Decoding the Variant-to-Function Relationship for LIPA, a Risk Locus for CAD
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ABSTRACT:
PROVIDER: PRJNA1016418 | ENA |
REPOSITORIES: ENA
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Project description:This SuperSeries is composed of the SubSeries listed below.
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Project description:Lysosomal acid lipase (Lipa), which is primarily produced in the liver, has been identified as one of the earliest and most impactful genetic factors linked to human coronary artery diseases. Despite its original source, it is also found to be highly expressed in macrophages. However, the functional importance of Lipa in macrophages has been largely unknown. Notably, individuals with certain risk alleles demonstrate elevated Lipa expression in monocytes and macrophages, but lower levels of hepatic and plasma Lipa, indicating a potential regulatory role of Lipa on atherosclerosis through its impact on macrophages. The development of atherosclerosis in genetic models lacking Lipa has presented challenges. Our hypothesis is that Lipa deficiency may influence atherosclerosis development by affecting macrophages. In order to investigate this, we established Lipa-deficient mice on an ApoE-knockout background, providing a model that enables us to evaluate the influence of Lipa on atherosclerosis. In our experiments, we observed hepatosplenomegaly and increased myeloid cell differentiation in Lipa−/−ApoE−/− mice fed a high-fat diet, which aligns with observations in humans with LIPA deficiency. Surprisingly, we also discovered that Lipa deficiency led to a significant inhibition of atherosclerosis in both Lipa+/−ApoE−/− and Lipa−/−ApoE−/− mice. Mechanistically, we found that such inhibition was linked to a notable reduction in foam cell formation and macrophage accumulation within atherosclerotic plaques. Notably, reduced Lipa expression in Lipa+/−ApoE−/− mice influenced foam cell formation and macrophage accumulation, but did not impact hepatic lipid metabolism or macrophage differentiation, as evidenced by flow cytometry and single-cell RNA-sequencing. These findings highlight a novel role for Lipa in modulating macrophage behavior during atherosclerosis, suggesting that Lipa may serve as a promising therapeutic target for the treatment of atherosclerosis.
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Project description:Triple-negative breast cancer (TNBC) has a poor clinical outcome, due to a lack of actionable therapeutic targets. Herein we define lysosomal acid lipase A (LIPA) as a viable molecular target in TNBC and identify a stereospecific small molecule (ERX-41) that binds LIPA. ERX-41 induces endoplasmic reticulum (ER) stress resulting in cell death, and this effect is on target as evidenced by specific LIPA mutations providing resistance. Importantly, we demonstrate that ERX-41 activity is independent of LIPA lipase function but dependent on its ER localization. Mechanistically, ERX-41 binding of LIPA decreases expression of multiple ER-resident proteins involved in protein folding. This targeted vulnerability has a large therapeutic window, with no adverse effects either on normal mammary epithelial cells or in mice. Our study implicates a targeted strategy for solid tumors, including breast, brain, pancreatic and ovarian, whereby small, orally bioavailable molecules targeting LIPA block protein folding, induce ER stress and result in tumor cell death.
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Project description:The plant cell wall degrading enzyme LipA (Lipase/Esterase A) is a Type II secretion system secreted protein of Xanthomonas oryzae pv. oryzae (Xoo; the casual of bacterial leaf blight of rice). LipA is an Xoo virulence factor. However, LipA is a double edged sword for Xoo as it induces rice defense responses such as programmed cell death/hypersensitive response like reaction (HR) and callose deposition. Prior treatment with LipA enhances resistance against subseqent Xoo infection. In order to understand the molecular events associated with Esterase (LipA) induced innate immune responsein rice , whole genome transcriptional profiling was performed using Affymetrix Rice GeneChips
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Project description:Treatment of rice tissues with purified preparations of a Xanthomonas oryzae pv. oryzae (Xoo) secreted plant cell wall degrading enzyme, Lipase/Esterase (LipA), elicits cell wall damage induced innate immune responses. LipA activity is required for induction of defense responses. In order to characterize the early events during elaboration of cell wall degrading enzyme, Lipase/Esterase (LipA) induced innate immune response in rice, we have performed global gene expression profiling of rice leaves treated with purified LipA at early time points, 30 minutes and 120min, after treatment. Whole genome transcriptional profiling was performed using Affymetrix Rice GeneChips Leaves of two weeks old green house grown susceptible rice cultivar (Taichung Native-1; TN-1) were infiltrated with either 30-40μl of purified Xoo Lipase/Esterase (LipA)(500μg/ml) or with buffer (10mM potassium phosphate buffer pH 6.0) alone (as described in Jha et al. 2007; MPMI vol 20, pp 31-40). The plants were shifted to a growth chamber (28oC; 80% relative humidity; 12/12h light/dark cycle) 48 hours before the treatment. 20-30 leaf pieces covering the infiltrated zone from each of the treatments were harvested 30 min. and 120 min. after infiltration. Total RNA isolated from the pooled samples was subjected for expression analysis using Affymetrix GeneChip System. The experiment was repeated with three different biological replicates using RNA isolated from three batches of rice leaves treated with the freshly purified Xoo Lipase/Esterase (LipA)and the buffer Gene Expression profiling of rice leaves undergoing an innate immune respone induced by LipA (Lipase/Esterase A) enzyme
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Project description:Single nucleotide polymorphisms are exceedingly common in non-coding loci, yet their impact on cellular dysfunction–especially under stressed conditions associated with coronary artery disease (CAD)–is still unclear. Here we show that when exposed to external stressors, the presence of polymorphisms in the non-coding 9p21.3 locus increases endothelial monolayer and microvessel dysfunction; endothelial cells (ECs) derived from induced pluripotent stem cells of patients homozygous for this risk haplotype (R/R WT) differentiated similarly to their non-risk (N/N) and isogenic knockout (R/R KO) counterparts; monolayers exhibited greater permeability and ROS signaling when the risk locus was present. Addition of the inflammatory cytokine TNFa further enhanced EC monolayer permeability but independent of risk haplotype. When wall shear stress was applied to ECs in a microfluidic vessel, R/R WT vessels were more permeable at lower shear stresses than R/R KO vessels. Transcriptomes of sheared cells clustered more by risk haplotype than by patient or clone, resulting in significant differential regulation of EC function and junction genes versus static conditions. A subset of previously identified CAD risk genes invert expression patterns in the presence of high shear concomitant with aberrant cell-cell adhesion, vessel permeability, and the risk haplotype, suggesting that shear stress could be a unique regulator of non-coding loci and its impact on CAD.
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