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Proteomics coupled transcriptomics reveals lipopolysaccharide inhibiting peroxisome proliferator-activated receptors signalling pathway to reduce lipid droplets accumulation in mouse liver

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE224012 | GEO | 2023/02/02

REPOSITORIES: GEO

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Proteomics coupled transcriptomics reveals lipopolysaccharide inhibiting peroxisome proliferator-activated receptors signalling pathway to reduce lipid droplets accumulation in mouse liver

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 |

Systematic genome perturbation reveals coordination of lipid droplets and metabolic gene regulation

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

Systematic genome perturbation reveals coordination of lipid droplets and metabolic gene regulation

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

A fluorescent perilipin 2 knock-in mouse model reveals a high abundance of lipid droplets in the developing and adult brain

Project description:Lipid droplets (LDs) are dynamic lipid storage organelles. They are tightly linked to metabolism and can exert protective functions, making them important players in health and disease. Most LD studies in vivo rely on staining methods, providing only a snapshot. We therefore developed a LD-reporter mouse by endogenously labelling the LD coat protein perilipin 2 (PLIN2) with tdTomato, enabling staining-free fluorescent LD visualisation in living and fixed tissues and cells. Here we validate this model under standard and high-fat diet conditions and demonstrate that LDs are highly abundant in various cell types in the healthy brain, including neurons, astrocytes, ependymal cells, neural stem/progenitor cells and microglia. Furthermore, we also show that LDs are abundant during brain development and can be visualized using live-imaging of embryonic slices. Taken together, our tdTom-Plin2 mouse serves as a novel tool to study LDs and their dynamics under both physiological and diseased conditions in all tissues expressing Plin2.

2024-05-15 | GSE267069 | GEO

Proteomic analysis of Metarhizium robertsii Lipid Droplets

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

Effect of simvastatin on pancreatic cancer cells

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

The impact of genetic stress by ATGL deficiency on the lipidome of lipid droplets from murine hepatocytes

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

Alarmin-loaded extracellular lipid droplets induce airway neutrophil infiltration during type 2 inflammation

Project description:Group 2 innate lymphoid cells (ILC2s) play a crucial role in allergic diseases by coordinating a complex network of various effector cell lineages involved in type 2 inflammation. However, their function in regulating airway neutrophil infiltration, a deleterious symptom of severe asthma, remains unknown. Here, we observed ILC2-dependent neutrophil accumulation in the bronchoalveolar lavage fluid (BALF) of allergic mice models. Chromatography followed by proteomics analysis identified the alarmin high mobility group box-1 (HMGB1) in the supernatant of lung ILC2s initiated neutrophil chemotaxis. Genetic perturbation of Hmgb1 in ILC2s reduced BALF neutrophil numbers and alleviated airway inflammation. HMGB1 was loaded onto the membrane of lipid droplets (LDs) released from activated lung ILC2s. Genetic inhibition of LD accumulation in ILC2s significantly decreased extracellular HMGB1 abundance and BALF neutrophil infiltration. These findings unveil a previously uncharacterized extracellular LD-mediated immune signaling delivery pathway by which ILC2s regulate airway neutrophil infiltration during allergic inflammation.

2024-09-21 | GSE245964 | GEO

Cardiomyocyte specific plin5 over expression

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

A proteomics approach to study the role of lipid droplets in plant defense

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

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