Gene expression of zebrafish larvae upon treating with lalistat or U18666A
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ABSTRACT:
ORGANISM(S): Danio rerio
PROVIDER: GSE129434 | 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 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.
2019-04-07 | GSE129433 | GEO
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: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:Metabolic dysfunction-associated steatotic liver disease (MASLD) is a prevalent liver pathology worldwide, closely associated with obesity and metabolic disorders. Increasing evidence suggests that macrophages play a crucial role in the development of MASLD. Several human studies have shown an inverse correlation between circulating lysosomal acid lipase (LAL) activity and MASLD. LAL is the sole enzyme known to degrade cholesteryl esters (CE) and triacylglycerols in lysosomes. Consequently, these substrates accumulate when their enzymatic degradation is impaired due to LAL deficiency (LAL-D). This study aimed to investigate the role of hepatic LAL activity and liver-resident macrophages (i.e., Kupffer cells (KC)) in MASLD. To this end, we analyzed lipid metabolism in hepatocyte-specific (hep)Lal-/- mice and depleted KC with clodronate treatment. When fed a high-fat/high-cholesterol diet (HF/HCD), hepLal-/- mice exhibited CE accumulation and an increased number of macrophages in the liver without significantly affecting liver injury. KC were depleted upon clodronate administration, whereas infiltrating/proliferating CD68-expressing macrophages were less affected. This led to exacerbated hepatic CE accumulation and dyslipidemia, as evidenced by increased LDL-cholesterol concentrations. The results suggest that hepatic LAL-D in HF/HCD-fed mice leads to macrophage infiltration into the liver, and KC depletion further aggravates hepatic CE levels and dyslipidemia, a finding also supported by our proteomics analysis.
2024-12-01 | PXD056343 | Pride
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 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:Objective: Lysosomal acid lipase (LAL) is the only enzyme known to hydrolyze cholesteryl esters (CE) and triacylglycerols in lysosomes at an acidic pH. Despite the importance of lysosomal hydrolysis in skeletal muscle (SM), research in this area is limited. We hypothesized that LAL may play an important role in SM development, function, and metabolism as a result of lipid and/or carbohydrate metabolism disruptions. Results: Mice with systemic LAL deficiency (Lal-/-) had markedly lower SM mass, cross-sectional area, and Feret diameter despite unchanged proteolysis or protein synthesis markers in all SM examined. In addition, Lal-/- SM showed increased total cholesterol and CE concentrations, especially during fasting and maturation. Regardless of increased glucose uptake, expression of the slow oxidative fiber marker MYH7 was markedly increased in Lal-/-SM, indicating a fiber switch from glycolytic, fast-twitch fibers to oxidative, slow-twitch fibers. Proteomic analysis of the oxidative and glycolytic parts of the SM confirmed the transition between fast- and slow-twitch fibers, consistent with the decreased Lal-/- muscle size due to the “fiber paradox”. Decreased oxidative capacity and ATP concentration were associated with reduced mitochondrial function of Lal-/- SM, particularly affecting oxidative phosphorylation, despite unchanged structure and number of mitochondria. Impairment in muscle function was reflected by increased exhaustion in the treadmill peak effort test in vivo. Conclusion: We conclude that whole-body loss of LAL is associated with a profound remodeling of the muscular phenotype, manifested by fiber type switch and a decline in muscle mass, most likely due to dysfunctional mitochondria and impaired energy metabolism, at least in mice.
2024-01-26 | PXD045665 | Pride
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: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:Here we report that the transcription factor cyclic AMP–responsive element–binding protein H (CREB-H, encoded by CREB3L3) is required for the maintenance of normal plasma triglyceride concentrations. CREB-H–deficient mice showed hypertriglyceridemia secondary to inefficient triglyceride clearance catalyzed by lipoprotein lipase (Lpl), partly due to defective expression of the Lpl coactivators Apoc2, Apoa4 and Apoa5 and concurrent augmentation of the Lpl inhibitor Apoc3. We identified multiple nonsynonymous mutations in CREB3L3 that produced hypomorphic or nonfunctional CREB-H protein in humans with extreme hypertriglyceridemia, implying a crucial role for CREB-H in human triglyceride metabolism. Total RNAs were isolated from the liver of three WT and three Creb3l3 deficient mice after a 24-h fasting. Littermates were used. Gene expression profiles were examined using Illumina WG-6 microarray chips.
2011-06-04 | E-GEOD-29643 | biostudies-arrayexpress