Search Results (4,921)

We investigated the roles of low-density lipoprotein receptor-related protein (LRP) 4 and its ligand Agrin in the pathophysiology of cartilage degeneration. Immunohistochemical analysis of human normal articular cartilage and cartilage tissues from patients with osteoarthritis (OA) obtained during surgery of the knee joint showed marked LRP4 expression in the early stages of OA, which then decreased with cartilage degeneration, whereas Agrin was consistently increased with cartilage degeneration. In normal human articular chondrocytes (NHACs), mild cyclic tensile strain (CTS) (0.5 Hz, 5% elongation, 2 h) increased the expression of LRP4 and aggrecan (ACAN), while intense CTS (0.5 Hz, 10% elongation, 6 h) increased the expression of Agrin without affecting LRP4 expression. Treatment with recombinant human (rh) Agrin downregulated the mRNA expression of LRP4 and ACAN, but upregulated the expression of LRP5/6, SRY-box transcription factor 9 (SOX9), Runt-related transcription factor 2 (RUNX2), and a disintegrin and metalloproteinase with thrombospondin motifs-4 (ADAMTS-4). Immunocytochemistry and Western blot analysis showed that rhAgrin treatment upregulated the expression of β-catenin and SOX9. Agrin knockdown by siAGRN transfection partially reduced the nuclear protein expression of β-catenin, which was increased with intense CTS. LRP4 knockdown by siLRP4 transfection increased the expression of LRP5/6, SOX9, RUNX2, ADAMTS-4, and Agrin. These results suggested that intense CTS increases the expression of Agrin, which might interfere with the role of LRP4 in the inhibition of LRP5/6 and their downstream β-catenin signaling, leading to cartilage degeneration. Full article

Background: PCSK9 inhibitors (PCSK9i) represent a newer form of atherosclerosis treatment. Inflammation and haemostasis are key processes in the development of atherosclerosis. In this study, we investigated the influence of therapy with PCSK9i in patients with coronary artery disease (CAD) on regulators for lipoprotein homeostasis, inflammation and coagulation. Methods: Using quantitative polymerase chain reaction (qPCR), we measured the expression of the genes involved in lipoprotein homeostasis, namely for sterol regulatory element-binding protein 1 (SREBP1), SREBP2, low-density lipoprotein receptor (LDLR), hepatic lipase type C (LIPC), LDLR-related protein 8 (LRP8), and the genes associated with inflammation and coagulation, such as cluster of differentiation (CD) 36 (CD36), CD63, and CD14 in 96 patients with CAD and 25 healthy subjects. Results: Significant differences in the expression of the investigated genes between patients and healthy controls were found. Treatment with PCSK9i also resulted in significant changes in the expression of all studied genes. Conclusions: We established that PCSK9i may have a significant effect on the gene expression of lipid regulators, inflammatory markers, and coagulation parameters, independent of their lipolytic effect. Full article

This study aimed to investigate the effects of aerobic exercise (AE) on triglyceride (TG), total cholesterol (TC), high-density lipoprotein (HDL), and low-density lipoprotein (LDL) levels in people with overweight or obesity. Searches were performed in PubMed, Scopus, Cochrane, and Web of Science, covering data up to 27 October 2023. A meta-analysis was conducted to determine the standardized mean difference (SMD) and 95% confidence interval. Nineteen studies met the inclusion criteria. AE significantly improved blood lipids in people with overweight or obesity (TG: SMD = −0.54; p < 0.00001; TC: SMD = −0.24; p = 0.003; HDL: SMD = 0.33; p = 0.003; LDL: SMD = −0.42; p = 0.0005). Both moderate-intensity and vigorous-intensity AE demonstrated significant impacts in reducing TC, TG, and LDL, whereas only moderate-intensity exercise significantly elevated HDL. Additionally, AE significantly optimized blood lipids in those with overweight, with TG being the only parameter showing improvement in individuals with obesity. Moreover, continuous AE notably improved HDL and TG, while interval AE significantly reduced TG, TC, and LDL. Lastly, a clear positive correlation emerged between the duration of the intervention and the decrease in LDL, and a distinct negative correlation was observed between session duration and the reduction of LDL. Full article

Background/Objectives: An elevated lipoprotein(a) [Lp(a)] level, which is a prevalent cardiovascular risk factor, is genetically determined by a size polymorphism of its apolipoprotein(a) [apo(a)] component. Despite its genetic control, Lp(a) level increases in response to dietary saturated fat (SFA) reduction. We tested the roles of apo(a) size and characteristics in modulating Lp(a) response to SFA reduction. Methods: We assessed apo(a) characteristics in 165 African Americans experiencing a 24% Lp(a) increase resulting from SFA reduction [16% at an average American Diet diet (AAD) to 6% at a DASH-type diet]. Apo(a) effects were tested based on the following factors: (1) the presence of a small atherogenic size (≤22 kringles), (2) phenotype (single or two isoforms), (3) isoform dominance, and (4) tertiles of combined kringle sizes. Results: There were no significant differences in Lp(a) increases between carriers vs. non-carriers of a small apo(a), between those with a single vs. two expressed isoforms, or in those with differing isoform dominance patterns (p > 0.05 for all). The extent of Lp(a) increase differed across increasing tertiles of combined kringle sizes (p = 0.006 for trend). In a multivariate model, the AAD Lp(a) level was a significant predictor of Lp(a) changes (p < 0.05). Relative increases in the allele-specific apo(a) level—an Lp(a) level associated with a defined apo(a) size—were similar across the apo(a) size spectrum. Conclusions: Reducing dietary SFA intake results in a 24% increase in Lp(a) level in African Americans across apo(a) sizes. Individuals with smaller apo(a) sizes reached an elevated Lp(a) level post-intervention compared to those with larger sizes, in some cases resulting in cardiovascular risk reclassification. Full article

Lysosomes in mammalian cells are recognized as key digestive organelles, containing a variety of hydrolytic enzymes that enable the processing of both endogenous and exogenous substrates. These organelles digest various macromolecules and recycle them through the autophagy–lysosomal system. Recent research has expanded our understanding of lysosomes, identifying them not only as centers of degradation but also as crucial regulators of nutrient sensing, immunity, secretion, and other vital cellular functions. The lysosomal pathway plays a significant role in vascular regulation and is implicated in diseases such as atherosclerosis. During atherosclerotic plaque formation, macrophages initially engulf large quantities of lipoproteins, triggering pathogenic responses that include lysosomal dysfunction, foam cell formation, and subsequent atherosclerosis development. Lysosomal dysfunction, along with the inefficient degradation of apoptotic cells and the accumulation of modified low-density lipoproteins, negatively impacts atherosclerotic lesion progression. Recent studies have highlighted that lysosomal dysfunction contributes critically to atherosclerosis in a cell- and stage-specific manner. In this review, we discuss the mechanisms of lysosomal biogenesis and its regulatory role in atherosclerotic lesions. Based on these lysosomal functions, we propose that targeting lysosomes could offer a novel therapeutic approach for atherosclerosis, shedding light on the connection between lysosomal dysfunction and disease progression while offering new insights into potential anti-atherosclerotic strategies. Full article

Background/Objectives: This research investigated the effects of myricitrin on hypercholesterolemia and non-alcoholic fatty liver disease (NAFLD) in mice given a high-cholesterol diet (HCD). Methods: C57BL/6J mice were maintained for 20 weeks on an HCD with or without myricitrin. Results: Myricitrin had no impact on the food consumption, body weight, or plasma triglyceride concentrations. However, myricitrin-supplemented mice had lower plasma total cholesterol (TC) concentrations and LDL + VLDL-cholesterol/TC proportion, and higher HDL-cholesterol/TC proportion than control mice, which resulted in a markedly decreased atherogenic index. Moreover, the levels of plasma C-reactive protein, oxidized LDL, lipoprotein(a), and plasminogen activator inhibitor-1, which are indicators for cardiovascular disease (CVD), were reduced, while levels of plasma paraoxonase, a cardioprotective enzyme, were greater in myricitrin-supplemented mice than in control mice. Myricitrin also meaningfully reduced liver weight and hepatic cholesterol content, and slightly alleviated fatty liver and fibrosis caused by an HCD. The plasma and hepatic cholesterol-lowering effects of myricitrin were partly associated with decreased activities of hepatic 3-hydroxy-3-methylglutaryl-CoA reductase and acyl-CoA:cholesterol acyltransferase, which are involved in cholesterol synthesis and esterification, respectively, as well as mRNA expression. Myricitrin also altered other hepatic genes implicated in cholesterol homeostasis, including the downregulation of SREBP2 and ABCA1 mRNA expression and the upregulation of LDLR mRNA expression. Moreover, myricitrin decreased TBARS levels in the liver and erythrocytes by activating antioxidant enzymes (SOD and catalase). Conclusions: These results indicate that dietary myricitrin may offer therapeutic benefits for HCD-caused hypercholesterolemia and NAFLD, and may help reduce CVD risk. Full article

Background: Pseudohypertriglyceridemia (pseudo-HTG) is a condition in patients with glycerol kinase deficiency or other disorders of glycerol metabolism, as well as in individuals with alcoholism, severe liver disease, or metabolic disturbances, and those receiving heparin therapy. Exogenous glycerol intake can also trigger this condition. However, the causes of pseudo-HTG are poorly understood, and a clinical algorithm for its diagnosing remains to be developed. Case presentation: We present the case of a 46-year-old man admitted to hospital with hypertriglyceridemia-induced severe acute pancreatitis (HTG-SAP) and type 2 diabetes mellitus. Upon admission, his plasma triglyceride (TG) level was critically high at 43.78 mmol/L (3877 mg/dL). During hospitalization, he developed acute renal insufficiency and diabetic ketoacidosis (DKA). Despite conventional lipid-lowering treatments, including extracorporeal lipoprotein apheresis, his TG levels remained elevated. The unusually clear serum led to suspicion of pseudo-HTG. A glycerol-corrected TG assay confirmed normal TG values, thereby diagnosing pseudo-HTG. Conclusions: This report presents the first confirmed case of pseudo-HTG verified through definitive glycerol kinase (GK) gene testing in a patient without glycerol kinase deficiency. We also include a review of the relevant literature and propose a clinical algorithm. The case report highlights the importance of considering pseudo-HTG in hypertriglyceridemia patients who do not respond well to the standard TG-lowering treatment. Our proposed clinical algorithm for diagnosing pseudo-HTG is potentially invaluable in clinical practice, and helps to prevent unnecessary lipid-lowering treatments for patients with pseudo-HTG. Full article

Hypertriglyceridemia (HTG) is associated with a residual risk of atherosclerotic cardiovascular disease. Extremely elevated triglyceride (TG) concentrations, particularly due to familial chylomicronemia syndrome (FCS), pose a risk for acute pancreatitis. Standard therapies with statins, fibrates, omega-3 fatty acids, and niacin may be insufficient to reduce elevated TG levels and improve clinical outcomes in patients with HTG. Novel antisense oligonucleotides and small interfering ribonucleic acids target the key modulators of TG-rich lipoprotein catabolism. Among apolipoprotein C-III (apoC-III) inhibitors, olezarsen and plozasiran appear to be safer alternatives for volanesorsen regarding the risk of drug-induced thrombocytopenia in patients with FCS or severe HTG. After the failure of vupanorsen, a new angiopoietin-like protein 3 (ANGPTL3) inhibitor, zodasiran, demonstrated the potential to decrease TG levels in patients with moderate HTG. Meanwhile, the fibroblast growth factor 21 (FGF21) analog, pegozafermin, became another candidate for the treatment of severe HTG. This comprehensive review outlines pharmacological targets in TG-rich lipoprotein metabolism, discusses international guidelines, and summarizes the latest evidence from clinical trials to provide insight into the current and emerging treatment options for primary HTG. Full article

Background: Metabolic-dysfunction-associated steatotic liver disease (MASLD) and obesity contribute to vascular dysfunction through oxidative stress, heightening cardiovascular risk. Oral supplementation with L-citrulline (L-cit), a precursor of L-arginine (L-arg) and nitric oxide, and high-intensity interval training (HIIT) may improve vascular function and cardiometabolic health. Objectives: This study aimed to evaluate the combined effects of L-cit supplementation and HIIT on arterial stiffness, body composition, glucose metabolism, lipid profile, and blood pressure (BP) in adolescents with MASLD and obesity. Methods: In this double-blind, placebo-controlled, randomized clinical trial (ClinicalTrials.gov (NCT05778266), 44 adolescents (15–19 years) with MASLD and obesity were assigned to HIIT + L-cit (n = 14), HIIT + placebo (n = 14), or L-cit (n = 15) for 12 weeks. HIIT sessions (85% and 60% peak heart rate during intense and recovery periods) occurred thrice weekly. Training volume progressively increased, and participants performed 20 min of HITT per session in the last 8 weeks. Results: Outcomes included pulse wave velocity (PWV), augmentation index (Aix75), VO2peak, body composition, BP, glucose and lipid profiles, and hepatic steatosis. Compared to L-cit, HIIT + L-cit improved non-high-density lipoprotein cholesterol (p = 0.04), very-low-density lipoprotein cholesterol (p = 0.01), triglycerides (p = 0.02), and VO2peak (p = 0.001). No significant between-group changes were found in PWV, AIx75, hepatic steatosis, and body composition. HIIT + placebo improved VO2peak (p = 0.002), and L-cit decreased the degree of steatosis (p = 0.038). Conclusions: HIIT + L-cit supplementation enhanced lipid profile and cardiorespiratory fitness, while HIIT + placebo improved cardiorespiratory capacity, and L-cit alone decreased hepatic steatosis. Thus, L-cit could be an adjuvant strategy to manage obesity-related MASLD in adolescents. Full article

Background/Objectives: Salt-based density gradient ultracentrifugation (SBUC) is frequently used to isolate lipoproteins for their subsequent analysis. However, the addition of salts may disrupt their molecular composition. Therefore, the aim of the present study was to assess the impact of SBUC upon the molecular composition of low-density lipoprotein (LDL) particles, compared to a validated non-salt method involving iodixanol gradient ultracentrifugation (IGUC). Methods: Whole human plasma was analysed for various lipid parameters before LDL particles were isolated using both SBUC and IGUC methods. Each fraction was then filtered to obtain low-molecular-weight compounds. The LDL molecular content of the resulting fractions from both methods was determined using untargeted liquid chromatography–mass spectrometry (LC-MS) in positive and negative modes. Results: A total of 1041 and 401 features were putatively identified using positive and negative modes, respectively. Differences were shown in the molecular composition of LDL prepared using SBUC and IGUC; in positive mode ionisation, the PLS-DA model showed reasonable fit and discriminatory power (R2 = 0.63, Q2 = 0.58, accuracy 0.88) and permutation testing was significant (p < 0.001). Conclusions: The findings reveal distinct differences in the small molecule composition of LDL prepared using the two methods, with IGUC exhibiting greater variation. In negative mode, both methods detected phospholipids, long-chain sphingolipids, and ceramides, but IGUC showed higher fold differences for some phospholipids. However, in positive mode, non-native brominated adducts were found in LDL isolated using SBUC and evidence of potential bacterial contamination was discovered in samples prepared using IGUC, both of which have the capacity to affect in vitro experiments. Full article

Lipoprotein(a) [Lp(a)] is a well-established causal risk factor for cardiovascular diseases (CVDs), as reported by multiple Mendelian randomization studies and large epidemiological studies. When elevated Lp(a) is combined with other risk factors, most notably elevated low-density lipoprotein cholesterol (LDL-C), a synergistic atherogenic effect has been reported. However, the current literature is conflicting regarding how Lp(a) interacts in the context of controlled LDL-C levels (e.g., <70 mg/dL) and whether reducing LDL-C can modify the atherogenic effect of Lp(a). In some studies, elevated Lp(a) was still significantly associated with a higher risk of cardiovascular events, despite controlled levels of LDL-C. In contrast, multiple studies have reported attenuation of the cardiovascular risk mediated by elevated Lp(a) with lower LDL-C levels. Moreover, the relationship between Lp(a) and triglycerides, high-density lipoprotein, and very low-density lipoprotein remains unclear. In this literature review, we summarize and discuss the current evidence regarding the interactions between Lp(a) and other lipid molecules, how they contribute to the pathogenesis of CVD, and future perspectives, particularly in the current era where promising targeted Lp(a)-lowering therapies are under development. Full article

Objectives: Since obesity and overweight are strongly associated with cardiovascular diseases, we investigated cardiovascular events risk in individuals who lost weight through bariatric surgery. Methods: Serum levels of glucose, insulin, triacylglycerol, HDL cholesterol, non-HDLDL cholesterol, and lipoprotein ratios were assessed in patients with obesity before and after bariatric surgery, including a 6-month follow-up period. Results: Bariatric surgery significantly improved BMI, triglyceride levels, glucose, and insulin sensitivity. However, HDL cholesterol levels dropped sharply in the first month (p < 0.0001), coinciding with elevated atherogenic indices, indicating a transient increase in cardiovascular risk. By 6 months, indices improved significantly, HDL recovered, and LDL particle size increased, suggesting reduced atherogenic potential. Conclusions: Individuals undergoing bariatric surgery have a higher cardiovascular events risk in the immediate postoperative period. Health professionals should be aware of and monitor these patients closely. Full article

Morphogens, which are non-classical transcription factors, according to several studies, display a crucial role in tissue patterning, organ architecture establishment, and human disease pathogenesis. Recent advances have expanded the morphogen participation to a wide range of human diseases. There are many genetic syndromes caused by mutations of components of morphogen signaling pathways. The aberrant morphogen pathways also promote cancer cell maintenance, renewal, proliferation, and migration. On the other hand, exosomes and their application in the biomedical field are of evolving significance. The evidence that membrane structures participate in the creation of morphogenic gradience and biodistribution of morphogen components renders them attractive as new therapeutic tools. This intercellular morphogen transport is performed by cell-derived structures, mainly exosomes and cytonemes, and extracellular substances like heparan sulphate proteoglycans and lipoproteins. The interaction between morphogens and Extracellular Vesicles has been observed at first in the most studied insect, Drosophila, and afterwards analogous findings have been proved in vertebrates. This review presents the protagonists and mechanisms of lipid-modified morphogens (Hedgehog and Wnt/β-catenin) biodistribution. Full article

Background/Objectives: Evolocumab inhibits proprotein convertase subtilisin/kexin type 9 (PCSK9) binding to low-density lipoprotein (LDL) receptors, thus allowing more LDL receptors to remove LDL cholesterol from the blood. We aimed to determine the effects of evolocumab on the plasma lipid profile, reactive oxygen species (ROS), and nitric oxide (NO) generation in the heart of adult male obese Zucker rats. Methods: The rats were divided into lean and obese controls and obese rats treated with evolocumab subcutaneously at a dose of 10 mg/kg every two weeks. After 6 weeks, the lipid profile was determined in the plasma, and NO synthase (NOS) activity, thiobarbituric acid reactive substance (TBARS), conjugated diene (CD) concentration, and protein expression of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, nuclear factor kappaB (NF-κB), endothelial NOS (eNOS), and phosphorylated eNOS (peNOS) were measured in the heart. Results: Evolocumab treatment did not reduce body weight, relative heart weight, or systolic blood pressure in obese Zucker rats. Evolocumab treatment, however, reduced plasma LDL levels, TBARS, and CD concentrations along with decreasing expression of NADPH oxidase and NF-kappaB proteins in the heart. On the other hand, evolocumab had no effect on NOS activity or eNOS and peNOS protein expression. Conclusions: Besides its lipid-lowering effect, evolocumab may exert antioxidant properties and protect cardiomyocytes from lipid peroxidation while not affecting NO production. Full article

Background/Objectives: Familial hypercholesterolemia (FH) is a monogenic dyslipidemia that leads to early cardiovascular events. Subclinical atherosclerosis refers to the formation of atheromatous plaques in arterial beds before any clinical events. In our study, we investigated the presence, extent, and independent predictors of subclinical atherosclerosis among patients diagnosed with FH. Methods: This was a single-center, prospective, and cross-sectional study. This original study included 215 patients diagnosed with FH from a cohort of 1145 individuals assessed according to the Dutch Lipid Clinical Network (DLCN) criteria. Carotid and femoral ultrasonography were performed, and the coronary artery calcium score was measured to screen for subclinical atherosclerosis. Apolipoprotein A-I, apolipoprotein B, and lipoprotein (a) were analyzed using the nephelometric method. Results: The study cohort comprised 136 females (63%) with a mean age of 54 (43–62) years. The stigmata rate was 18%. The rate of statin use during subclinical atherosclerosis screening was 32% and only eight patients (4%) attained LDL-C values < 70 mg/dL. Subclinical atherosclerosis was observed in 148 patients (69%), with rates of 48%, 47.5%, and 40.5% in the coronary arteries, carotid bifurcation, and femoral bifurcation, respectively. Advanced age, male sex, high pretreatment low-density lipoprotein-cholesterol (LDL-C) level, diabetes, and a low Apo A-I/Apo B ratio were identified as independent predictors of subclinical atherosclerosis. Lp(a) levels ≥ 30 mg/dL predicted coronary atherosclerosis, while diabetes and low Apo A-I/Apo B ratios predicted carotid atherosclerosis, and smoking predicted femoral atherosclerosis. Conclusions: Subclinical atherosclerosis is prevalent, and medication adherence remains suboptimal among FH patients. Screening for subclinical atherosclerosis may impact the treatment strategies, via an increase in physician commitment to treatment protocols and improving patient compliance. Full article