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Nonstatin therapy to reduce low-density lipoprotein cholesterol and improve cardiovascular outcomes.Cleveland Clinic Journal of Medicine Jan 2024Atherosclerotic cardiovascular disease (ASCVD) is a leading cause of morbidity and mortality, with low-density lipoprotein (LDL) cholesterol being a causative risk... (Review)
Review
Atherosclerotic cardiovascular disease (ASCVD) is a leading cause of morbidity and mortality, with low-density lipoprotein (LDL) cholesterol being a causative risk factor. Though statins have a decades-long track record of efficacy and safety, nonstatin agents may be used to reduce LDL cholesterol as an adjunct or alternative to statin therapy. Several new nonstatin medications have been approved in recent years, with robust data from clinical trials supporting their use in atherosclerotic disease. This review addresses the indications, evidence, and important prescribing considerations for using nonstatin lipid-lowering therapy and proposes a practical approach for determining when to initiate nonstatin therapy.
Topics: Humans; Cholesterol, LDL; Cardiovascular Diseases; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Cholesterol; Risk Factors; Atherosclerosis
PubMed: 38167398
DOI: 10.3949/ccjm.91a.23058 -
Journal of Innate Immunity 2024Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) is known as a major receptor for oxidized low-density lipoproteins (oxLDL) and plays a significant role... (Review)
Review
BACKGROUND
Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) is known as a major receptor for oxidized low-density lipoproteins (oxLDL) and plays a significant role in the genesis of atherosclerosis. Recent research has shown its involvement in cancer, ischemic stroke, and diabetes. LOX-1 is a C-type lectin receptor and is involved in the activation of immune cells and inflammatory processes. It may further interact with pathogens, suggesting a role in infections or the host's response.
SUMMARY
This review compiles the current knowledge of potential implications of LOX-1 in inflammatory processes and in host-pathogen interactions with a particular emphasis on its regulatory role in immune responses. Also discussed are genomic and structural variations found in LOX-1 homologs across different species as well as potential involvements of LOX-1 in inflammatory processes from the angle of different cell types and organ-specific interactions.
KEY MESSAGES
The results presented reveal both similar and different structures in human and murine LOX-1 and provide clues as to the possible origins of different modes of interaction. These descriptions raise concerns about the suitability, particularly of mouse models, that are often used in the analysis of its functionality in humans. Further research should also aim to better understand the mostly unknown binding and interaction mechanisms between LOX-1 and different pathogens. This pursuit will not only enhance our understanding of LOX-1 involvement in inflammatory processes but also identify potential targets for immunomodulatory approaches.
Topics: Animals; Humans; Mice; Atherosclerosis; Host-Pathogen Interactions; Inflammation; Lipoproteins, LDL; Scavenger Receptors, Class E
PubMed: 38232720
DOI: 10.1159/000535793 -
Life Science Alliance Jul 2023Viruses with an RNA genome are often the cause of zoonotic infections. In order to identify novel pro-viral host cell factors, we screened a haploid...
Viruses with an RNA genome are often the cause of zoonotic infections. In order to identify novel pro-viral host cell factors, we screened a haploid insertion-mutagenized mouse embryonic cell library for clones that are resistant to Rift Valley fever virus (RVFV). This screen returned the low-density lipoprotein receptor-related protein 1 (LRP1) as a top hit, a plasma membrane protein involved in a wide variety of cell activities. Inactivation of in human cells reduced RVFV RNA levels already at the attachment and entry stages of infection. Moreover, the role of LRP1 in promoting RVFV infection was dependent on physiological levels of cholesterol and on endocytosis. In the human cell line HuH-7, LRP1 also promoted early infection stages of sandfly fever Sicilian virus and La Crosse virus, but had a minor effect on late infection by vesicular stomatitis virus, whereas encephalomyocarditis virus was entirely LRP1-independent. Moreover, siRNA experiments in human Calu-3 cells demonstrated that also SARS-CoV-2 infection benefitted from LRP1. Thus, we identified LRP1 as a host factor that supports infection by a spectrum of RNA viruses.
Topics: Animals; Humans; Mice; Low Density Lipoprotein Receptor-Related Protein-1; COVID-19; SARS-CoV-2; Rift Valley fever virus; RNA, Small Interfering; Lipoproteins, LDL
PubMed: 37072184
DOI: 10.26508/lsa.202302005 -
Biomolecules & Biomedicine Jul 2023Atherosclerosis is a chronic process characterized by inflammation and the progressive accumulation of inflammatory cells and lipids in the blood vessel wall, resulting... (Review)
Review
Atherosclerosis is a chronic process characterized by inflammation and the progressive accumulation of inflammatory cells and lipids in the blood vessel wall, resulting in narrowing of the blood vessel's circumference. Treatment of people with dyslipidemia aims to reduce the risk of developing atherosclerotic disease and prevent major adverse cardiovascular events (MACE). The results of previous studies indicated that lipoprotein(a) (Lp(a)) is a critical causal factor in the estimated risk of developing a cardiovascular (CV) incident even after achieving desirable low-density lipoprotein (LDL) cholesterol levels. Lp(a) is a low-density lipoprotein particle, like LDL cholesterol. The levels of Lp(a) in plasma are genetically determined. Lp(a) catabolism is still controversial. The pathogenic potential of Lp(a) can be divided into three categories: promotion of plaque formation, thrombogenicity, and proinflammatory effects. Lp(a) levels above the 75th percentile reduced the risk of aortic valve stenosis and myocardial infarction, whereas higher levels (above 90th percentile) were associated with an increased risk of heart failure. However, no hypolipidemic agents have been approved for targeted use in patients with high Lp(a) levels. There are insufficient randomized controlled trials assessing CV outcomes that would support the evidence that current treatment options, which effectively lower Lp(a) levels, also effectively prevent CV event. However, according to some studies, there is strong evidence that better CV outcome is one of the benefits of such therapy. The results of ongoing clinical trials are eagerly awaited.
Topics: Humans; Lipoprotein(a); Risk Factors; Atherosclerosis; Myocardial Infarction; Cholesterol, LDL
PubMed: 37183706
DOI: 10.17305/bb.2023.8992 -
Journal of the American Heart... Jul 2023Background We aimed to examine separate and joint associations of remnant cholesterol (RC) accumulation and variability with the risk of carotid atherosclerosis (CAS) in...
Background We aimed to examine separate and joint associations of remnant cholesterol (RC) accumulation and variability with the risk of carotid atherosclerosis (CAS) in the general population. Methods and Results A total of 6213 participants who underwent 3 sequential health examinations during 2010 to 2015 were enrolled and were followed up until December 31, 2021. Cumulative RC (cumRC) and RC variability among the 3 visits were the exposure of interest in our study. Adjusted Cox models were performed to calculate the hazard ratio (HR) and 95% CI. C-statistics, integrated discrimination improvement, and the net reclassification index were used to estimate the incremental predictive ability. During a median follow-up of 4.00 years, 2613 participants developed CAS. Higher cumRC (HR, 1.33 [95% CI, 1.17-1.52]) and greater RC variability (HR, 1.22 [95% CI, 1.08-1.39]) were significantly associated with elevated risk of CAS, independent of traditional cardiovascular risk factors and low-density lipoprotein cholesterol. Participants were divided into 4 groups according to the median of cumRC and RC variability to assess their joint associations. Compared with "low cumRC and low variability," "high cumRC and high variability" had the highest risk of CAS, followed by "high cumRC and low variability" and "low cumRC and high variability." Finally, joint assessment of RC accumulation and variability had the significantly highest incremental effect on the predictive value of CAS versus single-time-point measures of RC. Conclusions Excessive cumRC levels and greater RC variability were each independently associated with higher incidence of CAS, and their coexistence could further yield significantly higher risks.
Topics: Humans; Risk Factors; Prospective Studies; Cholesterol; Cholesterol, LDL; Carotid Artery Diseases
PubMed: 37449561
DOI: 10.1161/JAHA.122.029352 -
Journal of Virology Jan 2024Pseudorabies virus (PRV) is the causative agent of Aujeszky's disease in pigs. The low-density lipoprotein receptor (LDLR) is a transcriptional target of the...
Pseudorabies virus (PRV) is the causative agent of Aujeszky's disease in pigs. The low-density lipoprotein receptor (LDLR) is a transcriptional target of the sterol-regulatory element-binding proteins (SREBPs) and participates in the uptake of LDL-derived cholesterol. However, the involvement of LDLR in PRV infection has not been well characterized. We observed an increased expression level of LDLR mRNA in PRV-infected 3D4/21, PK-15, HeLa, RAW264.7, and L929 cells. The LDLR protein level was also upregulated by PRV infection in PK-15 cells and in murine lung and brain. The treatment of cells with the SREBP inhibitor, fatostatin, or with SREBP2-specific small interfering RNA prevented the PRV-induced upregulation of LDLR expression as well as viral protein expression and progeny virus production. This suggested that PRV activated SREBPs to induce LDLR expression. Furthermore, interference in LDLR expression affected PRV proliferation, while LDLR overexpression promoted it. This indicated that LDLR was involved in PRV infection. The study also demonstrated that LDLR participated in PRV invasions. The overexpression of LDLR or inhibition of proprotein convertase subtilisin/kexin type 9 (PCSK9), which binds to LDLR and targets it for lysosomal degradation, significantly enhanced PRV attachment and entry. Mechanistically, LDLR interacted with PRV on the plasma membrane, and pretreatment of cells with LDLR antibodies was able to neutralize viral entry. An study indicated that the treatment of mice with the PCSK9 inhibitor SBC-115076 promoted PRV proliferation. The data from the study indicate that PRV hijacks LDLR for viral entry through the activation of SREBPs.IMPORTANCEPseudorabies virus (PRV) is a herpesvirus that primarily manifests as fever, pruritus, and encephalomyelitis in various domestic and wild animals. Owing to its lifelong latent infection characteristics, PRV outbreaks have led to significant financial setbacks in the global pig industry. There is evidence that PRV variant strains can infect humans, thereby crossing the species barrier. Therefore, gaining deeper insights into PRV pathogenesis and developing updated strategies to contain its spread are critical. This study posits that the low-density lipoprotein receptor (LDLR) could be a co-receptor for PRV infection. Hence, strategies targeting LDLR may provide a promising avenue for the development of effective PRV vaccines and therapeutic interventions.
Topics: Animals; Humans; Mice; Herpesvirus 1, Suid; Lipoproteins, LDL; Proprotein Convertase 9; Pseudorabies; Swine; Swine Diseases; Virus Internalization; Cell Line
PubMed: 38054618
DOI: 10.1128/jvi.01664-23 -
Archivos Espanoles de Urologia Apr 2024This work aimed to investigate the potential role of abnormal lipid metabolism in the development of prostate cancer (PCa).
BACKGROUND
This work aimed to investigate the potential role of abnormal lipid metabolism in the development of prostate cancer (PCa).
METHODS
A retrospective study design was used. The clinical data of 520 patients who underwent rectal prostate biopsy in our hospital from January 2020 to June 2023 were analysed. The patients were enrolled and divided into the anterior PCa group including 112 patients and benign prostatic hyperplasia (BPH) group including 408 patients. Univariate and multivariate logistic regression analyses were performed for the two patient groups, and further comparisons were made according to the Gleason score and TNM staging.
RESULTS
Low-density lipoprotein cholesterol (LDL-C) level may be an independent risk factor for PCa, and it was significantly associated with the risk of PCa (odds ratio (OR) = 1.363, = 0.030). Patients with PCa were further divided into the low risk group and the high risk group according to the Gleason score. Univariate analysis ( = 0.047) and logistic regression analysis (OR = 2.249, = 0.036) revealed that LDL-C was a significant factor influencing the Gleason score. Patients with PCa were categorised into four groups based on TNM staging. One-way analysis of variance (ANOVA) analysis ( = 0.015) and ordinal logistic regression analysis (OR = 2.414, = 0.007) demonstrated that LDL-C was a significant factor influencing TNM staging.
CONCLUSIONS
This study revealed the important role of LDL-C in the development of PCa, highlighting its influence as an independent risk factor. Thus, LDL-C may promote the proliferation and invasion of PCa cells.
Topics: Humans; Male; Retrospective Studies; Prostatic Neoplasms; Aged; Cholesterol, LDL; Middle Aged; Risk Factors; Neoplasm Grading; Neoplasm Staging
PubMed: 38715162
DOI: 10.56434/j.arch.esp.urol.20247703.30 -
Biomedicine & Pharmacotherapy =... Dec 2023CD36, a multifunctional glycoprotein, has been shown to play critical roles in tumor initiation, progression, metastasis, immune response, and drug resistance. CD36... (Review)
Review
CD36, a multifunctional glycoprotein, has been shown to play critical roles in tumor initiation, progression, metastasis, immune response, and drug resistance. CD36 serves as a receptor for a wide range of ligands, including lipid-related ligands (e.g., long-chain fatty acid (LCFA), oxidized low-density lipoprotein (oxLDL), and oxidized phospholipids), as well as protein-related ligands (e.g., thrombospondins, amyloid proteins, collagens I and IV). CD36 is overexpressed in various cancers and may act as an independent prognostic marker. While it was initially identified as a mediator of anti-angiogenesis through its interaction with thrombospondin-1 (TSP1), recent research has highlighted its role in promoting tumor growth, metastasis, drug resistance, and immune suppression. The varied impact of CD36 on cancer is likely ligand-dependent. Therefore, we focus specifically on the ligand-dependent role of CD36 in cancer to provide a critical review of recent advances, perspectives, and challenges.
Topics: Humans; Ligands; Neoplasms; CD36 Antigens; Drug Resistance; Immunity; Lipoproteins, LDL
PubMed: 37931517
DOI: 10.1016/j.biopha.2023.115834 -
Current Atherosclerosis Reports Feb 2024To discuss the history of cardiovascular outcomes trials of cholesteryl ester transfer protein (CETP) inhibitors and to describe obicetrapib, a next-generation, oral,... (Review)
Review
PURPOSE OF REVIEW
To discuss the history of cardiovascular outcomes trials of cholesteryl ester transfer protein (CETP) inhibitors and to describe obicetrapib, a next-generation, oral, once-daily, low-dose CETP inhibitor in late-stage development for dyslipidemia and atherosclerotic cardiovascular disease (ASCVD).
RECENT FINDINGS
Phase 1 and 2 trials have evaluated the safety and lipid/lipoprotein effects of obicetrapib as monotherapy, in conjunction with statins, on top of high-intensity statins (HIS), and with ezetimibe on top of HIS. In ROSE2, 10 mg obicetrapib monotherapy and combined with 10 mg ezetimibe, each on top of HIS, significantly reduced low-density lipoprotein cholesterol (LDL-C), non-high-density lipoprotein cholesterol (non-HDL-C), apolipoprotein B, total LDL particles, small LDL particles, small, dense LDL-C, and lipoprotein (a), and increased HDL-C. Phase 3 pivotal registration trials including a cardiovascular outcomes trial are underway. Obicetrapib has an excellent safety and tolerability profile and robustly lowers atherogenic lipoproteins and raises HDL-C. As such, obicetrapib may be a promising agent for the treatment of ASCVD.
Topics: Humans; Cholesterol Ester Transfer Proteins; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Cholesterol, LDL; Cholesterol, HDL; Atherosclerosis; Lipoproteins; Ezetimibe
PubMed: 38133847
DOI: 10.1007/s11883-023-01184-1 -
Journal of Diabetes Investigation Dec 2023Small dense low-density lipoprotein (sdLDL) is a more potent atherogenic lipoprotein than LDL. As sdLDL-cholesterol (C) levels are determined by triglyceride and LDL-C... (Randomized Controlled Trial)
Randomized Controlled Trial
Prospective randomized comparative study of the effect of pemafibrate add-on or double statin dose on small dense low-density lipoprotein-cholesterol in patients with type 2 diabetes and hypertriglyceridemia on statin therapy.
AIMS/INTRODUCTION
Small dense low-density lipoprotein (sdLDL) is a more potent atherogenic lipoprotein than LDL. As sdLDL-cholesterol (C) levels are determined by triglyceride and LDL-C levels, pemafibrate and statins can reduce sdLDL-C levels. However, it remains unclear whether adding pemafibrate or increasing statin doses would more effectively reduce sdLDL-C levels in patients receiving statin therapy.
MATERIALS AND METHODS
A total of 97 patients with type 2 diabetes and hypertriglyceridemia who were treated with statins were randomly assigned to the pemafibrate 0.2 mg/day addition or statin dose doubled, and followed for 12 weeks. sdLDL-C was measured by our established homogenous assay.
RESULTS
The percentage and absolute reductions of sdLDL-C levels were significantly greater in the pemafibrate add-on group than the statin doubling group (-32.8 vs -8.1%; -16 vs -3 mg/dL, respectively). Triglyceride levels were reduced only in the pemafibrate add-on group (-44%), and LDL-C levels were reduced only in the statin doubling group (-8%), whereas levels of non-high-density lipoprotein-C and apolipoprotein B were similarly decreased (7-9%) in both groups. The absolute reductions of sdLDL-C levels were closely associated with decreased triglyceride, LDL-C, non-high-density lipoprotein-C and apolipoprotein B. In the subgroup analysis, the effect of pemafibrate add-on on sdLDL-C reductions was observed irrespective of baseline lipid parameters or statin type. No serious adverse effects were observed in both groups.
CONCLUSIONS
In patients with type 2 diabetes and hypertriglyceridemia, the addition of pemafibrate to a statin is superior to doubling a statin in reducing sdLDL-C without increasing adverse effects.
Topics: Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Diabetes Mellitus, Type 2; Cholesterol, LDL; Prospective Studies; Hypertriglyceridemia; Triglycerides; Lipoproteins; Apolipoproteins
PubMed: 37647503
DOI: 10.1111/jdi.14076