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Nature Communications Jan 2024Members of the low-density lipoprotein receptor (LDLR) family, including LDLRAD3, VLDLR, and ApoER2, were recently described as entry factors for different alphaviruses....
Members of the low-density lipoprotein receptor (LDLR) family, including LDLRAD3, VLDLR, and ApoER2, were recently described as entry factors for different alphaviruses. However, based on studies with gene edited cells and knockout mice, blockade or abrogation of these receptors does not fully inhibit alphavirus infection, indicating the existence of additional uncharacterized entry factors. Here, we perform a CRISPR-Cas9 genome-wide loss-of-function screen in mouse neuronal cells with a chimeric alphavirus expressing the Eastern equine encephalitis virus (EEEV) structural proteins and identify LDLR as a candidate receptor. Expression of LDLR on the surface of neuronal or non-neuronal cells facilitates binding and infection of EEEV, Western equine encephalitis virus, and Semliki Forest virus. Domain mapping and binding studies reveal a low-affinity interaction with LA domain 3 (LA3) that can be enhanced by concatenation of LA3 repeats. Soluble decoy proteins with multiple LA3 repeats inhibit EEEV infection in cell culture and in mice. Our results establish LDLR as a low-affinity receptor for multiple alphaviruses and highlight a possible path for developing inhibitors that could mitigate infection and disease.
Topics: Horses; Animals; Mice; Alphavirus; Encephalitis Virus, Eastern Equine; Alphavirus Infections; Semliki forest virus; Lipoproteins, LDL
PubMed: 38172096
DOI: 10.1038/s41467-023-44624-x -
Journal of Thrombosis and Haemostasis :... Mar 2024Venous thromboembolism (VTE) has been associated with several modifiable factors (MFs) and cardiovascular comorbidities. However, the mechanisms are largely unknown. (Meta-Analysis)
Meta-Analysis
BACKGROUND
Venous thromboembolism (VTE) has been associated with several modifiable factors (MFs) and cardiovascular comorbidities. However, the mechanisms are largely unknown.
OBJECTIVES
We aimed to decipher proteomic pathways underlying the associations of VTE with MFs and cardiovascular comorbidities.
METHODS
A 2-stage network Mendelian randomization analysis was conducted to explore the associations between 15 MFs, 1151 blood proteins, and VTE using data from a genome-wide meta-analysis including 81 190 cases of VTE. We used protein data from 35 559 individuals as the discovery analysis, and from 2 independent studies including 10 708 and 54 219 participants as the replication analyses. Based on the identified proteins, we assessed the druggability and examined the cardiovascular pleiotropy.
RESULTS
The network Mendelian randomization analyses identified 10 MF-VTE, 86 MF-protein, and 34 protein-VTE associations. These associations were overall consistent in the replication analyses. Thirty-eight pathways with directionally consistent direct and indirect effects in the MF-protein-VTE pathway were identified. Low-density lipoprotein receptor-related protein 12 (LRP12: 34.3%-58.1%) and coagulation factor (F)XI (20.6%-39.6%) mediated most of the associations between 3 obesity indicators and VTE. Likewise, coagulation FXI mediated most of the smoking-VTE association (40%; 95% CI, 20%-60%) and insomnia-VTE association (27%; 95% CI, 5%-49%). Many VTE-associated proteins were highly druggable for thrombotic conditions. Five proteins (interleukin-6 receptor subunit alpha, LRP12, prothrombin, angiopoietin-1, and low-density lipoprotein receptor-related protein 4) were associated with VTE and its cardiovascular comorbidities.
CONCLUSION
This study suggests that coagulation FXI, a druggable target, is an important mediator of the associations of obesity, smoking, and insomnia with VTE risk.
Topics: Humans; Venous Thromboembolism; Proteomics; Sleep Initiation and Maintenance Disorders; Obesity; Lipoproteins, LDL; Risk Factors
PubMed: 38029854
DOI: 10.1016/j.jtha.2023.11.013 -
International Journal of Molecular... Jul 2023We previously described the role of low-density lipoprotein (LDL) in aggressiveness in papillary thyroid cancer (PTC). Moreover, the MAPK signaling pathway in the...
We previously described the role of low-density lipoprotein (LDL) in aggressiveness in papillary thyroid cancer (PTC). Moreover, the MAPK signaling pathway in the presence of BRAF V600E mutation is associated with more aggressive PTC. Although the link between MAPK cascade and LDL receptor (LDLR) expression has been previously described, it is unknown whether LDL can potentiate the adverse effects of PTC through it. We aimed to investigate whether the presence of LDL might accelerate the oncogenic processes through MAPK pathway in presence or absence of BRAF V600E in two thyroid cell lines: TPC1 and BCPAP (wild-type and BRAF V600E, respectively). LDLR, PI3K-AKT and RAS/RAF/MAPK (MEK)/ERK were analyzed via Western blot; cell proliferation was measured via MTT assay, cell migration was studied through wound-healing assay and LDL uptake was analyzed by fluorometric and confocal analysis. TPC1 demonstrated a time-specific downregulation of the LDLR, while BCPAP resulted in a receptor deregulation after LDL exposition. LDL uptake was increased in BCPAP over-time, as well as cell proliferation (20% higher) in comparison to TPC1. Both cell lines differed in migration pattern with a wound closure of 83.5 ± 9.7% after LDL coculture in TPC1, while a loss in the adhesion capacity was detected in BCPAP. The siRNA knockdown of LDLR in LDL-treated BCPAP cells resulted in a p-ERK expression downregulation and cell proliferation modulation, demonstrating a link between LDLR and MAPK pathway. The modulation of BRAF-V600E using vemurafenib-impaired LDLR expression decreased cellular proliferation. Our results suggest that LDLR regulation is cell line-specific, regulating the RAS/RAF/MAPK (MEK)/ERK pathway in the LDL-signaling cascade and where BRAF V600E can play a critical role. In conclusion, targeting LDLR and this downstream signaling cascade, could be a new therapeutic strategy for PTC with more aggressive behavior, especially in those harboring BRAF V600E.
Topics: Humans; Proto-Oncogene Proteins B-raf; Phosphatidylinositol 3-Kinases; Mutation; Thyroid Neoplasms; Thyroid Cancer, Papillary; Receptors, LDL; Lipoproteins, LDL; Mitogen-Activated Protein Kinase Kinases; Cell Line, Tumor
PubMed: 37446330
DOI: 10.3390/ijms241311153 -
Journal of Dental Research Jan 2024Systemic metabolic signatures of oral diseases have been rarely investigated, and prospective studies do not exist. We analyzed whether signs of current or past...
Systemic metabolic signatures of oral diseases have been rarely investigated, and prospective studies do not exist. We analyzed whether signs of current or past infectious/inflammatory oral diseases are associated with circulating metabolites. Two study populations were included: the population-based Health-2000 ( = 6,229) and Parogene ( = 452), a cohort of patients with an indication to coronary angiography. Health-2000 participants ( = 4,116) provided follow-up serum samples 11 y after the baseline. Serum concentrations of 157 metabolites were determined with a nuclear magnetic resonance spectroscopy-based method. The associations between oral parameters and metabolite concentrations were analyzed using linear regression models adjusted for age, sex, number of teeth, smoking, presence of diabetes, and education (in Health-2000 only). The number of decayed teeth presented positive associations with low-density lipoprotein diameter and the concentrations of pyruvate and citrate. Negative associations were found between caries and the unsaturation degree of fatty acids (FA) and relative proportions of docosahexaenoic and omega-3 FAs. The number of root canal fillings was positively associated with very low-density lipoprotein parameters, such as diameter, cholesterol, triglycerides, and number of particles. Deepened periodontal pockets were positively associated with concentrations of cholesterol, triglycerides, pyruvate, leucine, valine, phenylalanine, and glycoprotein acetyls and negatively associated with high-density lipoprotein (HDL) diameter, FA unsaturation degree, and relative proportions of omega-6 and polyunsaturated FAs. Bleeding on probing (BOP) was associated with increased concentrations of triglycerides and glycoprotein acetyls, as well as decreased proportions of omega-3 and omega-6 FAs. Caries at baseline predicted alterations in apolipoprotein B-containing lipoproteins and HDL-related metabolites in the follow-up, and both caries and BOP were associated with changes in HDL-related metabolites and omega-3 FAs in the follow-up. Signs of current or past infectious/inflammatory oral diseases, especially periodontitis, were associated with metabolic profiles typical for inflammation. Oral diseases may represent a modifiable risk factor for systemic chronic inflammation and thus cardiometabolic disorders.
Topics: Humans; Prospective Studies; Triglycerides; Fatty Acids; Cholesterol; Lipoproteins, LDL; Inflammation; Glycoproteins; Pyruvates
PubMed: 37968796
DOI: 10.1177/00220345231203562 -
Progress in Lipid Research Nov 2023Macrophages are essential innate immune cells and form our first line of immune defense. Also known as professional phagocytes, macrophages interact and take up various... (Review)
Review
Macrophages are essential innate immune cells and form our first line of immune defense. Also known as professional phagocytes, macrophages interact and take up various particles, including lipids. Defective lipid handling can drive excessive lipid accumulation leading to foam cell formation, a key feature of various cardiometabolic conditions such as atherosclerosis, non-alcoholic fatty liver disease, and obesity. At the same time, intracellular lipid storage and foam cell formation can also be viewed as a protective and anti-lipotoxic mechanism against a lipid-rich environment and associated elevated lipid uptake. Traditionally, foam cell formation has primarily been linked to cholesterol uptake via native and modified low-density lipoproteins. However, other lipids, including non-esterified fatty acids and triacylglycerol (TAG)-rich lipoproteins (very low-density lipoproteins and chylomicrons), can also interact with macrophages. Recent studies have identified multiple pathways mediating TAG uptake and processing by macrophages, including endocytosis and receptor/transporter-mediated internalization and transport. This review will present the current knowledge of how macrophages take up different lipids and lipoprotein particles and address how TAG-rich lipoproteins are processed intracellularly. Understanding how macrophages take up and process different lipid species such as TAG is necessary to design future therapeutic interventions to correct excessive lipid accumulation and associated co-morbidities.
Topics: Triglycerides; Fatty Acids; Macrophages; Lipoproteins; Foam Cells; Lipoproteins, LDL
PubMed: 37619883
DOI: 10.1016/j.plipres.2023.101250 -
Current Atherosclerosis Reports Nov 2023Atherosclerotic cardiovascular disease (ASCVD) is still the leading cause of death worldwide. Despite excellent pharmacological approaches, clinical registries... (Review)
Review
PURPOSE OF REVIEW
Atherosclerotic cardiovascular disease (ASCVD) is still the leading cause of death worldwide. Despite excellent pharmacological approaches, clinical registries consistently show that many people with dyslipidemia do not achieve optimal management, and many of them are treated with low-intensity lipid-lowering therapies. Beyond the well-known association between low-density lipoprotein cholesterol (LDL-C) and cardiovascular prevention, the atherogenicity of lipoprotein(a) and the impact of triglyceride (TG)-rich lipoproteins cannot be overlooked. Within this landscape, the use of RNA-based therapies can help the treatment of difficult to target lipid disorders.
RECENT FINDINGS
The safety and efficacy of LDL-C lowering with the siRNA inclisiran has been documented in the open-label ORION-3 trial, with a follow-up of 4 years. While the outcome trial is pending, a pooled analysis of ORION-9, ORION-10, and ORION-11 has shown the potential of inclisiran to reduce composite major adverse cardiovascular events. Concerning lipoprotein(a), data of OCEAN(a)-DOSE trial with olpasiran show a dose-dependent drop in lipoprotein(a) levels with an optimal pharmacodynamic profile when administered every 12 weeks. Concerning TG lowering, although ARO-APOC3 and ARO-ANG3 are effective to lower apolipoprotein(apo)C-III and angiopoietin-like 3 (ANGPTL3) levels, these drugs are still in their infancy. In the era moving toward a personalized risk management, the use of siRNA represents a blossoming armamentarium to tackle dyslipidaemias for ASCVD risk reduction.
Topics: Humans; Cholesterol, LDL; RNA, Small Interfering; Dyslipidemias; Atherosclerosis; Lipoprotein(a); Cardiovascular Diseases; Angiopoietin-Like Protein 3
PubMed: 37792132
DOI: 10.1007/s11883-023-01156-5 -
International Immunopharmacology Jul 2023Atherosclerosis is the pathological basis of acute cardiovascular and cerebrovascular diseases. Oxidized LDL has been recognized as a major atherogenic factor in the... (Review)
Review
Atherosclerosis is the pathological basis of acute cardiovascular and cerebrovascular diseases. Oxidized LDL has been recognized as a major atherogenic factor in the vessel wall for decades. A growing body of evidence suggests that oxidized LDL modulates macrophage phenotypes in atherosclerosis. This article reviews the research progress on the regulation of macrophage polarization by oxidized LDL. Mechanistically, oxidized LDL induces macrophage polarization via cell signaling, metabolic reprogramming, epigenetic regulation, and intercellular regulation. This review is expected to provide new targets for the treatment of atherosclerosis.
Topics: Humans; Epigenesis, Genetic; Lipoproteins, LDL; Atherosclerosis; Macrophages
PubMed: 37210916
DOI: 10.1016/j.intimp.2023.110338 -
Journal of Immunology (Baltimore, Md. :... Nov 2023Lipid accumulation in macrophages (Mφs) is a hallmark of atherosclerosis, yet how lipid accumulation affects inflammatory responses through rewiring of Mφ metabolism...
Oxidized Low-Density Lipoprotein Accumulation Suppresses Glycolysis and Attenuates the Macrophage Inflammatory Response by Diverting Transcription from the HIF-1α to the Nrf2 Pathway.
Lipid accumulation in macrophages (Mφs) is a hallmark of atherosclerosis, yet how lipid accumulation affects inflammatory responses through rewiring of Mφ metabolism is poorly understood. We modeled lipid accumulation in cultured wild-type mouse thioglycolate-elicited peritoneal Mφs and bone marrow-derived Mφs with conditional (Lyz2-Cre) or complete genetic deficiency of Vhl, Hif1a, Nos2, and Nfe2l2. Transfection studies employed RAW264.7 cells. Mφs were cultured for 24 h with oxidized low-density lipoprotein (oxLDL) or cholesterol and then were stimulated with LPS. Transcriptomics revealed that oxLDL accumulation in Mφs downregulated inflammatory, hypoxia, and cholesterol metabolism pathways, whereas the antioxidant pathway, fatty acid oxidation, and ABC family proteins were upregulated. Metabolomics and extracellular metabolic flux assays showed that oxLDL accumulation suppressed LPS-induced glycolysis. Intracellular lipid accumulation in Mφs impaired LPS-induced inflammation by reducing both hypoxia-inducible factor 1-α (HIF-1α) stability and transactivation capacity; thus, the phenotype was not rescued in Vhl-/- Mφs. Intracellular lipid accumulation in Mφs also enhanced LPS-induced NF erythroid 2-related factor 2 (Nrf2)-mediated antioxidative defense that destabilizes HIF-1α, and Nrf2-deficient Mφs resisted the inhibitory effects of lipid accumulation on glycolysis and inflammatory gene expression. Furthermore, oxLDL shifted NADPH consumption from HIF-1α- to Nrf2-regulated apoenzymes. Thus, we postulate that repurposing NADPH consumption from HIF-1α to Nrf2 transcriptional pathways is critical in modulating inflammatory responses in Mφs with accumulated intracellular lipid. The relevance of our in vitro models was established by comparative transcriptomic analyses, which revealed that Mφs cultured with oxLDL and stimulated with LPS shared similar inflammatory and metabolic profiles with foamy Mφs derived from the atherosclerotic mouse and human aorta.
Topics: Humans; Mice; Animals; NF-E2-Related Factor 2; Lipopolysaccharides; NADP; Macrophages; Lipoproteins, LDL; Glycolysis; Atherosclerosis; Hypercholesterolemia; Cholesterol; Antioxidants; Hypoxia-Inducible Factor 1, alpha Subunit
PubMed: 37756544
DOI: 10.4049/jimmunol.2300293 -
Current Opinion in Lipidology Aug 2023LDL in its oxidized form, or 'oxLDL', is now generally acknowledged to be highly proatherogenic and to play a significant role in atherosclerotic plaque formation.... (Review)
Review
PURPOSE OF REVIEW
LDL in its oxidized form, or 'oxLDL', is now generally acknowledged to be highly proatherogenic and to play a significant role in atherosclerotic plaque formation. Therefore, there has been increasing interest in understanding the significance of oxLDL and its receptors in different phases of atherosclerosis, leading to the accumulation of additional data at the cellular, structural, and physiological levels. This review focuses on the most recent discoveries about these receptors and how they influence lipid absorption, metabolism, and inflammation in various cell types.
RECENT FINDINGS
Two crystal structures of lectin-like oxLDL receptor-1 (LOX-1), one with a small molecule inhibitor and the other with a monoclonal antibody have been published. We recently demonstrated that the 'surface site' of LOX1, adjacent to the positively charged 'basic spine region' that facilitates oxLDL binding, is a targetable site for drug development. Further, recent human studies showed that soluble LOX-1 holds potential as a biomarker for cardiovascular disease diagnosis, prognosis, and assessing the efficacy of therapy.
SUMMARY
Receptor-mediated oxLDL uptake results in cellular dysfunction of various cell types involved in atherogenesis and plaque development. The current advancements clearly demonstrate that targeting oxLDL-LOX-1 axis may lead to development of future therapeutics for the treatment of atherosclerotic cardiovascular and cerebrovascular diseases.
Topics: Humans; Receptors, Oxidized LDL; Scavenger Receptors, Class E; Atherosclerosis; Plaque, Atherosclerotic; Lipoproteins, LDL; Inflammation; Receptors, LDL
PubMed: 37171285
DOI: 10.1097/MOL.0000000000000884 -
Current Atherosclerosis Reports Nov 2023Recent large clinical trials have failed to show that triglyceride-rich lipoprotein-lowering therapies decrease the risk of atherosclerotic cardiovascular disease... (Review)
Review
PURPOSE OF REVIEW
Recent large clinical trials have failed to show that triglyceride-rich lipoprotein-lowering therapies decrease the risk of atherosclerotic cardiovascular disease (ASCVD). In this review, we reconcile these findings with evidence showing that elevated levels of triglyceride-rich lipoproteins and the cholesterol they contain, remnant cholesterol, cause ASCVD alongside low-density lipoprotein (LDL) cholesterol.
RECENT FINDINGS
Results from observational epidemiology, genetic epidemiology, and randomized controlled trials indicate that lowering of remnant cholesterol and LDL cholesterol decrease ASCVD risk by a similar magnitude per 1 mmol/L (39 mg/dL) lower non-high-density lipoprotein cholesterol (remnant cholesterol+LDL cholesterol). Indeed, recent guidelines for ASCVD prevention recommend the use of non-high-density lipoprotein cholesterol instead of LDL cholesterol. Current consensus is moving towards recognizing remnant cholesterol and LDL cholesterols as equals per 1 mmol/L (39 mg/dL) higher levels in the risk assessment of ASCVD; hence, triglyceride-rich lipoprotein-lowering therapies should also lower levels of non-HDL cholesterol to reduce ASCVD risk.
Topics: Humans; Cholesterol, LDL; Triglycerides; Lipoproteins; Cholesterol; Atherosclerosis
PubMed: 37768410
DOI: 10.1007/s11883-023-01153-8