); (ii) rats on a normal diet exposed to constant light (ND‐LL); (iii) rats on a high‐fat diet exposed to standard light–dark cycle (HFD‐LD); and (iv) and rats on a high‐fat diet exposed to constant light (HFD‐LL). After 12 weeks of treatment, rats were sacrificed and pathophysiological assessments were performed. Targeted lipidomics was used to measure sphingolipids, including ceramides, glucosylceramides, and lactosylceramides, sphingomyelins, and sphingosine‐1‐phosphates in plasma and liver tissues. Results: In normal chow rats, constant light exposure led to glucose abnormalities and dyslipidemia. In high‐fat‐fed rats, constant light exposure exacerbated glucose abnormalities, dyslipidemia, insulin resistance, and inflammation and aggravated steatohepatitis. Compared with HFD‐LD rats, HFD‐LL had decreased plasma sphingosine‐1‐phosphate and elevated liver concentrations of total ceramide and specific ceramide species (ceramide d18:0/24:0, ceramide d18:1/22:0, ceramide d18:1/24:0, and ceramide d18:1/24:1), which were associated with increased hepatocyte apoptosis. Conclusions: Constant light exposure causes dysregulation of sphingolipids and promotes steatohepatitis in high‐fat‐fed rats. [ABSTRACT FROM AUTHOR]

Background and Purpose: Identifying safe and effective compounds that target to mitophagy to eliminate impaired mitochondria may be an attractive therapeutic strategy for non-alcoholic fatty liver disease. Here, we investigated the effects of cyanidin-3-O-glucoside (C3G) on non-alcoholic fatty liver disease (NAFLD) and the underlying mechanism.Experimental Approach: Non-alcoholic fatty liver disease was induced by a high-fat diet for 16 weeks. C3G was administered during the last 4 weeks. In vivo, recombinant adenoviruses and AAV8 were used for overexpression and knockdown of PTEN-induced kinase 1 (PINK1), respectively. AML-12 and HepG2 cells were used for the mechanism study.Key Results: C3G administration suppressed hepatic oxidative stress, NLR family pyrin domain containing 3 (NLRP3) inflammasome activation and steatosis and improved systemic glucose metabolism in mice with NAFLD. These effects of C3G were also observed in palmitic acid-treated AML-12 cells and hepatocytes from NAFLD patients. Mechanistic investigations revealed that C3G increased PINK1/Parkin expression and mitochondrial localization and promoted PINK1-mediated mitophagy to clear damaged mitochondria. Knockdown of hepatic PINK1 abolished the mitophagy-inducing effect of C3G, which blunted the beneficial effects of C3G on oxidative stress, NLRP3 inflammasome activation, hepatic steatosis and glucose metabolism.Conclusion and Implications: These results demonstrate that PINK1-mediated mitophagy plays an essential role in the ability of C3G to alleviate NAFLD and suggest that C3G may be a potential drug candidate for NAFLD treatment. [ABSTRACT FROM AUTHOR]

Phosphatidylinositol‐specific phospholipase C (PI‐PLC) is involved in stress signalling but its signalling function remains largely unknown in crop plants. Here, we report that the PI‐PLC4 from rice (Oryza sativacv), OsPLC4, plays a positive role in osmotic stress response. Two independent knockout mutants, plc4‐1 and plc4‐2, exhibited decreased seedling growth and survival rate whereas overexpression of OsPLC4 improved survival rate under high salinity and water deficiency, compared with wild type (WT). OsPLC4 hydrolyses PI, phosphatidylinositol 4‐phosphate (PI4P), and phosphatidylinositol‐4,5‐bisphosphate (PIP2) to generate diacylglycerol (DAG) in vitro. Knockout of OsPLC4 attenuated salt‐induced increase of phosphatidic acid (PA) whereas overexpression of OsPLC4 decreased the level of PI4P and PIP2 under salt treatment. Applications of DAG or PA restored the growth defect of plc4‐1 to WT but DAG kinase inhibitor 1 blocked the complementary effect of DAG in plc4‐1 under salt stress. In addition, the loss of OsPLC4 compromised the increase of inositol triphosphate and free cytoplasmic Ca2+ ([Ca2+]cyt) and inhibited the induction of genes involved in Ca2+ sensor and osmotic stress response to salt stress. The results indicate that OsPLC4 modulates the activity of two signalling pathways, PA and Ca2+, to affect rice seedling response to osmotic stress. Synopsis: High salinity is a major stress challenging rice production. This study showsthat the phosphatidylinositol‐hydrolyzing phospholipase C4 is involved in rice response to NaCl. OsPLC4 modulates the stress response through lipid‐ and Ca2+‐mediated signaling. High salinity is a major stress challenging rice production. This study shows that the phosphatidylinositol‐hydrolyzing phospholipase C4 is involved in rice response to NaCl. OsPLC4 modulates the stress response through lipid‐ and Ca2+‐mediated signalling. [ABSTRACT FROM AUTHOR]

Abstract: Seipin, the gene that causes Berardinelli‐Seip congenital lipodystrophy type 2 (BSCL2), is important for adipocyte differentiation and lipid homeostasis. Previous studies in Drosophila revealed that Seipin promotes ER calcium homeostasis through the Ca2+‐ATPase SERCA, but little is known about the events downstream of perturbed ER calcium homeostasis that lead to decreased lipid storage in Drosophila dSeipin mutants. Here, we show that glycolytic metabolites accumulate and the downstream mitochondrial TCA cycle is impaired in dSeipin mutants. The impaired TCA cycle further leads to a decreased level of citrate, a critical component of lipogenesis. Mechanistically, Seipin/SERCA‐mediated ER calcium homeostasis is important for maintaining mitochondrial calcium homeostasis. Reduced mitochondrial calcium in dSeipin mutants affects the TCA cycle and mitochondrial function. The lipid storage defects in dSeipin mutant fat cells can be rescued by replenishing mitochondrial calcium or by restoring the level of citrate through genetic manipulations or supplementation with exogenous metabolites. Together, our results reveal that Seipin promotes adipose tissue lipid storage via calcium‐dependent mitochondrial metabolism. [ABSTRACT FROM AUTHOR]

Flower glycerolipids are the yet-to-be discovered frontier of the lipidome. Although ample evidence suggests important roles for glycerolipids in flower development, stage-specific lipid profiling in tiny Arabidopsis flowers is challenging. Here, we utilized a transgenic system to synchronize flower development in Arabidopsis., The transgenic plant PAP1:: AP1- GR ap1-1 cal-5 showed synchronized flower development upon dexamethasone treatment, which enabled massive harvesting of floral samples of homogenous developmental stages for glycerolipid profiling., Glycerolipid profiling revealed a decrease in concentrations of phospholipids involved in signaling during the early development stages, such as phosphatidic acid and phosphatidylinositol, and a marked increase in concentrations of nonphosphorous galactolipids during the late stage. Moreover, in the midstage, phosphatidylinositol 4,5-bisphosphate concentration was increased transiently, which suggests the stimulation of the phosphoinositide metabolism. Accompanying transcriptomic profiling of relevant glycerolipid metabolic genes revealed simultaneous induction of multiple phosphoinositide biosynthetic genes associated with the increased phosphatidylinositol 4,5-bisphosphate concentration, with a high degree of differential expression patterns for genes encoding other glycerolipid-metabolic genes. The phosphatidic acid phosphatase mutant pah1 pah2 showed flower developmental defect, suggesting a role for phosphatidic acid in flower development., Our concurrent profiling of glycerolipids and relevant metabolic gene expression revealed distinct metabolic pathways stimulated at different stages of flower development in Arabidopsis. [ABSTRACT FROM AUTHOR]

Nitric oxide is implicated in the pathogenesis of various neuropathologies characterized by oxidative stress. Although nitric oxide has been reported to be involved in the exacerbation of oxidative stress observed in several neuropathologies, existent data fail to provide a holistic description of how nitrergic pathobiology elicits neuronal injury. Here we provide a comprehensive description of mechanisms contributing to nitric oxide induced neuronal injury by global transcriptomic profiling. Microarray analyses were undertaken on RNA from murine primary cortical neurons treated with the nitric oxide generator DETA-NONOate (NOC-18, 0.5 mM) for 8-24 hrs. Biological pathway analysis focused upon 3672 gene probes which demonstrated at least a ±1.5-fold expression in a minimum of one out of three time-points and passed statistical analysis (one-way anova, P < 0.05). Numerous enriched processes potentially determining nitric oxide mediated neuronal injury were identified from the transcriptomic profile: cell death, developmental growth and survival, cell cycle, calcium ion homeostasis, endoplasmic reticulum stress, oxidative stress, mitochondrial homeostasis, ubiquitin-mediated proteolysis, and GSH and nitric oxide metabolism. Our detailed time-course study of nitric oxide induced neuronal injury allowed us to provide the first time a holistic description of the temporal sequence of cellular events contributing to nitrergic injury. These data form a foundation for the development of screening platforms and define targets for intervention in nitric oxide neuropathologies where nitric oxide mediated injury is causative. [ABSTRACT FROM AUTHOR]

Mycolic acids are attractive diagnostic markers for tuberculosis (TB) infection because they are bacteria-derived, contain information about bacterial species, modulate host-pathogen interactions and are chemically inert. Here, we present a novel approach based on mass spectrometry. Quantification of specific precursor → fragment transitions of approximately 2000 individual mycolic acids (MAs) resulted in high analytical sensitivity and specificity. We next used this tool in a retrospective case-control study of patients with pulmonary TB with varying disease burdens from South Korea, Vietnam, Uganda and South Africa. MAs were extracted from small volume sputum (200 µl) and analysed without the requirement for derivatization. Infected patients (70, 19 of whom were HIV+) could be separated from controls (40, 20 of whom were HIV+) with a sensitivity and specificity of 94 and 93%, respectively. Furthermore, we quantified MA species in lung tissue of TB-infected mice and demonstrated effective clearance of MA levels following curative rifampicin treatment. Thus, our results demonstrate for the first time the feasibility and clinical relevance of direct detection of mycobacterial lipids as biomarkers of TB infection. [ABSTRACT FROM AUTHOR]

Very long-chain polyunsaturated fatty acids (VLC-PUFAs), such as docosahexaenoic acid (DHA) and docosapentaenoic acid (DPA), have recently made it to the realm of "magical molecules" based on their multiple presumably beneficial effects in biological systems, making these PUFAs particularly interesting in biomedicine. Their specific biological functions, however, remain enigmatic. Here we provide evidence derived from studies in the amoeba Chaos that indicates a structural role for ω-6 DPA in cell membrane organization, which may help to explain the multiple diverse effects of VLC-PUFA in healthy and diseased states. Amoeba Chaos mitochondria undergo a remarkable and reversible morphological transition into cubic morphology on starvation. This morphological transition is reflected in major changes in fatty acid and lipid composition, as determined by gas liquid chromatography and mass spectrometry, in particular by a drastic increase in C22:5 modified phosphatidylcholine plasmalogen, phosphatidylethanolamine plasmalogen, and phosphatidylinositol species. Liposomes produced in vitro from lipids of starved amoeba cells show a high propensity to form hexagonal tubular and cubic morphologies. Addition of ω-6 DPA, but not of ω-3 DPA, to the cell culture also induced mitochondrial membrane transformation into cubic morphology in fed cells, demonstrating for the first time an important structural role of ω-6 DPA-containing lipids in cell membrane organization. [ABSTRACT FROM AUTHOR]