👤 Jiaxin Shen

Lipolysis of triglyceride-rich lipoproteins by peripheral lipoprotein lipase (LPL) plays an essential role in maintaining systemic cholesterol/lipid homeostasis. Human genetic studies have unequivocally demonstrated that activation of LPL pathway reduces risks for both coronary artery disease (CAD) and type 2 diabetes (T2D). Although sterol regulatory element-binding protein 2 (SREBP2) is well established as the master transcription factor that regulates the hepatic biosynthesis of both cholesterol and fatty acids, whether and how its activity in liver interacts with peripheral LPL pathway remains unknown. Here, it is demonstrated that acute liver-specific depletion of SREBP2 results in divergent effects on the regulation of peripheral LPL activity in mice, depending on the presence or absence of low-density lipoprotein receptors (LDLR). SREBP2 deficiency drastically elevates peripheral LPL activity through downregulation of plasma angiopoietin-related protein 3 (ANGPTL3) levels in LDLR-deficient mice. Moreover, in addition to SREBP2's transcriptional regulation of ANGPTL3, it is found that SREBP2 promotes proteasome-based degradation of ANGPTL3 in the presence of LDLR. Remarkably, acute depletion of hepatic SREBP2 protects against hypercholesterolemia and atherosclerosis, in which atherosclerotic lesions are reduced by 45% compared to control littermates. Taken together, these findings outline a liver-peripheral crosstalk mediated by SREBP2-ANGPTL3-LPL axis and suggest that SREBP2 inhibition can be an effective strategy to tackle homozygous familial hypercholesterolemia (HoFH). Show less

The gut microbiota influences host immunity and metabolism, and changes in its composition and function have been implicated in several non-communicable diseases. Here, comparing germ-free (GF) and specific pathogen-free (SPF) mice using spatial transcriptomics, single-cell RNA sequencing, and targeted bile acid metabolomics across multiple organs, we systematically assessed how the gut microbiota's absence affected organ morphology, immune homeostasis, bile acid, and lipid metabolism. Through integrated analysis, we detect marked aberration in B, myeloid, and T/natural killer cells, altered mucosal zonation and nutrient uptake, and significant shifts in bile acid profiles in feces, liver, and circulation, with the alternate synthesis pathway predominant in GF mice and pronounced changes in bile acid enterohepatic circulation. Particularly, autophagy-driven lipid droplet breakdown in ileum epithelium and the liver's zinc finger and BTB domain-containing protein (ZBTB20)-Lipoprotein lipase (LPL) (ZBTB20-LPL) axis are key to plasma lipid homeostasis in GF mice. Our results unveil the complexity of microbiota-host interactions in the crosstalk between commensal gut bacteria and the host. Show less

Individuals with diabetes are susceptible to cardiac dysfunction and heart failure, potentially resulting in mortality. Metabolic disorders frequently occur in patients with diabetes, and diabetes usually leads to remodeling of heart structure and cardiac dysfunction. However, the contribution and underlying mechanisms of metabolic and structural coupling in diabetic cardiac dysfunction remain elusive. Two mouse models of type 2 diabetes (T2DM) were used to assess alterations in glucose/lipid metabolism and cardiac structure. The potential metabolic-structural coupling molecule ACBP (acyl-coenzyme A-binding protein) was screened from 4 published datasets of T2DM-associated heart disease. In vivo loss-of-function and gain-of-function approaches were used to investigate the role of ACBP in diabetic cardiac dysfunction. The underlying mechanisms of metabolic and structural coupling were investigated by stable-isotope tracing metabolomics, coimmunoprecipitation coupled with mass spectrometry, and chromatin immunoprecipitation sequencing. Diabetic mouse hearts exhibit enhanced lipid metabolism and impaired ultrastructure with marked cardiac systolic and diastolic dysfunction. Analysis of 4 T2DM public datasets revealed that Our findings demonstrated that ACBP mediates the bidirectional regulation of cardiomyocyte metabolic and structural associations and identified a promising therapeutic target for ameliorating cardiac dysfunction in patients with T2DM. Show less

Based on the special role of mitochondria in tumour energy metabolism. We hope to explore the pathogenesis and potential therapeutic targets of Hepatocellular carcinoma by analysing the expression of 1136 mitochondrial proteins in hepatocellular carcinoma and their mechanisms in the Human.MitoCarta3.0 database. The expression of 1136 mitochondrial proteins in HCC was analysed by the TCGA database. We selected the top eight mitochondrial proteins among the highly expressed mitochondrial proteins that had not been studied in HCC and were statistically (P < 0.05) significant, according to fold change. Protein expression was verified by real-time quantitative reverse transcription polymerase chain reaction in tumours and adjacent paracancerous tissues of 34 pairs of HCC patients. Further in HCC cells, the expression of FDPS, DNA2 and MYO19 was verified. Clinical correlations of FDPS, DNA2 and MYO19 were analysed by UALCAN and KM-plot databases. Immune correlation of FDPS, DNA2 and MYO19 was analysed by TIMER2.0 and Sangerbox3.0 online databases. Mitochondrial proteins were expressed on all 24 chromosomes. More than 2/3 of the mitochondria were 100-600 bp long, of which 204 were secondary transmembrane proteins. 1136 mitochondrial proteins, of which 202 are not included in the TCGA database. Of the 934 mitochondrial proteins included in the TCGA database, 706 were highly expressed and 228 were poorly expressed in HCC. Further validated by HCC tissues and cells, the study found that significantly high expression of FDPS, DNA2 and MYO19 was negatively correlated with the prognosis of HCC patients. The results of the immune correlation analysis showed that DNA2 and MYO19 may be involved in regulating the infiltration of immune cells. 934 out of 1136 mitochondrial proteins in the Human.MitoCarta3.0 database were differentially expressed in HCC, suggesting that mitochondrial proteins play an important biological role in the development of HCC. Further experimental validation and bioinformatics analyses showed that functional mitochondrial proteins are potential pathophysiological mechanisms for malignant progression of HCC. Mitochondrial proteins, in the future, have the potential to be valuable therapeutic targets for HCC. Show less

To investigate the mechanisms by which berberine (BBR) improves macrophage efferocytosis dysfunction and alleviates inflammation induced by oxidized low-density lipoprotein (ox-LDL), a macrophage efferocytosis dysfunction model was established by inducing RAW264.7 cells with ox-LDL. This model was employed to assess the enhancing efferocytosis and anti-inflammatory effects of BBR in vitro. Flow cytometry was used to detect the efferocytosis function of RAW264.7 cells, while enzyme-linked immunosorbent assay (ELISA) measured inflammatory factor levels. Reverse transcription real-time quantitative polymerase chain reaction (RT-qPCR) and Western blotting were utilized to assess mRNA and protein expression levels of the PPARγ/LXRα axis and efferocytosis-related molecules. Results showed that efferocytosis significantly increased in RAW264.7 cells following protective intervention with BBR, evidenced by markedly higher expression of efferocytosis-related molecules GAS6, MerTK, and ABCA1 compared to the ox-LDL group. Additionally, BBR reduced the production of pro-inflammatory cytokines, enhanced the release of pro-resolving mediators, and mitigated inflammation. BBR enhanced efferocytosis by upregulating the expression of PPARγ/LXRα proteins and mRNA. In the presence of the PPARγ inhibitor (GW9662) and the LXRα inhibitor (GSK2033), levels of GAS6, MerTK, and ABCA1, as well as the expression levels of PPARγ/LXRα proteins and mRNA, were significantly lower compared to the BBR group. Furthermore, the inhibition of efferocytosis and production of anti-inflammatory cytokines were markedly weaker in the BBR+GW9662 and BBR+GSK2033 groups. These findings suggest that BBR exerts effects through the PPARγ/LXRα pathway, enhancing efferocytosis, regulating macrophage phenotype, inhibiting pro-inflammatory cytokine production, promoting pro-resolving mediators release, and demonstrating anti-atherosclerosis effects. Show less

Meningioma is a common primary central nervous system tumor that can cause a heavy burden on patients. Despite its well-established treatment modalities, pharmacological treatments are not sufficiently abundant. Therefore, we explored potential therapeutic targets for meningiomas by integrating genomic and proteomic data. We integrated meningioma data from the UK Biobank and Finnish databases and subsequently explored potential therapeutic targets for meningiomas through multi-omics data using bioinformatics techniques and Mendelian randomization. These targets were finally evaluated using phenotype-wide association group analysis. We found that BET1L, COL17A1, CFAP43, SH3PXD2A, TTC28, ZNRF3, SLK, AKR1C3, NRXN3, and RSPO3 can be potential therapeutic targets for meningiomas. This study provides evidence and explores the biological significance of BET1L, COL17A1, CFAP43, SH3PXD2A, TTC28, ZNRF3, SLK, AKR1C3, NRXN3, and RSPO3 as potential therapeutic targets for meningiomas, providing new insights into the development of targeted therapy for meningiomas. Show less

Asthma severity assessment is essential for asthma management. Transcriptomics contributes substantially to asthma pathogenesis. Then, this study aimed to explore asthma severity-associated transcriptomics profile and promising biomarkers for asthma severity prediction. In discovery cohort, induced sputum cells from 3 non-severe and 3 severe asthma patients were collected and analyzed using RNA-seq. Multivariate analysis was performed to explore asthma severity-associated transcriptomics profile and differential expressed genes (DEGs). The Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) were used for pathway enrichment analysis. Subsequently, based on the previous study and clinical experience, the mRNA expressions of 6 overlapped asthma severity-associated DEGs and Distinct asthma severity-associated transcriptomics profile was identified in induced sputum cells in discovery cohort. Then, 345 DEGs were found, of which 38 terms and 32 pathways were enriched using GO and KEGG, respectively. In validation cohort, the mRNA expressions of Collectively, this study provides the first identification of the association between induced sputum cells transcriptomics profile and asthma severity, indicating the potential value of transcriptomics for asthma management. The study also reveals the promising value of serum C3 for predicting asthma severity in clinical practice. Show less

Renal failure related death caused by diabetic kidney disease (DKD) is an inevitable outcome for most patients. This study aimed to identify the critical genes involved in the onset and progression of DKD and to explore potential therapeutic targets of DKD. We conducted a batch of protein quantitative trait loci (pQTL) Mendelian randomization analysis to obtain a group of proteins with causal relationships with DKD and then identified key proteins through colocalization analysis to determine correlations between variant proteins and disease outcomes. Subsequently, the specific mechanisms of key regulatory genes involved in disease progression were analyzed through transcriptome and single-cell analysis. Finally, we validated the mRNA expression of five key genes in the DKD mice model using reverse transcription quantitative PCR (RT-qPCR). Five characteristic genes, known as protein kinase B beta (AKT2), interleukin-2 receptor beta (IL2RB), neurexin 3(NRXN3), slit homolog 3(SLIT3), and TATA box binding protein like protein 1 (TBPL1), demonstrated causal relationships with DKD. These key genes are associated with the infiltration of immune cells, and they are related to the regulatory genes associated with immunity. In addition, we also conducted gene enrichment analysis to explore the complex network of potential signaling pathways that may regulate these key genes. Finally, we identified the effectiveness and reliability of these selected key genes through RT-qPCR in the DKD mice model. Our results indicated that the AKT2, IL2RB, NRXN3, SLIT3, and TBPL1 genes are closely related to DKD, which may be useful in the diagnosis and therapy of DKD. Show less

Poly(A) binding protein cytoplasmic 4 (PABPC4) has been regarded as a prognostic marker in many malignancies. In this study, we evaluated PABPC4 expression at both messenger ribonucleic acid (mRNA) and protein levels. The prognostic value of PABPC4 in patients with prostate cancer (PCa) was also investigated. The Cancer Genome Atlas (TCGA) database, Gene Expression Omnibus (GEO) database, our analysis of Chinese Prostate Cancer Genome and Epigenome Atlas (CPGEA), and 65 pairs of ribonucleic acid (RNA) sequencing data from our center were employed to detect the expression of PABPC4 in PCa tissues. Tissue microarrays (TMAs) were utilized to detect the expression of the PABPC4 protein, and survival analysis as well as risk factor analysis were conducted. In the 65 pairs of sequencing data, the expression of PABPC4 in tumor tissues was significantly higher than that in paired adjacent tissues (P<0.001), and its expression also presented significant differences among different Gleason groups (P=0.041). In the CPGEA data, the expression of PABPC4 in tumor tissues was significantly higher than that in control tissues (P<0.001), and the expression of PABPC4 in M1 patients was higher than that in M0 patients, although no significant statistical difference was shown (P=0.051). In the TCGA data, the expression of PABPC4 in tumor tissues was significantly higher than that in control tissues (P<0.001). The expression of pT3/4 (pathological tumor stage 3 and pathological tumor stage 4) in high-stage tumor tissues was significantly higher than that in low-stage tumor tissues (pT2) (P=0.02), the expression of pT3/4 in GSE21034 and GSE32571 tumor tissues was significantly higher than that in control tissues (P<0.001), and the expression of pT3/4 in primary tumor tissues was higher than that in metastatic tissues in GSE6752 (P<0.001). The TCGA data revealed that patients with high PABPC4 expression had poorer overall survival (OS) than those with low PABPC4 expression (P=0.04), and the TMA data indicated that patients with high PABPC4 expression had a poor prognosis (P=0.004). Our study demonstrated that PABPC4 was overexpressed at mRNA and protein levels in PCa. We found that patients with high PABPC4 expression had a shorter biochemical recurrence (BCR)-free survival and OS, showing its value as a prognostic biomarker in patients with PCa. Show less

Phosphatidylinositol-3 kinases (PI3Ks) play a critical role in maintaining cardiovascular health and the development of cardiovascular diseases (CVDs). Specifically, vacuolar Protein Sorting 34 (VPS34) or PIK3C3, the only member of Class III PI3K, plays an important role in CVD progression. The main function of VPS34 is inducing the production of phosphatidylinositol 3-phosphate, which, together with other essential structural and regulatory proteins in forming VPS34 complexes, further regulates the mammalian target of rapamycin activation, autophagy, and endocytosis. VPS34 is found to have crucial functions in the cardiovascular system, including dictating the proliferation and survival of vascular smooth muscle cells and cardiomyocytes and the formation of thrombosis. This review aims to summarize our current knowledge and recent advances in understanding the function and regulation of VPS34 in cardiovascular health and disease. We also discuss the current development of VPS34 inhibitors and their potential to treat CVDs. Show less

Epidemiology has shown a strong relationship between fine particulate matter (PM) exposure and cardiovascular disease. However, it remains unknown whether PM aggravates myocardial ischemia-reperfusion (I/R) injury, and the related mechanisms are unclear. Our previous study has shown that adipose stem cell-derived exosomes (ADSC-Exos) contain high levels of Show less

Idiopathic frozen shoulder (FS) can lead to difficulties in daily activities and significantly impact the quality of life. Early diagnosis and treatment can help alleviate symptoms and restore shoulder function. Therefore, we aimed to explore the diagnostic biomarkers and potential mechanisms of FS from a transcriptomics perspective. Total RNA was extracted from tissue samples of 15 FS and 11 controls. At the outset, we conducted differential expression analysis, weighted gene co-expression network analysis (WGCNA), and utilized the cytoHubba plugin, complemented by two machine learning algorithms, receiver operating characteristic (ROC) analysis, and expression level evaluation to identify biomarkers for FS. Subsequently, a nomogram was constructed based on the biomarkers. Additionally, we conducted enrichment and immune infiltration analyses to explore the mechanisms associated with these biomarkers. Finally, we confirmed the expression patterns of the biomarkers at the clinical level through reverse transcription-quantitative polymerase chain reaction (RT-qPCR). This study established a link between FS biomarkers that have strong diagnostic potential and specific immune responses, highlighting possible targets for diagnosing and treating FS. Show less

HUWE1, a member of HECT E3 ubiquitin ligase family, is implicated in a variety of cellular processes. Recent studies find that HUWE1 also plays critical roles in germ cell development and inactivation of HUWE1 causes germ cell loss in both male and female mice. In this study, we found that Huwe1 was also highly expressed in testicular Sertoli cells. Inactivation of Huwe1 in Sertoli cells resulted in loss of cell polarity, which in turn caused germ cells loss and male infertility. Further study revealed that dysregulation in the expression of cytoskeletal and adhesion-related molecules, as well as a significant increase in EMT-related trans-factors SNAI1&2 in Huwe1-deficient Sertoli cells. Intriguingly, the protein level of WT1 was significantly increased in Huwe1-deficient Sertoli cells, and overexpression of Wt1 in Sertoli cells also caused the defects in spermatogenesis which was consistent with Huwe1 CKO mouse model. Furthermore, the defect of spermatogenesis in Huwe1 CKO mice was partially rescued by deleting one allele of Wt1 gene. Mechanistic studies revealed that WT1 interacts with HUWE1 protein and it could be ubiquitinated by HUWE1. Our study demonstrates that HUWE1 is involved in the establishment of Sertoli cell polarity mainly by regulating the protein level of WT1 gene. Show less

This study aimed to investigate the effect of saltwater stir-fried Plantaginis Semen(SPS) on renal fibrosis in rats and decipher the underlying mechanism. Thirty-six Sprague-Dawley rats were randomly assigned into control, model, losartan potassium, and low-, medium-, and high-dose(15, 30, and 60 g·kg~(-1), respectively) SPS groups. Rats in other groups except the control group were subjected to unilateral ureteral obstruction(UUO) to induce renal fibrosis, and the modeling and gavage lasted for 14 days. After 14 consecutive days of treatment, the levels of serum creatinine(Scr) and blood urea nitrogen(BUN) in rats of each group were determined by an automatic biochemical analyzer. Hematoxylin-eosin(HE) and Masson staining were used to evaluate pathological changes in the renal tissue. Western blot and immunofluorescence assay were conducted to determine the protein levels of fibronectin(FN), collagen Ⅰ, vimentin, and α-smooth muscle actin(α-SMA) in the renal tissue. The mRNA levels of epithelial-mesenchymal transition(EMT)-associated transcription factors including twist family bHLH transcription factor 1(TWIST1), snail family transcriptional repressor 1(SNAI1), and zinc finger E-box binding homeobox 1(ZEB1), as well as inflammatory cytokines such as interleukin-1β(IL-1β), interleukin-6(IL-6), and tumor necrosis factor-α(TNF-α), were determined by RT-qPCR. Human renal proximal tubular epithelial(HK2) cells exposed to transforming growth factor-β(TGF-β) for the modeling of renal fibrosis were used to investigate the inhibitory effect of SPS on EMT. Network pharmacology and Western blot were employed to explore the molecular mechanism of SPS in alleviating renal fibrosis. The results showed that SPS significantly reduced Scr and BUN levels and alleviated renal injury and collagen deposition in UUO rats. Moreover, SPS notably down-regulated the protein levels of FN, collagen Ⅰ, vimentin, and α-SMA as well as the mRNA levels of SNAI1, ZEB1, TWIST1, IL-1β, IL-6, and TNF-α in the kidneys of UUO rats and TGF-β-treated HK-2 cells. In addition, compared with Plantaginis Semen without stir-frying with saltwater, SPS showed increased content of specific compounds, which were mainly enriched in the mitogen-activated protein kinase(MAPK) signaling pathway. SPS significantly inhibited the phosphorylation of extracellular signal-regulated kinase(ERK) and p38 MAPK in the kidneys of UUO rats and TGF-β-treated HK2 cells. In conclusion, SPS can alleviate renal fibrosis by attenuating EMT through inhibition of the MAPK signaling pathway. Show less

Parkinson's Disease (PD), a prevalent neurodegenerative condition, is distinguished by its motor dysfunction. Induced pluripotent stem cells (iPSCs), derived from PD patients, constitute an exquisite investigative tool for elucidating the pathophysiology of the disease, assessing candidate therapeutics, and probing the potential for regenerative medicine approaches. The present study was designed to establish an iPSC line, designated TUSMi013-A, from the dermal fibroblasts of a 66-year-old female afflicted with PD, harboring mutations in VPS13C and TBP. This iPSC line offers a significant resource for the dissection of PD etiology and the innovation of novel therapeutic strategies. Show less

The dual activation of glucagon-like peptide-1 receptor (GLP-1R) and glucose-dependent insulinotropic polypeptide receptor (GIPR) has emerged as a promising therapeutic strategy for managing type 2 diabetes and obesity. Tirzepatide, a dual agonist peptide, has exhibited superior clinical efficacy in glycemic and weight control compared to selective GLP-1R agonists. Nevertheless, the structural basis of Tirzepatide's extended half-life, attributed to an acylation side chain on the parent peptide, raises questions regarding its partial agonistic activity. Employing molecular dynamics simulations, we explored the dynamic processes of peptide-receptor interactions. We uncovered a crucial salt bridge between parent peptide and GLP-1R/GIPR at K20, a feature not discernible in cryo-electron microscopy structures. Building upon these insights, we developed an optimization strategy based on the parent peptide which involved repositioning the acylation side chain. The results of both in vitro and in vivo experiments demonstrated that the optimized peptide has twofold to threefold increase in agonistic activity compared to Tirzepatide while maintaining its extended half-life in plasma. This led to the design of BGM0504, which proved to be more effective than its predecessor, Tirzepatide, in both laboratory and animal studies. Show less

High altitude pulmonary edema (HAPE) is an idiopathic, noncardiogenic form of pulmonary edema that occurs at high altitudes. It is characterized by a severe clinical course and carries a significant mortality risk. Despite its clinical relevance, the molecular mechanisms underlying HAPE are not well understood. We conducted whole-transcriptome RNA sequencing on blood samples from 6 pairs of HAPE patients and healthy controls to identify differentially expressed (DE) mRNAs, miRNAs, circRNAs, lncRNAs, along with alternative splicing (AS) events, gene fusions, and novel transcripts. To explore the regulatory dynamics, we constructed ceRNA networks and analyzed immune cell infiltration patterns, further annotating the biological functions of these transcripts. For empirical validation, we selected five circRNAs from the ceRNA network and conducted RT-qPCR on 50 paired samples. Additionally, we assessed the correlations between circRNA expression levels and clinical data to evaluate their diagnostic potential. We observed 2,023 differentially expressed mRNAs (DEmRNAs), 84 DEmiRNAs, 200 DEcircRNAs, and 3,573 DElncRNAs. A total of 139 'A3SS' events, 103 'A5SS' events, 545 'MXE' events, 14 'RI' events, and 1,482 'SE' events were identified in the AS events analysis between the two groups. Two ceRNA networks were constructed. T cells, follicular helper, and Macrophages M1 cells exhibited the strongest positive correlation (R=0.82), while naive B cells and memory B cells demonstrated the strongest negative correlation (R=-0.62). In total, the expression of three circRNAs was significantly different in a larger cohort. Hsa_circ₀₀₅₈₄₉₇, hsa_circ₀₀₈₁₀₀₆, and hsa_circ₀₀₈₃₂₂₀ demonstrated consistent with the RNA sequencing results. These three circRNAs strongly correlate with clinical indicators and exhibit potential as diagnostic biomarkers. Finally, we verified five genes (CXCR4, HSD17B2, ANGPTL4, TIMP3, N4BP3) that were differentially expressed in endothelial cells under normoxia and hypoxia through bioinformatics and RT-qPCR analyses. This study elucidates the differential expression of coding and non-coding RNAs (ncRNAs) in HAPE, identifies new transcripts and genes, and enhances our understanding of the transcriptional characteristics of HAPE. Moreover, it highlights the potential role of circRNAs in advancing the diagnosis and treatment of HAPE. Show less

Lung adenocarcinoma (LUAD) is one of the most common malignant tumors with high mortality. Anoikis resistance is an important mechanism of tumor cell proliferation and migration. Our research is devoted to exploring the role of anoikis in the diagnosis, classification, and prognosis of LUAD. We downloaded the expression profile, mutation, and clinical data of LUAD from The Cancer Genome Atlas (TCGA) database. The "ConsensusClusterPlus" package was then used for the cluster analysis, and least absolute shrinkage and selection operator (LASSO) and multivariate Cox regression analyses were used to establish the prognostic model. We verified the reliability of the model using a Gene Expression Omnibus (GEO) data set. A gene set variation analysis (GSVA) was conducted to investigate the functional enrichment differences in the different clusters and risk groups. The CIBERSORT algorithm and a single-sample gene set enrichment analysis (ssGSEA) were used to analyze immune cell infiltration. The tumor mutation burden (TMB) and Tumor Immune Dysfunction and Exclusion (TIDE) scores were used to evaluate the patients' sensitivity to immunotherapy. Immunohistochemical staining of tissue microarrays was used to verify the correlation between ANGPTL4 expression and the clinicopathological characteristics and prognosis of LUAD patients. First, we screened 135 differentially expressed anoikis-related genes (ARGs) and 23 prognosis-related ARGs from TCGA-LUAD data set. Next, 494 LUAD samples were allocated to cluster A and cluster B based on the 23 prognosis-related ARGs. The Kaplan-Meier (K-M) analysis showed the overall survival (OS) of cluster B was better than that of cluster A. The clinicopathological characteristics and functional enrichment analyses revealed significant differences between clusters A and B. The tumor microenvironment (TME) analysis showed that cluster B had more immune cell infiltration and a higher TME score than cluster A. Subsequently, a LASSO Cox regression model of LUAD was constructed with ten ARGs. The K-M analysis showed that the low-risk patients had longer OS than the high-risk patients. The receiver operating characteristic curve, nomogram, and GEO data set verification results showed that the model had high accuracy and reliability. The level of immune cell infiltration and TME score were higher in the low-risk group than the high-risk group. The high-risk group had stronger sensitivity to immune checkpoint block therapy and weaker sensitivity to chemotherapy drugs than the low-risk group. ANGPTL4 expression was correlated with stage, tumor differentiation, tumor size, lymph node metastasis, and OS. We discovered novel molecular subtypes and constructed a novel prognostic model of LUAD. Our findings provide important insights into subtype classification and the accurate survival prediction of LUAD. We also identified ANGPTL4 as a prognostic indicator of LUAD. Show less

Angiopoietin-like protein 4 (ANGPTL4) is recognized as a crucial regulator in lipid metabolism. Acetyl-CoA carboxylases (ACACAs) play a role in the β-oxidation of fatty acids. Yet, the functions of ANGPTL4 and ACACA in dyslipidemia of obstructive sleep apnea (OSA) remain unclear. This study included 125 male OSA subjects from the Shanghai Sleep Health Study (SSHS) who were matched for age, body mass index (BMI), and lipid profile. Serum ANGPTL4 levels were measured Serum ANGPTL4 levels significantly decreased with increasing OSA severity (non-OSA: 59.6 ± 17.4 ng/mL, mild OSA: 50.0 ± 17.5 ng/mL, moderate OSA: 46.3 ± 15.5 ng/mL, severe OSA: 19.9 ± 14.3 ng/mL, respectively, Serum ANGTPL4 levels were significantly decreased in OSA patients, particularly among individuals with severe OSA. Although functional ANGTPL4 T266M variants were not associated with lipid levels in OSA, ANGTPL4 T266M could enhance binding affinity for the ACACA protein, potentially regulating lipid metabolism. Show less

Colorectal cancer (CRC) is characterized by high morbidity, high mortality, and limited response to immunotherapies. The peripheral immune system is an important component of tumor immunity, and enhancements of peripheral immunity help to suppress tumor progression. However, the functional alterations of the peripheral immune system in CRC are unclear. Here, we used mass spectrometry-based quantitative proteomics to establish a protein expression atlas for the peripheral immune system in CRC, including plasma and five types of immune cells (CD4 Show less

Platelets are small anucleate cells that play a key role in thrombosis and hemostasis. Our group previously identified apolipoprotein A-IV (apoA-IV) as an endogenous inhibitor of thrombosis by competitive blockade of the αIIbβ3 integrin on platelets. ApoA-IV inhibition of platelets was dependent on the N-terminal D5/D13 residues, and enhanced with absence of the C-terminus, suggesting it sterically hinders its N-terminal platelet binding site. The C-terminus is also the site of common apoA-IV polymorphisms apoA-IV-1a (T347S) and apoA-IV-2 (Q360H). Interestingly, both are linked with an increased risk of cardiovascular disease, however, the underlying mechanism remains unclear. Here, we generated recombinant apoA-IV and found that the Q360H or T347S polymorphisms dampened its inhibition of platelet aggregation in human platelet-rich plasma and gel-filtered platelets, reduced its inhibition of platelet spreading, and its inhibition of P-selectin on activated platelets. Using an ex vivo thrombosis assay, we found that Q360H and T347S attenuated its inhibition of thrombosis at both high (1800s Show less

Familial hypercholesterolemia (FH) is an inherited disorder mainly marked by increased low-density lipoprotein cholesterol (LDL-C) concentrations and a heightened risk of early-onset arteriosclerotic cardiovascular disease (ASCVD). This study seeks to characterize the genetic spectrum and genotype‒phenotype correlations of FH in Chinese pediatric individuals. Data were gathered from individuals diagnosed with FH either clinically or genetically at multiple hospitals across mainland China from January 2016 to June 2024. In total, 140 children and adolescents (mean age of 6.00 years) with clinically and genetically diagnosed FH were enrolled in the study, with 87 distinct variants identified in the LDLR, APOB and PCSK9 genes. Among the variants, 11 variants were newly identified worldwide, with 9 classified as "pathogenic" or "likely pathogenic", and 2 classified as "variants of uncertain significance". Additionally, the 5 most common variants in the study were c.1448G > A (p.W483*), c.1879G > A (p.A627T), c.1216C > A (p.R406R), and c.1747C > T (p.H583Y) in the LDLR gene, as well as c.10579C > T (p.R3527W) in the APOB gene, accounting for 49.29% (69/140) of all patients. These variants are primarily observed in the Asian or Chinese population and are distinct from those present in Caucasian groups. In this cohort, 105 patients were diagnosed with heterozygous FH (HeFH), while 35 were diagnosed with homozygous FH (HoFH). Finally, only 28.57% of the patients (40/140) were using lipid-lowering medications with 33.33% of HoFH patients initiating treatment after the age of 8. Additionally, only 3 compound heterozygous patients (2.14%) underwent liver transplantation because of significantly high lipid levels. This study reveals the variable genotypes and phenotypes of children with FH in China and illustrates that the genotypes in the Chinese population differ from those in Caucasians, providing a valuable dataset for the clinical genetic screening of FH in China. Furthermore, the older age at diagnosis and treatment highlights the underdiagnosis and undertreatment of Chinese FH pediatric patients, suggesting that early identification should be improved through lipid or genetic screening, and that more timely and regular pharmacological treatments should be implemented. Show less

Dyslipidemia is a common comorbidity in patients with cancer, yet the impact of abnormal lipid levels on tumor prognosis remains contentious. This study was conducted to synthesize the current evidence regarding the prognostic utility of blood lipid levels, including high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), total cholesterol (TC), triglycerides (TG), apolipoprotein A1 (ApoA1), and apolipoprotein B (ApoB), in predicting overall survival (OS) and disease-free survival (DFS) in cancer patients. A comprehensive literature search was performed across electronic databases to assess the associations between blood lipid levels and OS or DFS in cancer patients. Pooled hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated to analyze the data. The research protocol was previously submitted to the International Prospective Register of Systematic Reviews (PROSPERO): CRD42023458597. Our study represents the largest and most extensive evaluation of the prognostic significance of blood lipid levels in cancer to date. It includes a meta-analysis of 156 eligible studies involving 85,173 cancer patients. The findings revealed a significant association between elevated levels of HDL-C, TC, and ApoA1 and improved OS and DFS in cancer patients. In contrast, no significant relationships were identified between LDL-C, TG, and ApoB levels and the OS or DFS of cancer patients. Blood lipids, particularly HDL-C, TC, and ApoA1, emerge as accessible and cost-effective biomarkers that may aid in assessing survival outcomes in cancer patients and potentially inform clinical decision-making. Show less

Parkinson's disease (PD) and Alzheimer's disease (AD) are common neurodegenerative diseases with multifaceted etiology. Nutritional and metabolic abnormalities are frequently implicated in PD and AD. In this observational study, we analyzed a series of nutritional markers, and aimed to understand their association with AD and PD risk. A total of 424 PD patients, 314 AD patients, and 388 healthy controls were included. Nutritional markers including Hemoglobin A1c, vitamin B12, folate, apolipoprotein B (ApoB), apolipoprotein A1 (ApoA1), low-density lipoprotein (LDL), high-density lipoprotein, triglyceride, total cholesterol (TC), uric acid and homocysteine (HCY) were measured. Significance for odds ratios examining was Multifactor risk analysis showed that ApoB, LDL, and TC reduce PD risk, while HCY increase PD risk. ApoA1 and HCY are protective and risk factors for AD, respectively. The cross-sectional study demonstrates that HCY and lipid metabolism markers are associated with PD and AD risks. Our findings support the involvement of one-carbon metabolism and lipid metabolism disturbance in PD and AD. Show less

The role of circulating metabolome in cognitive impairment is inconclusive, and whether the associations are in the severity-dependent manner remains unclear. We aimed to identify plasma metabolites associated with cognitive impairment and evaluate the added predictive capacity of metabolite biomarkers on incident cognitive impairment beyond traditional risk factors. In the Rugao Longevity and Ageing Study (RuLAS), plasma metabolome was profiled by nuclear magnetic resonance spectroscopy. Participants were classified into the cognitively normal, moderately impaired, and severely impaired groups according to their performance in two objective cognitive tests. A two-step strategy of cross-sectional discovery followed by prospective validation was applied. In the discovery stage, we included 1643 participants (age: 78.9 ± 4.5 years) and conducted multinomial logistic regression. In the validation stage, we matched 68 incident cases of cognitive impairment (moderately-to-severely impaired) during the 2-year follow-up with 204 cognitively normal controls by age and sex at a 1:3 ratio, and conducted conditional logistic regression. We identified 28 out of 78 metabolites cross-sectionally related to severely impaired cognition, among which IDL particle number, ApoB in IDL, leucine, and valine were prospectively associated with 28%, 28%, 29%, and 33% lower risk of developing cognitive impairment, respectively. Incorporating 13 metabolite biomarkers selected through Lasso regression into the traditional risk factors-based prediction model substantially improved the ability to predict incident cognitive impairment (AUROC: 0.839 vs. 0.703, P < 0.001; AUPRC: 0.705 vs. 0.405, P < 0.001). This study identified specific plasma metabolites related to cognitive impairment. Incorporation of specific metabolites substantially improved the prediction performance for cognitive impairment. Show less

In zebrafish, maternally deposited yolk is the source of nutrients for embryogenesis prior to digestive system maturation. Yolk nutrients are processed and secreted to the growing organism by an extra-embryonic tissue, the yolk syncytial layer (YSL). The export of lipids from the YSL occurs through the production of triacylglycerol-rich lipoproteins. Here we report that mutations in the triacylglycerol synthesis enzyme, diacylglycerol acyltransferase-2 (Dgat2), cause yolk sac opacity due to aberrant accumulation of cytoplasmic lipid droplets in the YSL. Although triacylglycerol synthesis continues, it is not properly coupled to lipoprotein production as dgat2 mutants produce fewer, smaller, ApoB-containing lipoproteins. Unlike DGAT2-null mice, which are lipopenic and die soon after birth, zebrafish dgat2 mutants are viable, fertile, and exhibit normal mass and adiposity. Residual Dgat activity cannot be explained by the activity of other known Dgat isoenzymes, as dgat1a;dgat1b;dgat2 triple mutants continue to produce YSL lipid droplets and remain viable as adults. Further, the newly identified diacylglycerol acyltransferase, Tmem68, is also not responsible for the residual triacylglycerol synthesis activity. Unlike overexpression of Dgat1a and Dgat1b, monoacylglycerol acyltransferase-3 (Mogat3b) overexpression does not rescue yolk opacity, suggesting it does not possess Dgat activity in the YSL. However, mogat3b;dgat2 double mutants exhibit increased yolk opacity and often have structural alterations of the yolk extension. Quadruple mogat3b;dgat1a;dgat1b;dgat2 mutants either have severely reduced viability and stunted growth or do not survive past 3 days post fertilization, depending on the dgat2 mutant allele present. Our study highlights the remarkable ability of vertebrates to synthesize triacylglycerol through multiple biosynthetic pathways. Show less

Presbycusis, or age-related hearing loss (ARHL) has been a common disability disease among the elderly population. It is particularly essential to identify the underlying role of related risk factors for ARHL diagnosis and treatment. Observational studies have shown that cardiovascular disease may be a factor in ARHL. Serum lipids are a key risk factor for cardiovascular disease. Therefore, it may be a potentially influencing factor for elderly deafness. We conduct the study to analyze the causal relationship between serum lipids and European elderly deafness. Using genetic variation data related to serum lipids (total cholesterol levels [TCL], total triglycerides levels [TGL], and lipoprotein fractions, including apolipoprotein A1 levels [APOA1L], apolipoprotein B levels [APOBL], high-density lipoprotein cholesterol levels [HDL], and low-density lipoprotein cholesterol levels [LDL]) as instrumental variables, the outcome events were summarized from the genome-wide association study data of elderly deafness, and Mendelian randomization (MR) analysis was used in our analysis. The relationship between serum lipids levels and ARHL was analyzed using five methods, including inverse variance weighted, weighted mode, MR-Egger, weighted median, and simple mode. The study aims to use bidirectional MR analysis. Among all 5 methods, no significant causal effects were found between serum lipids (TCL OR = 0.936, p = .488; TGL OR = 0.955, p = 0.657; APOA1L OR = 0.864, p = .061; APOBL OR = 0.979, p = .786; HDL OR = 0.998, p = .979; LDL OR = 1.089, p = .281) and presbycusis. The findings of MR causal inference analysis did not support the causal relationship between presbycusis and serum lipids, including cholesterol, triglycerides, and lipoprotein fractions (APOA1L, APOBL, HDL and LDL). Show less

Zebrafish are an ideal model organism to study lipid metabolism and to elucidate the molecular underpinnings of human lipid-associated disorders. Unlike murine models, to which various standardized high lipid diets such as a high-cholesterol diet (HCD) are available, there has yet to be a uniformly adopted zebrafish HCD protocol. In this study, we have developed an improved HCD protocol and thoroughly tested its impact on zebrafish lipid deposition and lipoprotein regulation in a dose- and time-dependent manner. The diet stability, reproducibility, and fish palatability were also validated. Fish fed HCD developed hypercholesterolemia as indicated by significantly elevated ApoB-containing lipoproteins (ApoB-LPs) and increased plasma levels of cholesterol and cholesterol esters. Feeding of the HCD to larvae for 8 days produced hepatic steatosis that became more stable and sever after 1 day of fasting and was associated with an opaque liver phenotype (dark under transmitted light). Unlike larvae, adult fish fed HCD for 14 days followed by a 3-day fast did not develop a stable fatty liver phenotype, though the fish had higher ApoB-LP levels in plasma and an upregulated lipogenesis gene fasn in adipose tissue. In conclusion, our HCD zebrafish protocol represents an effective and reliable approach for studying the temporal characteristics of the physiological and biochemical responses to high levels of dietary cholesterol and provides insights into the mechanisms that may underlie fatty liver disease. Show less

Unexplained recurrent pregnancy loss (URPL) is a clinical dilemma in reproductive fields. Its diagnosis is mainly exclusionary after extensive clinical examination, and some of the patients may still face the risk of miscarriage. We analyzed follicular fluid (FF) from Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis showed that the DEPs are involved in the biological processes (BP) of complement and coagulation cascades. Apolipoproteins (APOs) are key proteins in the PPI network. ELISA confirmed that APOB was low-expressed in both the FF and peripheral blood of URPL patients. Dysregulation of the immune network intersecting coagulation and inflammatory response is an essential feature of URPL, and this disequilibrium exists as early as the oogenesis stage. Therefore, earlier intervention is necessary to prevent the development of URPL. Moreover, aberrant lipoprotein regulation appears to be a key factor contributing to URPL. The mechanism by which these factors are involved in the complement and coagulation cascade pathways remains to be further investigated, which also provides new candidate targets for URPL treatment. Show less

Diabetes mellitus is generally accompanied by dyslipidaemia, but inconsistent relationships between lipid profiles and diabetes are noted. Moreover, genetic variations in insertion/deletion (I/D) polymorphisms at angiotensin-converting enzyme gene (ACE) and T/C polymorphisms in the angiotensin type 1 receptor gene (AGTR1) are related to diabetes and lipid levels, but the associations are controversial. Thus, the current research aimed to explore the effects of ACE I/D, AGTR1 rs5182 and diabetes mellitus on serum lipid profiles in 385 Chinese participants with an average age of 75.01 years. The ACE I/D variant was identified using the polymerase chain reaction (PCR) method, whereas the AGTR1 rs5182 polymorphism was identified using the PCR-based restriction fragment length polymorphism (PCR-RFLP) method and verified with DNA sequencing. Total cholesterol (TC), triglyceride (TG), apolipoprotein A (ApoA), apolipoprotein B (ApoB), high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C) levels were measured using routine methods, and the lipid ratios were calculated. ACE I/D, but not AGTR1 rs5182, was a predictor of TG/HDL-C for the whole study population. Both ACE I/D and AGTR1 rs5182 were predictors of HDL-C and LDL-C levels in females but not in males. Moreover, in females, diabetes mellitus and ACE I/D were identified as predictors of TG and TG/HDL-C, whereas AGTR1 rs5182 and diabetes mellitus were predictors of TG/HDL-C. Moreover, diabetes mellitus and the combination of ACE I/D and AGTR1 rs5182 variations were predictors of TG and TG/HDL-C exclusively in females. The results demonstrated the potential for gender-dependent interactions of ACE I/D, AGTR1 rs5182, and diabetes on lipid profiles. These findings may serve as an additional explanation for the inconsistent changes of blood lipids in individuals with diabetes mellitus, thereby offering a novel perspective for the clinical management of blood lipid levels in diabetic patients. Show less