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Adipose triglyceride lipase is a therapeutic target in advanced prostate cancer that promotes metabolic plasticity

ABSTRACT: The project aims to understand whether phosphorylation of ATGL changes any of its lipase interactors.

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Homo Sapiens (human)

SUBMITTER: Antrix Jain

LAB HEAD: Daniel E. Frigo

PROVIDER: PXD045042 | Pride | 2023-11-21

REPOSITORIES: Pride

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			Action	DRS
	52427_1_MSPCL_998_V5IP_Ctrl1_B1B3_half.msf	Msf
	52427_1_MSPCL_998_V5IP_Ctrl1_B1B3_half.raw	Raw
	52427_1_MSPCL_998_V5IP_Ctrl1_B2B4_half.msf	Msf
	52427_1_MSPCL_998_V5IP_Ctrl1_B2B4_half.raw	Raw
	52428_1_MSPCL_998_V5IP_Ctrl2_B1B3_half.msf	Msf

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Secretomics of human pluripotent stem cell derived neural progenitor cells and induced astrocytes.

Project description:This study examines and compares the protein content in conditioned media collected from neural cell types generated from human pluripotent stem cells. Conditioned media was prepared for 48 hours at a final endpoint of differentiation day 12. Both groups are from parental line WTC11 and cultured as a monolayer on matrigel. Both groups contain a transgene cassette for doxycycline-inducible expression of sox9 and nfia. Doxycycline was only included in the iAstro groups, whereas it was omitted in the neural progenitor cell groups.

2022-01-19 | PXD030821 | Pride

Partial loss of CFIm25 causes aberrant alternative polyadenylation and learning deficits

Project description:We previously showed that NUDT21-spanning copy-number variations (CNVs) are associated with intellectual disability (ID), and that NUDT21-encoded CFIm25 regulates the protein levels of at least one dose-sensitive, ID-associated protein: MeCP2 (Gennarino et al., 2015). However, the patients’ CNVs also spanned multiple other genes raising the possibility that loss or gain of these other genes caused their symptoms. To determine if reduced NUDT21 function alone is sufficient to cause disease, we generated Nudt21 heterozygous null mice to mimic the human state of reduced expression. We found that although these mice have 50% reduced Nudt21 mRNA, they only have 30% less of its cognate protein, CFIm25. Despite this partial protein-level compensation, the Nudt21+/- mice have learning deficits and cortical hyperexcitability. Further, to determine the molecular mechanism driving neural dysfunction, we partially inhibited NUDT21 in human embryonic stem cell-derived neurons to reduce CFIm25 by 30%. This reduction in CFIm25 was sufficient to induce misregulated alternative polyadenylation (APA) and protein levels in hundreds of genes, dozens of which are associated with intellectual disability and whose dysregulation is likely contributing to disease symptoms. Altogether, these results indicate that disruption of NUDT21-regulated APA events in the brain can cause intellectual disability.

2019-08-14 | PXD014842 | Pride

Inhibition of adipose triglyceride lipase alleviates non-alcoholic steatohepatitis in diabetic mice via impaired PPARa signalling favouring hydrophilic bile acid composition

Project description:Inhibition of adipocyte triglyceride lipase (ATGL/PNPLA2) activity in insulin resistance and non-alcoholic fatty liver disease is an attractive therapeutic target. This study evaluated the impact of Atglistatin-mediated ATGL inhibition on non-alcoholic steatohepatitis (NASH) development in diabetic and hyperlipidaemic mice. Streptozotocin-injected male mice were fed an HFD to induce NASH. We analysed liver histology, hepatic lipid content, immunohistochemistry, RNA sequencing, and serum biochemistry. Mechanistically, we treated Caco2 cells, human primary ileum-derived organoids, and HepG2 ATGL KD cells with the novel human ATGL inhibitor NG-497 and WY14643. Atglistatin reduced body and liver weights, total liver lipid content, and improved blood sugar levels consistent with improved liver enzymes, histological liver injury, and NAFLD activity scores. Mechanistically, Atglistatin reduced Cpt1a and Abca1, suggesting impaired Ppara signalling that favours hydrophilic bile acids (BA) synthesis since Cyp7a1, Cyp27a1, and Cyp2c70 were increased while Cyp8b1 was reduced. Accordingly, Intestinal lipid transporters, Abca1 and Cd36, were reduced, consistent with the reduction of liver TAG species, mostly linoleic acids. We used human-specific ATGL inhibitor NG-497 to validate the mouse findings. The NG-497-treated human primary ileum organoids and Caco2 cells showed reduced ATGL, ABCA1, FATP5, CD36, and MTTP. PPARa signalling was impaired in the ileum organoids and HepG2 treated with NG-497 and in HepG2 ATGL KD since PPARa, CPT1a, AOX, ABCA1, and CYP8B1 were reduced, and CYP7A1 increased. Inhibition of ATGL activity reduces the availability of ligands for Ppara activation leading to impaired Ppara signalling, which translate into hydrophilic BA that interferes with dietary lipid absorption, improving metabolic disturbances. The validation with the NG-497 should open a new clinical avenue for NAFLD clinical trial and treatment.

2024-11-01 | GSE236832 | GEO

Multiple reproductive tract-specific whey acidic protein four-disulfide core genes demonstrate functional requirement for sperm differentiation and function in mice

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2024-11-26 | PXD053290 | Pride

Murine podocyte mitochondrial complexsome analysis

Project description:Proximity labeling discovered a few mitochondrial cristae organizing proteins as NDUFS4 interacting protein. However proximity labeling is unable to differentiate between a direct interaction or a mere close association between NDUFS4 and cristae forming proteins. Additionally, it does not specify if the association of NDUFS4 with these proteins occurs in the context of individual complexes or RSCs. Consequently, to explore whether these cristae forming proteins comigrate and are retained within different complexes in RSCs, we performed complexsome profiling analysis on isolated mitochondria from HG-treated Ndufs4 overexpressed podocytes, with HG-treated cells as control. We separated ETC complexes with BN-PAGE, sliced five distinct bands representing distinct RSCs, labeled 1–5, after Coomassie blue staining, followed by mass spectrometry (LC-MS/MS).

2024-02-08 | PXD041203 | Pride

The proteome of cytomatrix and cytosol

Project description:The cytoplasm is an essential part of the cell involved in protein synthesis, energy generation, nutrient processing, transport, metabolism, and homeostasis, but its structure and function are not entirely understood. Almost five decades ago, dynamic nano-compartments of the cytoplasm were observed by high voltage electron microscopy in every living cell. However, the validity of these constructs, have been questioned and counterclaimed as artifacts of histo-techniques. We developed a new method to separate and characterize two different cytoplasmic compartments that we named cytomatrix and cytosol (or cytomedia). Using two compositional different solvents we were able sequentially extract the cytosol (cyto-solution) first then separate the cytomatrix from the nucleus. Our method allows fractionate the cell into three fractions: the cytosol, cytomatrix, and the nucleus.

2023-03-11 | PXD031043 | Pride

Loss of adipose triglyceride lipase aids cancer growth in 3D

Project description:Shotgun proteomic analysis of 3D-grown or on CAM-assay grown lung cancer cells lacking or expressing the major triglyceride lipase adipose triglyceride lipase (ATGL)

2021-05-21 | PXD021105 | Pride

APEX proximity labeling of murine NDUFS4 interacting proteins in podocytes

Project description:In this project we used an unbiased approach to identify the proteins that interact with NDUFS4 in the mouse podocytes using the APEX2 proximity labeling system. An immortalized murine podocyte was permanently transduced with a doxycycline (DOX) inducible NDUFS4-APEX2 chimeric construct. The cells were treated with DOX for 72 h to induce NDUFS4-APEX2 expression, followed by H2O2 activation of APEX2 mediated biotinylation of neighboring proteins. Biotinylated proteins were pull down by streptavidin beads and analyzed by LC-MS/MS. Cells without DOX induction or with DOX but without H2O2 activation were used as controls

2024-02-08 | PXD041378 | Pride

Transcription profiling of six tissues from ATGL knock-out versus wild type mice

Project description:Gene expression profiling in 6 tissues (white adipose tissue (WAT), brown adipose tissue (BAT), cardiac muscle (CM), liver (LIV), kidney (KID), skeletal muscle (SM)) from ATGL(-/-) mice versus wildtype (ATGL+/+) mice.

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Off-target effects of the lysosomal acid lipase inhibitors Lalistat-1 and Lalistat-2 on neutral lipid hydrolases

Project description:Lysosomal acid lipase (LAL) is the key enzyme of lysosomal lipid hydrolysis, which degrades cholesteryl esters (CE), triacylglycerols (TG), diacylglycerols (DG), and retinyl esters. The role of LAL in various cellular processes has mostly been studied in LAL-deficient (Lal-/-) mice, which share phenotypical characteristics with humans suffering from LAL deficiency. In vitro, the cell-specific functions of LAL have been commonly investigated by using the LAL inhibitors Lalistat-1 (L1) and Lalistat-2 (L2). Here, we show that pharmacological LAL inhibition but not genetic loss of LAL impairs isoproterenol-stimulated lipolysis and neutral TG hydrolase (TGH) and CE hydrolase (CEH) activities in mature adipocytes, indicating that L1 and L2 inhibit other lipid hydrolases apart from LAL. Since adipose triglyceride lipase (ATGL) and hormone-sensitive lipase (HSL) are the major enzymes that degrade cytosolic TG and CE, respectively, at neutral pH, we hypothesized that L1 and L2 also inhibit ATGL and/or HSL through off-target effects. In fact, both inhibitors drastically reduced neutral CEH activity in cells overexpressing mouse and human HSL and neutral TGH activity in cells overexpressing mouse and human ATGL, albeit to a lesser extent. By performing serine hydrolase-specific activity-based labeling in combination with quantitative proteomics, we confirmed that L2 inhibits HSL and other lipid hydrolases, whereas L1 treatment results in less pronounced inhibition of neutral lipid hydrolases. These results demonstrate that commonly used concentrations of L2 (and L1) are not suitable for investigating the role of LAL-specific lipolysis in lysosomal function, signaling pathways, and autophagy.

2022-05-13 | PXD030672 | Pride

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