Gene expression of zebrafish larvae upon treating with lalistat
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ABSTRACT:
ORGANISM(S): Danio rerio
PROVIDER: GSE129433 | GEO | 2019/04/07
REPOSITORIES: GEO
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Project description:To test if HIF pathway is regulated by lipids in zebrafish larvae, we have employed whole genome microarray expression profiling as a discovery platform to identify induced genes upon lalistat or U18666A treatment. Lalistat is a specific inhibitor for lysosomal acid lipase (LAL), which is required for break down triglyceride or cholesterol ester to release free fatty acids. U18666A is a specific inhibitor for NPC, which is required for export free cholesterol oout of lysosomes.
2019-04-07 | GSE129434 | 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: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:Background & Aims Recent studies showed that patients suffering from lysosomal acid lipase-deficiency (LAL-D) benefit tremendously from enzyme replacement therapy (ERT), however, the outcomes on liver histology in treated patients were inconsistent. The promising results of the pan-PPAR agonist lanifibranor in alleviating liver inflammation in patients with nonalcoholic steatohepatitis prompted us to investigate the effects of lanifibranor on liver pathology in LAL knockout (Lal-/-) mice. Methods Lal-/- mice were daily gavaged with lanifibranor or vehicle for 21 days. The effects of the treatment were assessed by measuring body and organ weights, plasma lipids and lipoproteins, as well as hematological parameters, followed by liver proteomics and metabolomics. Results Lanifibranor treatment slightly altered organ weights without affecting the total body weight of Lal-/- mice. We observed major changes in the proteome, with multiple proteins related to lipid metabolism, peroxisomal, and mitochondrial activities being upregulated and inflammation-related proteins being downregulated in the livers of treated mice. Hepatic lipid levels and histology remained unaltered, whereas plasma triglyceride and total cholesterol levels were decreased and the lipoprotein profile of lanifibranor-treated Lal-/- mice improved. Conclusions Lanifibranor treatment positively affected liver inflammation and lipoprotein homeostasis in Lal-/- mice. These findings support further evaluation of lanifibranor in combination with ERT for phenotype improvement in Lal-/- mice and a possible exploration avenue for the treatment of LAL-D in humans.
2024-06-12 | PXD047957 | 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
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:Triglyceride-rich lipoproteins and their remnants contribute to atherosclerosis, possibly by carrying remnant cholesterol and/or by exerting a pro-inflammatory effect on macrophages. Nevertheless, little is known about how macrophages process triglyceride-rich lipoproteins. We show that uptake by macrophages of VLDL-sized emulsion particles is dependent on the enzyme lipoprotein lipase via its C-terminal domain. Subsequent internalization of VLDL-triglycerides by macrophages is carried out by caveolae-mediated endocytosis, followed by hydrolysis by lysosomal acid lipase. STARD3 is required for the transfer of lysosomal fatty acids to the ER for lipid storage, while NPC1 likely is involved in promoting the extracellular efflux of fatty acids. Our data provide novel insights into how macrophages process VLDL-derived triglycerides and suggest that macrophages have the remarkable capacity to excrete internalized triglycerides as fatty acids.
2022-05-21 | GSE203250 | GEO
Project description:Lysosomal acid lipase (LAL) is a crucial enzyme responsible for the hydrolysis of triglycerides (TGs) and cholesteryl esters (CEs) in the lysosomes. LAL deficiency results in the extensive storage of CEs and TGs in the liver and the spleen, inducing hepatosplenomegaly, and can be a life-threatening condition with patients rarely surviving beyond 6 months of age in the most aggressive form. Using messenger ribonucleic acid (mRNA) for protein replacement is an innovative approach to treating LAL deficiency. Here, we describe the development of a new lipid-based nanoparticle (LNP) formulation capable of efficiently delivering LAL mRNA and restoring LAL activity in affected organs mediating significant reversal of the pathological progression in a highly predictive preclinical model. A combinatorial library of mRNA-LNPs was generated and screened both in vitro and in vivo to yield a new formulation with a higher potency than an FDA-approved MC3-based nano-formulation. In vivo evaluation revealed that the new formulation could promote a more sustained and superior LAL expression. Multiple injection regimen was able to mitigate hepatosplenomegaly and reduce the lipid accumulation of CEs and TGs by 20-30% in the liver and 50% in the spleen. Furthermore, liver inflammation processes and development of fibrosis were significantly diminished. These findings provide strong evidence that mRNA-LNP is a very promising approach for the chronic treatment of LAL deficiency and support the clinical translation of mRNA therapy to overcome side effects and challenges encountered with traditional enzyme replacement therapies.
2024-12-06 | GSE280933 | GEO
Project description:Background: Despite recent studies investigating the involvement of single cells in regional differences of the small intestine (SI), the metabolic contribution of the duodenum, jejunum, and ileum to the overall intestinal metabolism is still unclear. Basic procedures and main findings: Using an untargeted proteomics approach, we identified similarities and differences between the three intestinal tracts of C57BL/6J mice and found that proteins highly abundant in the mouse ileum correlated with high ileal expression of the corresponding genes in humans. Consistent with human data, we detected increasing abundance of lysosomal acid lipase (LAL) in C57BL/6J mice from the duodenum to ileum. LAL is the only enzyme known to degrade triacylglycerols and cholesteryl esters within the lysosome. Lipid accumulation in various organs along with gastrointestinal disturbances and malabsorption are typical features of patients and mice with LAL deficiency. We previously demonstrated that macrophages massively infiltrate the SI of Lal-deficient (KO) mice, especially the duodenum. To identify potential mechanisms behind the intestinal lipid accumulation and infiltration of immune cells, we used untargeted proteomics. Our results revealed a general inflammatory response and a common lipid-associated macrophage phenotype in all three intestinal segments of Lal KO mice, accompanied by higher expression of GPNMB and increased concentrations of circulating sTREM2. However, only duodenal macrophages activated a metabolic switch from lipids to other pathways such as glycolysis, TCA cycle, and oxidative phosphorylation to meet their high energy demand. Unexpectedly, these pathways were downregulated in the jejunum and ileum of Lal KO mice. Conclusion: Our results provide new insights into the process of absorption in control mice and the basis for novel markers of LAL-D and/or systemic inflammation in LAL-D.
2024-02-20 | PXD048378 | Pride
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