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Liu, W.

Publications and source records attributed to Liu, W..

At least 217 records · Page 12Linked to original sources

Deep Learning Driven Cell-Type-Specific Embedding for Inference of Single-Cell Co-expression Networks

The inference of gene co-expression module in specific cell types is important for understanding of cell-type-specific biological processes. We have developed DeepCSCN, an unsupervised deep-learning framework, to infer gene co-expression modules from single-cell RNA sequencing (scRNA-seq) data. Utilizing a global-to-local network construction approach, DeepCSCN can infer co-expression at the whole sample level and construct cell-type-specific co-expression networks. Systematic evaluations on eight public scRNA-seq datasets show that DeepCSCN significantly outperforms eight existing methods in co-expression network construction. Furthermore, DeepCSCN effectively identifies cell-type-specific co-expression networks that are more enriched for cell-specific functional pathways compared to current methods. Finally, application of DeepCSCN on public scRNA-seq data revealed 280 cell-specific gene modules across 27 cell types, including epithelial cells, immune cells, and myonuclei, demonstrating its versatility and accuracy in elucidating cell-type-specific gene co-expression regulation. DeepCSCN offers a powerful tool for researchers to dissect the intricate gene co-expression networks within distinct cell types.

bioinformatics↗

PTEN neddylation aggravates CDK4/6 inhibitor resistance in breast cancer

The gradual emergence of a novel therapeutic approach lies in the restoration of tumor suppressive machinery. PTEN is a crucial negative regulator of the PI3K/Akt signaling pathway. Protein neddylation modification contributes to PTEN inactivation and fuels breast cancer progression. Here, we highlight that an elevated level of PTEN neddylation is markedly associated with resistance to palbociclib, a CDK4/6 inhibitor used in luminal subtype breast cancer patients. Mechanistically, PTEN neddylation activates the PI3K/Akt signaling pathway, and more notably, upregulates the activity of the AP-1 transcription factor. Our data showed that PTEN neddylation stabilizes JUND, a transcription factor involved in the AP-1 complex, by disrupting its interaction with the E3 ubiquitin ligase ITCH. Consequently, activated JUND leads to the release of cytokines and chemokines, which in turn may drive an inflammatory tumor microenvironment, potentially contributing to drug resistance. Then, we identified Echinacoside as a potent inhibitor of PTEN neddylation both in vivo and in vitro by disrupting its interaction with XIAP, the E3 ligase responsible for PTEN neddylation. Combination of Echinacoside effectively overcome resistance to palbociclib in breast cancer treatment. These findings highlight targeting PTEN neddylation as a promising strategy for restoring tumor suppressor activity and overcoming resistance.

cell biology↗

Neutralizing antibodies elicited in sequentially immunized macaques recognize V3 residues on altered conformations of HIV-1 Env trimer

Eliciting broadly neutralizing antibodies that protect against diverse HIV-1 strains is a primary goal of AIDS vaccine research. We characterized Ab1456 and Ab1271, two heterologously-neutralizing antibodies elicited in non-human primates by priming with an engineered V3-targeting SOSIP Env immunogen and boosting with increasingly native-like SOSIP Envs derived from different strain backgrounds. Structures of Env trimers in complex with these antibodies revealed V3 targeting, but on conformational states of Env distinct from the typical closed, prefusion trimeric SOSIP structure. Env trimers bound by Ab1456 adopted conformations resembling CD4-bound open Env states in the absence of soluble CD4, whereas trimers bound by Ab1271 exhibited a trimer apex-altered conformation to accommodate antibody binding. The finding that elicited antibodies cross-neutralized by targeting altered, non-closed, prefusion Env trimer conformations provides important information about Env dynamics that is relevant for HIV-1 vaccine design aimed at raising antibodies to desired epitopes on closed pre-fusion Env trimers. Highlights- Sequential immunization regimen elicits V3 antibodies targeting non-closed Envs - Cryo-EM structures reveal recognition of multiple Env conformational states - Neutralization by elicited antibody does not require antibody-virus preincubation Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=154 SRC="FIGDIR/small/605918v1_ufig1.gif" ALT="Figure 1"> View larger version (46K): org.highwire.dtl.DTLVardef@6210b1org.highwire.dtl.DTLVardef@35f683org.highwire.dtl.DTLVardef@cb2d3corg.highwire.dtl.DTLVardef@106e066_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

Understanding the development of neural abnormalities in adolescents with mental health problems: a longitudinal study

Many mental health problems are neurodevelopmental in nature and have an onset during childhood. Mental health disorders are associated with neural abnormalities, but it is unclear when those emerge and how this relates to the development of different mental health problems. We used data from the largest longitudinal neurodevelopmental study to identify the structural and functional brain changes that co-occur with the onset of six mental health problems. The results showed premorbid brain-wide abnormalities that were comparable between internalizing and different from externalizing problems, and differential neurodevelopmental trajectories for specific brain regions in 11- to 12-year-old adolescents who developed ADHD, conduct, depressive and oppositional defiant problems. These results reveal that the onset of different mental health problems co-occur with common as well as problem-specific brain abnormalities.

neuroscience↗

Unravelling Plankton Adaptation in Global Oceans through the Analysis of Lipidomes

A recent global survey of planktonic lipids showed a fundamental temperature-mediated regulation of lipid unsaturation in the global oceans [Holm H, et al. (2022) Science 376:1487-1491]. We expand the analysis of this dataset, both spatially and methodologically, to examine diverse environmental stressors across the ocean. Utilizing weighted correlation network analysis, we analyzed 3,164 lipid features in the dataset comprising 930 samples of suspended particulate matter, taken across a broad range of oceanographic conditions and water depths up to 600 meters. A total of 16 lipid clusters being co-expressed across diverse environments were identified. This analysis reveals universal relationships between environmental factors and the lipidome of the planktonic community. The largest lipid cluster, comprising 481 lipid features, including glycerolipids with polyunsaturated fatty acids, exhibited a significant enrichment in polar oceans, suggesting the highest lipid diversity in these ocean regions. Remarkably, marine plankton in these regions employ both desaturation and chain shortening for cold acclimation. Additionally, one lipid cluster strongly linked to the plankton residing in the surface of tropical and subtropical oceans was enriched with non-phosphorus lipids. We suggest this adaptive response enables the plankton to cope with phosphorous scarcity and heat stress. Notably, in the subsurface of these regions, a co-expressed cluster of highly unsaturated lipids is consistent with an enhanced production of polyunsaturated fatty acids by phytoplankton, possibly for low light adaptation. This adaptation is important as it may represent a source of essential fatty acids below the warm sea surface where such vital compounds may be diminished in the warmer future. SignificanceMarine plankton is vital for marine ecosystems and climate regulation. We analyzed a large lipidomics dataset of 930 samples collected from global oceans. This allowed us to explore how plankton adapt their lipidomes across different environments. Our findings show distinct lipid clusters correlating with specific environmental conditions, revealing mechanisms like chain shortening to cope with cold stress, enrichment of non-phosphorus lipids in tropical surface waters, and increased polyunsaturated fatty acids in low-light tropical subsurface areas. These adaptations are crucial for understanding how climate change will impact marine ecosystems.

microbiology↗

Engineering Microglial Cells to Promote Spinal Cord Injury Recovery

Spinal cord injury (SCI) can result in irreversible damage, leading to lifelong paralysis for affected individuals. Microglias dual impact on neuronal regeneration after SCI, driven by their distinct roles at different stages, merits further study. We conducted a bioinformatic analysis of single-cell transcriptomes (scRNA), spatial transcriptomic (ST) data, and bulk RNA-seq data from Gene Expression Omnibus (GEO) datasets. The data were processed using R packages such as "Seurat", "DESeq2","limma" and "GSVA." Additionally, we utilized Gene Set Enrichment Analysis (GSEA) and the Enrichr web servers. Analysis of single-cell data and spatial transcriptomics has revealed notable changes in the microglial cell landscape in SCI. These changes encompass the inhibition of innate microglial cells, while reactive microglial cells exhibit pronounced reactive hyperplasia. Moreover, the TGF{beta} signaling pathway plays a crucial role in regulating the migration of innate microglial cells to enhance SCI recovery. However, reactive microglial cells exhibiting high Trem2 expression contribute to the neuroinflammatory response and can effectively modulate neural cell death in SCI. In particular, inhibiting Trem2 in reactive microglial cells not only reduces inflammation but also mitigates spinal cord injury, and enhancing the TGF{beta} signaling pathway. Whats more, the use of iPSC-derived microglial cells, which have demonstrated their capacity to augment the potential for replacing the functions of naive microglial cells, iPSC-derived microglia have the potential to replace the functions of naive microglial cells, holds significant promise in addressing SCI. Therefore, we posit that the engineering of microglial cells to promote the SCI recovery. The approach of inhibiting Trem2-mediated neuroinflammatory responses and transplanting iPSC-derived microglia with long-term TGF{beta} stimulation may offer potential improvements in SCI recovery.

neuroscience↗

Droplet-AI-empowered high-throughput screening of cell-free gene expression

Cell-free gene expression (CFE) systems enable transcription and translation using crude cellular extracts, offering a versatile platform for synthetic biology by eliminating the need to maintain living cells. This allows direct manipulation of molecular components and the focused synthesis of specific products. However, the optimization of CFE systems is constrained by cumbersome composition, high costs, and limited yields due to numerous additional components required to maintain biocatalytic efficiency. While optimizing such complicated systems is daunting for existing high-throughput screening means, we introduce DropAI, a droplet-based, AI-driven screening strategy designed to optimize CFE systems with high throughput and economic efficiency. DropAI employs microfluidics to generate picoliter reactors and utilizes a fluorescent color-based coding-decoding system to address and screen a vast array of additive combinations. The in-droplet screening is complemented by in silico optimization, where experimental results train a machine-learning model to estimate the contribution of the components and predict high-yield combinations, which are then validated in vitro. Applying DropAI to an Escherichia coli-based CFE system, we simplified a set of 12 additives to only 3 essential components. Through further optimization, we achieved a 2.1-fold cost reduction and a 1.9-fold increase in yield for the expression of superfolder green fluorescent protein (sfGFP). This optimized formulation was further validated across 12 different proteins. Notably, the established E. coli model is successfully adapted to a Bacillus subtilis-based system through transfer learning, leading to doubled yield through prediction. DropAI thus offers a generalizable and scalable method for optimizing CFE systems, enhancing their potential for biochemical engineering and biomanufacturing applications.

bioengineering↗

Digital Immunoassay for Rapid Detection of SARS-CoV-2 Infection in a Broad Spectrum of Animals

The ability of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) to infect a wide-range of species raises significant concerns regarding both human-to-animal and animal-to-human transmission. There is an increasing demand for highly sensitive, rapid, and simple diagnostic assays that can detect viral infection across various species. In this study, we developed a biosensor assay that adapted a monoclonal-antibody (mAb)-based blocking ELISA format into an Activate Capture + Digital Counting (AC + DC)-based immunoassay. The assay employs a photonic crystal (PC) biosensor, gold-nanoparticle (AuNP) tags, SARS-CoV-2 nucleocapsid (N) protein, and specific anti-N mAb to detect antibody responses in animals exposed with SARS-CoV-2. We demonstrated a simple 2-step 15-min test that was capable of detecting as low as 12.5 ng of antibody in controlled standard serum samples. Based on an evaluation of 176 cat serum samples with known antibody status, an optimal percentage of inhibition (PI) cut-off value of 0.588 resulted in a diagnostic sensitivity of 98.3% and a diagnostic specificity of 96.5%. The test is highly repeatable with low variation coefficients of 2.04%, 2.73%, and 4.87% across different runs, within a single run, and on a single chip, respectively. The test was further employed to detect antibody responses in multiple animal species as well as investigate dynamics of antibody response in experimentally infected cats. This test platform provides an important tool for rapid field surveillance of SARS-CoV-2 infection across multiple species.

microbiology↗

Post-encoding administration of oxytocin selectively enhances memory consolidation of male faces in females

Oxytocin plays a critical role in modulating social cognition and enhancing human memory for faces. However, it remains unclear which stage of memory oxytocin affects to enhance face memory. Our study explored oxytocins potential to selectively enhance the consolidation of social memories, specifically human faces, and whether this effect varies between genders. In two preregistered, randomized, double-blind, placebo-controlled trials with heterosexual participants (total N=294, comprising 149 males and 145 females), we explored how oxytocin affects memory consolidation. We administered oxytocin immediately after encoding (i.e., Study1) and 30 minutes before retrieval in a parallel study (i.e., Study2). This design allowed us to confirm that oxytocins effects were indeed due to consolidation rather than retrieval. We found that administering oxytocin post-encoding, but not before-retrieval, significantly improved female participants ability to recognize male faces 24 hours later, with no similar enhancement observed in males recognizing opposite-gender faces. Together with our analyses of social placebo effects and approachability rating during encoding, we concluded that oxytocin enhanced consolidation of long-term social memories in humans. Our results not only advance the understanding of the neurobiological mechanisms underlying social memory consolidation but also highlight oxytocin as a pharmacological tool for selectively enhancing human memory consolidation. HighlightsO_LIOxytocin selectively enhances memory consolidation of human faces, with gender-specific effects. C_LIO_LIIn females, oxytocin after encoding improves recognition of male faces after 24 hours. C_LIO_LIOxytocin-induced enhancement of social memory is due to enhanced consolidation, not retrieval or encoding. C_LIO_LIOxytocin shows potential for selectively modulating memory consolidation in humans. C_LI

neuroscience↗

Cell-Graph Compass: Modeling Single Cells with Graph Structure Foundation Model

Inspired by the advancements in pre-trained Large Language Models, there has been a surge of studies in the Life Sciences focusing on constructing foundation models with large scale single-cell RNA-seq data. These studies typically involve pre-training a transformer model on large-scale single-cell sequencing data, followed by fine-tuning for a variety of downstream tasks, achieving notable performance. However, these models all share a common short-coming: to utilize the transformer architecture, originally designed for textual data, they artificially impose a sequential structure on genes within cells, simplifying the complex interactions between genes. Furthermore, they focus solely on transcriptomic data, neglecting other relevant biological information. To address these issues, here we introduce Cell-Graph Compass (CGC), the first foundational model that leverages graph structures to model single cells and describes cells from multiple perspectives, including transcriptional profiles, gene text summaries, transcription factor regulatory networks, gene co-expression patterns, and gene positional relationships. By incorporating self-attention mechanisms, we pretrained the model on 50 million human single-cell sequencing data, resulting in a robust digital representation of cells. Extensive downstream experiments demonstrate that our approach can capture meaningful biological knowledge and achieve superior results in various problem scenarios, achieving the state-of-the-art (SOTA).

bioinformatics↗

Muscone-specific olfactory protein reveals the putative scent-marking pheromone in the Sunda pangolin (Manis javanica)

The Sunda pangolin (Manis javanica) is a burrowing and nocturnal animal, and they have poor vision, thus, intraspecies communication relies on olfaction, such as mating, warning, and scent-marking. However, the intraspecies pheromone in pangolins remains unknown. In this study, all the odorant-binding proteins in Sunda pangolins were functionally expressed, and they were screened against a panel of 32 volatiles that were derived from the pangolins urine, feces, and anal gland secretions. Reverse chemical ecology identified that M. javanica odorant-binding protein 3 (MjavOBP3) possesses the highest binding affinity to muscone. A subsequent behavior-tracking assay showed that only males can sense muscone; thus, we hypothesize that muscone is a male-specific scent-marking pheromone. Meanwhile, the structural study showed that Tyr117 contributes the most to muscones binding, which was further validated by site-directed mutagenesis. The findings clarify the scent-marking mechanism in pangolins, and muscone could potentially be used to support the monitoring and conservation of this endangered animal. Author SummaryThe Sunda pangolin is an endangered mammal that is native to Southeast Asia and is threatened due to its economic value. They are cave-living and nocturnal, poor vision; thus, their intraspecies communication is highly reliant on olfaction. Although they are generally solitary, they have been observed to have some social aspects in the wild, such as breeding and territorial behaviors, which are mediated by scents. However, no previous study has investigated the type of pheromones and how they are detected. Using the reverse chemical ecology approach, MjavOBP3 was found to bind to muscone with high affinity, and behavior-tracking assay was performed under well-controlled artificial rearing conditions, which showed only male pangolins can recognize muscone, suggesting its potential male-specific pheromone role.

zoology↗

How Error Correction Affects PCR Deduplication: A Survey Based on UMI Datasets of Short Reads

Next-Generation Sequencing (NGS) data is widely utilised for various downstream applications in bioinformatics, and numerous techniques have been developed for PCR-deduplication and error-correction to eliminate bias and errors introduced during the sequencing. This study first-time provides a joint overview of recent advances in PCR-deduplication and error-correction on short reads. In particular, we utilise UMI-based PCR-deduplication strategies and sequencing data to assess the performance of the solely-computational PCR-deduplication approaches and investigate how error correction affects the performance of PCR-deduplication. Our survey and comparative analysis reveal that the deduplicated reads generated by the solely-computational PCR-deduplication and error-correction methods exhibit substantial differences and divergence from the sets of reads obtained by the UMI-based deduplication methods. The existing solely-computational PCR-deduplication and error-correction tools can eliminate some errors but still leave hundreds of thousands of erroneous reads uncorrected. All the error-correction approaches raise thousands or more new sequences after correction which do not have any benefit to the PCR-deduplication process. Upon these discoveries, we offer practical suggestions to enhance the existing computational approaches for improving the quality of short-read sequencing data.

bioinformatics↗

Feedback control of recurrent dynamics constrains learning timescales during motor adaptation

Neural activity has been observed to lie on low-dimensional manifolds, constraining what new behaviors can be easily learned. We propose that beyond this geometric constraint, learning on fast timescales is limited by how neural activity can flow over time within these manifolds--i.e., by the systems underlying dynamics. In primary motor cortex (M1), these neural dynamics are shaped not only by internal recurrence but also by sensory feedback that can continually update cortical activity. Modeling recurrent neural networks with adaptive feedback controllers in a brain-computer interface (BCI) task, we show that feedback-driven dynamics determine not just the robustness but also the flexibility of motor output. Through a control-theoretic approach, we quantitatively link learning speed and success for individual BCI decoders to the structure of input-driven network dynamics. We show that rapid learning is fundamentally limited by the networks controllability--the ease with which inputs can steer neural activity along desired directions. Crucially, this dynamical systems perspective explains a continuous form of experimentally-observed learning variability across decoders with similar geometry, that has not been addressed previously. We also make a testable prediction that rapid adaptation to new BCI decoders depends on upstream input plasticity, such as remapping of sensory feedback, beyond local plasticity within M1. Overall, our work identifies potential network mechanisms for fast but limited motor learning, and clarifies how constraints on learning arise from both the geometry of neural activity and its underlying dynamical structure.

neuroscience↗

Oxidized low-density lipoprotein potentiates angiotensin II-induced Gq activation through the AT1-LOX1 receptor complex: Implications for renal dysfunction

Chronic kidney disease (CKD) and atherosclerotic heart disease, frequently associated with dyslipidemia and hypertension, represent significant health concerns. We investigated the interplay among these conditions, focusing on the role of oxidized low-density lipoprotein (oxLDL) and angiotensin II (Ang II) in renal injury via G protein q subunit (Gq) signaling. We hypothesized that oxLDL enhances Ang II-induced Gq signaling via the AT1 (Ang II type 1 receptor)-LOX1 (lectin-like oxLDL receptor) complex. Based on CHO and renal cell model experiments, oxLDL alone did not activate Gq signaling. However, when combined with Ang II, it significantly potentiated Gq-mediated inositol phosphate 1 production and calcium influx in cells expressing both LOX-1 and AT1 but not in AT1-expressing cells. This suggests a critical synergistic interaction between oxLDL and Ang II in the AT1-LOX1 complex. Conformational studies using AT1 biosensors have indicated a unique receptor conformational change due to the oxLDL-Ang II combination. In vivo, wild-type mice fed a high-fat diet with Ang II infusion presented exacerbated renal dysfunction, whereas LOX-1 knockout mice did not, underscoring the pathophysiological relevance of the AT1-LOX1 interaction in renal damage. These findings highlight a novel mechanism of renal dysfunction in CKD driven by dyslipidemia and hypertension and suggest the therapeutic potential of AT1-LOX1 receptor complex in patients with these comorbidities.

molecular biology↗

Hierarchical model of human brain oscillations

The brain operates at the critical transition between order and disorder which supports optimal information processing. Whole-brain computational modeling is a powerful tool for uncovering the system-level mechanisms behind large-scale brain activity in both healthy and pathological states. However, most previous approaches have focused on either functional connectivity or criticality, making it difficult to capture both aspects simultaneously. Here, we introduce a new method based on a Hierarchical Kuramoto model that incorporates two levels of hierarchy. In our model, each node contains a large number of coupled oscillators, which allows us to examine both local synchronization and long-distance interactions between brain regions. The model produces critical-like dynamics marked by emergent long-range temporal correlations (LRTCs) and both inter-areal phase synchronization and amplitude correlations during the transition from asynchronous to synchronous states. Notably, structure-function coupling shows distinct patterns: correlations with structural connectivity peak at criticality for LRTCs and amplitude correlations, but decay for local and inter-areal phase synchronization. Comparisons with human resting-state magnetoencephalography (MEG) data reveal that the models behavior most closely resembles MEG phase synchronization and multi-peak power spectra on the subcritical side of an extended critical regime, supporting the hypothesis that the human brain operates in this state.

neuroscience↗

A high-continuity and annotated reference genome of allotetraploid Siberian wildrye (Elymus sibiricus L., Poaceae: Triticeae)

Elymus sibiricus L. (Siberian wildrye, Es), a species belonging to the wheat tribe, is extensively employed as forage and for the reclamation of degraded grasslands within the Qinghai-Tibet Plateau (QTP). This study provides a high-quality reference genome assembly for the allotetraploid Es, which is composed of 14 pseudomolecules with the total genome size of 6.57 Gb. Our finding suggest that large-scale bursts of retrotransposons are critical for the genome expansion of Es. We discovered a translocation event between the Es4H and Es6H chromosomes with a low frequency of combination. Phylogenetic analyses of 90 Es accessions and 25 diploid accessions representing proposed ancestors from various habitats revealed the existence of four distinct populations. We further provided support for the hypothesis that the QTP is the center of origin and genetic diversity for Es. Collectively, our study offers valuable insights into the evolution of Es, as well as providing genomic resources for genetic enhancement in the Elymus genus and wheat tribe.

genomics↗

Turn `noise' to signal: accurately rectify millions of erroneous short reads through graph learning on edit distances

Although the per-base erring rate of NGS is very low at 0.1% to 0.5%, the percentage/probability of erroneous reads in a short-read sequencing dataset can be as high as 10% to 15% or in the number of millions. Correction of these wrongly sequenced reads to retrieve their huge missing value will improve many downstream applications. As current methods correct only some of the errors at the cost of introducing many new errors, we solve this problem by turning erroneous reads into their original states, without bringing up any non-existing reads to keep the data integrity. The novelty of our method is originated in a computable rule translated from PCR erring mechanism that: a rare read is erroneous if it has a neighbouring read of high abundance. With this principle, we construct a graph to link every pair of reads of tiny edit distances to detect a solid part of erroneous reads; then we consider them as training data to learn the erring mechanisms to identify possibly remaining hard-case errors between pairs of high-abundance reads. Compared with state-of-the-art methods on tens of datasets of UMI-based ground truth, our method has made a remarkably better performance under 19 metrics including two entropy metrics that measure noise levels in a dataset. Case studies found that our method can make substantial impact on genome abundance quantification, isoform identification, SNP profiling, and genome editing efficiency estimation. For example, the abundance level of the reference genome of SARS-CoV-2 can be increased by 12% and that of Monkeypox can be boosted by 52.12% after error correction. Moreover, the number of distinct isomiRs is decreased by 31.56%, unveiling there are so many previously identified isomiRs that are actually sequencing errors. Author summaryDetecting short-read sequencing errors and correcting the related erroneous reads is a long-standing problem in bioinformatics. Current error correction algorithms correct only small parts of the errors but simultaneously introduce thousands of non-existing sequences. We present a new method to rectify erroneous reads under 300 bp produced by PCR-involved miRNA-sequencing, small RNA sequencing, or paired-end RNA sequencing, regardless of platform or sample type. Our method is the first kind considering the PCR erring mechanism and machine learning technique to improve sequencing data quality by turning millions of erroneous short reads into their original state without bringing up any non-existing sequences into the read set. Our error correction method can make a significant impact on a wide range of cutting-edge downstream applications. The observations and advantages in the case studies lay down strong evidence to question the accuracies of current downstream research outcomes and open new avenues to conduct downstream analysis whenever short-read data are adopted.

bioinformatics↗

Pro-renin Receptor Inhibited ABCA1/G1 Expression Associated with Low HDL-c and Promoted Atherosclerosis

Background(Pro)renin receptors [(P)RR] binding both renin and its inactive proenzyme for prorenin induce increasing the efficiency of angiotensin I conversion and the production of angiotensin II (Ang II). Recently, (P)RR was reported to played a pathological role in diabetic renal disease independent of Ang II. Ang II is involved in lipid metabolism and atherosclerosis, but the (P)RR participation in atherosclerosis remains unclear. Thus, the objective of this study was to examine the relative importance of Ang II-independent actions of (P)RR and its mechanism in the development of atherosclerosis. MethodsClinical demographic characteristics and laboratory profile data of 1189 essential hypertensive were collected. Patients were divided into four groups based on the quartiles of plasma renin activity (PRA). The plasma lipoprotein levels of four groups were compared. Furthermore, we examined serum and liver lipoprotein levels, as well as ATP-binding cassette transporter A1 (ABCA1) and ATP-binding cassette transporter G1 (ABCG1) expression in ApoE-/- mice treated with prorenin. ABCA1 and ABCG1 expression and their function in mediating cholesterol efflux were evaluated in THP-1 cells by prorenin treatment. Agonists of the peroxisome proliferator-activated receptor-{gamma} (PPAR-{gamma}) and liver X receptor (LXR) were used to investigate the mechanism involved in vitro. ResultsPlasma TC, TG, LDL-c, and apoB were significantly increased, and HDL-c and apoA were dramatically decreased with a trend of higher plasma renin activity (PRA) ( all P < 0.05) in hypertensive patients. Prorenin accelerated atherosclerosis by inhibiting mRNA and protein expression of ABCA1/ABCG1 in the liver of ApoE-/- mice. Prorenin binding to (P)RR inhibited the functions of ABCA1- and ABCG1-mediated cholesterol efflux. Furthermore, Prorenin reduced ABCA1/G1 expression of THP-1 cells through PPAR{gamma}/LXR pathway. Conclusions(P)RR activated by prorenin inhibited the expression of ABCA1/ABCG1 through the PPAR{gamma}/LXR pathway and the functions of ABCA1- and ABCG1-mediated cholesterol efflux, resulting in dyslipidemia and eventually atherosclerosis. HighlightsWith RPA increases in hypertension, plasma TC, TG, LDL-c, and apoB were higher, while HDL-c and apoA were lower. Prorenin binding to (P)RR accelerated atherosclerosis by inhibiting ABCA1/G1 expression and function. Prorenin reduced ABCA1/G1 expression of THP-1 cells through PPAR{gamma}/LXR pathway.

pathology↗