Proteomics coupled transcriptomics reveals lipopolysaccharide inhibiting peroxisome proliferator-activated receptors signalling pathway to reduce lipid droplets accumulation in mouse liver
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE224012 | GEO | 2023/02/02
REPOSITORIES: GEO
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Project description:Lipid droplets (LDs) are multifunctional organelles consisting of a central compartment of non-polar lipids shielded from the cytoplasm by a phospholipid monolayer. The excessive accumulation of lipid droplets in cells is closely related to the development and progression of many diseases in humans and animals, such as liver-related and cardiovascular diseases. Thus, regulating the LDs size and abundance is necessary to maintain metabolic homeostasis. In this study, we found that LPS stimulation reduced the LDs content in the mouse liver. We tried to explain the possible molecular mechanisms at the broad protein and mRNA levels, finding that inhibition of the peroxisome proliferator-activated receptors (PPAR) signalling pathway by LPS may be a critical factor in reducing LDs content.
2023-01-27 | PXD039724 | iProX
Project description:Lipid droplets (LDs) store lipids for metabolic energy and are central to cellular lipid homeostasis. The mechanisms coordinating lipid storage in LDs with cellular metabolism are unclear but relevant to obesity-related diseases. Here we utilized genome-wide screening to identify genes that modulate lipid storage in human macrophages, a cell type relevant to metabolic diseases. Among ~550 genes regulating lipid storage, we identify MLX, a basic helix-loop-helix leucine-zipper transcription factor that regulates multiple metabolic processes. We show that MLX and family members MLXIP/MondoA and MLXIPL/ChREBP bind LDs via C-terminal amphipathic helices. When LDs increase in cells, LD binding of MLX, MLXIP/MondoA, and MLXIPL/ChREBP reduces their transcriptional activity, whereas the absence of LDs results in hyperactivation. Our findings uncover an unexpected component to a lipid storage response, in which binding of MLX transcription factors to the LD surface modulates their activity, adjusting the expression of metabolic genes to lipid storage levels.
2020-01-01 | GSE126002 | GEO
Project description:Lipid droplets (LDs) store lipids for metabolic eneergy and are central to cellular lipid homeostasis. The mechanisms coordinating lipid storage in LDs with cellular metabolism are unclear but relevant to obesity-related diseases. Here we utilized genome-wide screening to identify genes that modulate lipid storage in human macrophages, a cell type relevant to metabolic diseases. Among ~550 genes regulating lipid storage, we identify MLX, a basic helix-loop-helix leucine-zipper transcription factor that regulates multiple metabolic processes. We show that MLX and family members MLXIP/MondoA and MLXIPL/ChREBP bind LDs via C-terminal amphipathic helices. When LDs increase in cells, LD binding of MLX, MLXIP/MondoA, and MLXIPL/ChREBP reduces their transcriptional activity, whereas the absence of LDs results in hyperactivation. Our findings uncover an unexpected component to a lipid storage response, in which binding of MLX transcription factors to the LD surface modulates their activity, adjusting the expression of metabolic genes to lipid storage levels.
2021-09-08 | PXD012640 | Pride
Project description:Metarhizium robertsii is one of the model fungus species widely used studying insect-fungus interactions. Our previous studies have shown the accumulation of lipid droplets (LDs) play an essential role in generation of cellular turgor pressure to assist fungal penetration of insect cuticles, and autophagy-related proteins are connected with LD biogenesis and cellular accumulation in M. robertsii. However, full proteomes of LDs are unclear in terms of the species of proteins involved in lipid biosynthesis and degradation. We performed experiments by growing the fungi in different nutrient conditions, isolated the LDs and extracted the LD proteins from the cultures after being grown in a nutrient-rich medium (i.e. Sabouraud dextrose broth, SDB), a minimum medium without nitrogen source (MM-N) and MM-N supplemented with oleate. The protein samples were then subject to LC-MS/MS proteome profilings for identifying and postulating the proteins/pathways involved in lipid metabolisms.
2022-03-01 | PXD001552 | Pride
Project description:The aim of our study was to assess the impact of simvastatin on the amount of cytosolic lipid droplets (LDs), which are implicated in many biological processes including proliferation, inflammation, carcinogenesis, apoptosis, necrosis or growth arrest. Human pancreatic cancer cells MiaPaCa-2 were treated with simvastatin (6 and 12 _M) for 24 hours. Changes in expression of genes related to lipid metabolism in the simvastatin-treated cells were examined by DNA microarray analysis. The treatment of the cells with simvastatin increased their intracellular content of LDs, partially due to the uptake of cholesterol and triacylglycerides from medium; but in particular, due to enhanced synthesis of triacylglycerides as proved by detection of significant overexpression of genes related to de novo synthesis of triacylglycerides and phospholipids. Further, simvastatin markedly influenced expression of genes directly affecting cell proliferation and signaling.
2013-11-21 | E-MTAB-1501 | biostudies-arrayexpress
Project description:We showed earlier that nutritional stress like starvation or high fat diet resulted in phenotypic changes in the lipidomes of hepatocyte lipid droplets (LDs), representative for the pathophysiological status of the mouse model. Here we extend our former study by adding genetic stress due to knock-out (KO) of adipocyte triglyceride lipase (ATGL), the rate limiting enzyme in LD lipolysis. An intervention trial for 6 weeks with male wild-type (WT) and ATGL-KO mice was carried out; both genotypes were fed lab chow or were exposed to short-time starvation. Isolated LDs were analyzed by LC-MS/MS. Triacylglycerol, diacylglycerol and phosphatidylcholine lipidomes, in that order, provided best phenotypic signatures characteristic for respective stresses applied to the animals. This was evidenced at lipid species level by principal component analysis, calculation of average values for chain-lengths and numbers of double bonds, and by visualization in heat maps. Structural backgrounds for analyses and metabolic relationships were elaborated at lipid molecular species level. Relating our lipidomic data to non-alcoholic fatty liver diseases of nutritional and genetic etiologies with or without accompanying insulin resistance, phenotypic distinction in hepatocyte LDs dependent on insulin status emerged. Taken together, lipidomes of hepatocyte lipid droplets are sensitive responders to nutritional and genetic stress.
2014-08-19 | MTBLS81 | MetaboLights
Project description:Presence of ectopic lipid droplets (LDs) in cardiac muscle is associated to lipotoxicity and tissue dysfunction. However, presence of LDs in heart is also observed in physiological conditions, such as at times when cellular energy needs and energy production from mitochondria fatty acid (FA) ?-oxidation are high (fasting). This suggests that development of tissue lipotoxicity and dysfunction is not simply due to the presence of LDs in cardiac muscle but due at least in part to alterations in LD function. To examine the function of cardiac LDs, we obtained transgenic mice with heart-specific plin5 over-expression (MHC-plin5), a member of the perilipin protein family. Hearts from MHC-plin5 mice expressed at least 4-fold higher levels of plin5 and exhibit a 3.5- fold increase in triglyceride content versus non-transgenic littermate. Chronic cardiac excess of LDs was found to result in mild heart dysfunction with decreased expression of PPAR? target genes, decreased mitochondria function and left ventricular concentric hypertrophia. Lack of more severe heart function complications may have been prevented by a strong increased expression of oxidative induced genes via NF-E2-related factor 2 anti-oxidative pathway. Perilipin 5 regulates the formation and stabilization of cardiac LDs, and promotes cardiac steatosis without major heart function impairment. Hearts from Four MCH-Plin5 mice and four control mice at the age of 12 weeks were harvested
2013-02-09 | E-GEOD-44192 | biostudies-arrayexpress
Project description:Lipid Droplets (LDs), classically viewed as lipid storage particles, are recently emerging as dynamic organelles associated with stress responses and development; however, their involvement in plant immunity has been little investigated. Here we studied LDs in Arabidopsis thaliana leaves that respond to Pseudomonas syringae pv. tomato DC3000 avrRpm1 by inducing a hypersensitive defense reaction (HR), as well as during senescence. We established a protocol to reproducibly isolate LDs from a limited amount of tissue and performed a proteomic analysis of LDs from Pseudomonas-infected (for 24 h and 72 h) and senescent leaves. The proteomes defined shared ~50% similarity, with an enrichment of proteins associated with the Gene Ontology terms “transport” and “responses to stress”. As validation, we confirmed LD localization of glycerol-3-phosphate-acetyltransferase 8 (GPAT8) and GPAT4, enzymes required for e.g., cutin biosynthesis, by transient expression of GFP fusions in HR-induced leaves of Nicotiana benthamiana. Similarly, we proved the localization to LDs of aldehyde dehydrogenase 3F1 (ALDH3F1), α-dioxygenase1 (α-DOX1) and caleosin3 (CLO3), all involved in the synthesis of fatty acid derivatives. Moreover, we found that PAD3 (phytoalexin deficient 3) was distributed in patches along the ER and plasma membrane, and in LDs near dead cells. The nature of these proteins and of the additional components characterized in the LDs, together with the phenotypic examination of selected mutants, established a functional link between LDs and plant immunity. Our data suggest that these organelles participate in protein trafficking and in lipid changes that affect the interaction of plants with invading pathogens.
2022-02-23 | PXD011499 | Pride
Project description:Neural stem/progenitor cells (NSPCs) generate new neurons throughout adulthood. However, the underlying regulatory processes are still not fully understood. Lipid metabolism plays an important role in regulating NSPC activity: build-up of lipids is crucial for NSPC proliferation, whereas break-down of lipids has been shown to regulate NSPC quiescence. Despite their central role for cellular lipid metabolism, the role of lipid droplets (LDs), the lipid storing organelles, in NSPCs remains underexplored. Here we show that LDs are highly abundant in adult mouse NSPCs, and that LD accumulation is significantly altered upon fate changes such as quiescence and differentiation. NSPC proliferation is influenced by the number of LDs, inhibition of LD build-up, breakdown or usage, and the asymmetric inheritance of LDs during mitosis. Furthermore, high LD-containing NSPCs have increased metabolic activity and capacity, but do not suffer from increased oxidative damage. Together, these data indicate an instructive role for LDs in driving NSPC behaviour.
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Project description:Melanoma exhibits numerous transcriptional cell states including neural crest-like cells as well as pigmented melanocytic cells. How these different cell states relate to distinct tumorigenic phenotypes remains unclear. Here, we use a zebrafish melanoma model to identify a transcriptional program linking the melanocytic cell state to a dependence on lipid droplets, the specialized organelle responsible for lipid storage. Single-cell RNA-sequencing of these tumors show a concordance between genes regulating pigmentation and those involved in lipid and oxidative metabolism. This state is conserved across human melanoma cell lines and patient tumors. This melanocytic state demonstrates increased fatty acid uptake, an increased number of lipid droplets, and dependence upon fatty acid oxidative metabolism. Genetic and pharmacologic suppression of lipid droplet production is sufficient to disrupt cell cycle progression and slow melanoma growth in vivo. Because the melanocytic cell state is linked to poor outcomes in patients, these data indicate a metabolic vulnerability in melanoma that depends on the lipid droplet organelle.
2023-03-26 | GSE201378 | GEO