Gene profile of Myeloid derived Suppressive Cells from the Bone Marrow of Lysosomal Acid Lipase Knock-out Mice
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE29401 | GEO | 2012/03/06
SECONDARY ACCESSION(S): PRJNA140175
REPOSITORIES: GEO
Similar Datasets
Project description:Expression profile of MDSC isolated from Bone marrow of lysosomal acid Lipase mice compared to the WT counterpart four samples
2012-03-06 | E-GEOD-29401 | biostudies-arrayexpress
Project description:BackgroundLysosomal acid lipase (LAL) controls development and homeostasis of myeloid lineage cells. Loss of the lysosomal acid lipase (LAL) function leads to expansion of myeloid-derived suppressive cells (MDSCs) that cause myeloproliferative neoplasm.Methodology/principal findingsAffymetrix GeneChip microarray analysis identified detailed intrinsic defects in Ly6G(+) myeloid lineage cells of LAL knock-out (lal-/-) mice. Ingenuity Pathway Analysis revealed activation of the mammalian target of rapamycin (mTOR) signaling, which functions as a nutrient/energy/redox sensor, and controls cell growth, cell cycle entry, cell survival, and cell motility. Loss of the LAL function led to major alteration of large GTPase and small GTPase signal transduction pathways. lal-/- Ly6G(+) myeloid cells in the bone marrow showed substantial increase of cell proliferation in association with up-regulation of cyclin and cyclin-dependent kinase (cdk) genes. The epigenetic microenvironment was significantly changed due to the increased expression of multiple histone cluster genes, centromere protein genes and chromosome modification genes. Gene expression of bioenergetic pathways, including glycolysis, aerobic glycolysis, mitochondrial oxidative phosphorylation, and respiratory chain proteins, was also increased, while the mitochondrial function was impaired in lal-/- Ly6G(+) myeloid cells. The concentration of reactive oxygen species (ROS) was significantly increased accompanied by up-regulation of nitric oxide/ROS production genes in these cells.Conclusions/significanceThis comprehensive gene profile study for the first time identifies and defines important gene pathways involved in the myeloid lineage cells towards MDSCs using lal-/- mouse model.
| S-EPMC3288004 | biostudies-literature
Project description:Renal cell carcinoma (RCC), the most common form of kidney cancer, is a heterogeneous disease with clear cell RCC (ccRCC) being the most prevalent and aggressive subtype. While most ccRCC tumors have elevated expression of angiopoietin-like 4 (ANGPTL4), in our study we identified a significant subset of patients whose cancers show no increase in ANGPTL4 expression. These patients have a worse prognosis compared to the patients with high expression of ANGPTL4. These ANGPTL4-low cancers are characterized by the increased frequency of wild-type Von Hippel-Lindau (wt VHL), a gene that is commonly mutated in ccRCC, and an enrichment for genes associated with lipid metabolism. Using RCC tumor models with wild type VHL, we demonstrate that ANGPTL4 behaves as a tumor suppressor. The loss of ANGPTL4 in ccRCC cell lines results in increased tumor growth and colony formation in a lysosomal acid lipase (LAL)-dependent manner, a phenotype rescued by the expression of N-terminus ANGPTL4. At the mechanistic level, the loss of ANGPTL4 increases lysosomal acid lipase activity in ccRCC cells. This data suggests that ANGPTL4 enacts its tumor-suppressive effects in ccRCC by regulating LAL activity. Importantly, the identified patient cohort with low ANGPTL4 expression may exhibit increased reliance on lipid metabolism, which can be a point of target for future therapy.
2024-07-30 | GSE273236 | GEO
Project description:ANGPTL4 suppress clear cell renal cell carcinoma via inhibition lysosomal acid lipase
| PRJNA1140650 | ENA
Project description:Rescue of lysosomal acid lipase deficiency in mice by AAV liver gene transfer
| PRJNA1062373 | ENA
Project description:Non-alcoholic fatty liver disease (NAFLD) is characterized by the accumulation of lipid droplets (LD) in hepatocytes. NAFLD development and progression is associated with an increase in hepatic cholesterol and decreased autophagy and lipophagy flux. Previous studies have shown that the expression of lysosomal acid lipase (gene=LIPA, protein=LAL), which can hydrolyze both triglyceride and cholesteryl esters, is inversely correlated with the severity of NAFLD. In addition, ablation of LAL activity results in profound NAFLD. Based on this, we predicted that overexpressing LIPA in the livers of mice fed a Western diet (FPC) would prevent the development of NAFLD. As expected, mice fed the FPC diet exhibited numerous markers of NAFLD including hepatomegaly, lipid accumulation, and inflammation. Unexpectedly, LAL overexpression did not attenuate steatosis and had only minor effects on neutral lipid composition. However, LAL overexpression exacerbated inflammatory gene expression and infiltration of immune cells in mice fed the FPC diet. LAL overexpression also resulted in abnormal phagosome accumulation and lysosomal lipid accumulation depending upon the dietary treatment. Hepatic overexpression of LAL drove immune cell infiltration and inflammation and did not attenuate the development of NAFLD suggesting that targeting LAL expression is not a viable route to treat NAFLD.
2021-11-03 | GSE180377 | GEO
Project description:Hepatic Lysosomal Acid Lipase Overexpression Worsens Hepatic Inflammation in Mice Fed a Western Diet
| PRJNA748030 | ENA
Project description:Lysosomal acid lipase deficiency (LAL-D) is an autosomal recessive disorder caused by mutation in LIPA gene, which results in fat accumulation in liver and spleen leading to multi-organ failure. The severe form of LAL-D (infantile-onset; ≤5% residual LAL activity), if left untreated, results in premature death within the first year of life due to failure to thrive and hepatic insufficiency. Enzyme replacement therapy is the only available supportive treatment consisting in weekly systemic injection of recombinant LAL. Here, we characterize a novel LAL-D mouse model and develop a curative gene therapy treatment based on the in vivo administration of recombinant AAV8 (rAAV8) vector encoding for human LIPA transgene under the control of hepatocyte-specific promoter. We define the minimal AAV dose required to rescue disease lethality and to produce and secrete sufficient LAL to correct cholesterol and triglycerides accumulation in liver, spleen, blood cells and plasma. Finally, using liver transcriptomic and biochemical analysis, we also show the impairment of mitochondria associated with LAL-D and its recovery by gene therapy. Overall, our in vivo gene therapy strategy achieves stable long-term LAL expression to correct disease phenotype in LAL-D mouse model and opens a new therapeutic option for LAL-D patients.
2024-06-01 | GSE252742 | GEO
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
Project description:Lysosomal acid lipase (LAL) is the sole lysosomal enzyme responsible for the degradation of cholesteryl esters and triacylglycerols at acidic pH. Impaired LAL activity leads to LAL deficiency (LAL-D), a severe and fatal disease characterized by ectopic lysosomal lipid accumulation. Reduced LAL activity also contributes to the development and progression of non-alcoholic fatty liver disease (NAFLD). To advance our understanding of LAL-related liver pathologies, we performed comprehensive proteomic profiling of livers from mice with systemic genetic loss of LAL (Lal-/-) and from mice with hepatocyte-specific LAL-D (hepLal-/-). Lal-/- mice exhibited drastic proteome alterations, including dysregulation of multiple proteins related to metabolism, inflammation, liver fibrosis, and cancer. Global loss of LAL activity impaired both acidic and neutral lipase activities and resulted in hepatic lipid accumulation, indicating a complete metabolic shift in Lal-/- livers. Hepatic inflammation and immune cell infiltration were evident, with numerous upregulated inflammation-related gene ontology biological process terms. In contrast, both young and mature hepLal-/- mice displayed only minor changes in the liver proteome, suggesting that loss of LAL solely in hepatocytes does not phenocopy metabolic alterations observed in mice globally lacking LAL. These findings provide valuable insights into the mechanisms underlying liver dysfunction in LAL-D and may help in understanding why decreased LAL activity contributes to NAFLD. Our study highlights the importance of LAL in maintaining liver homeostasis and demonstrates the drastic consequences of its global deficiency on the liver proteome and liver function.
2023-10-24 | PXD042478 | Pride