ABSTRACT
Familial Hypercholesterolemia (FH) is an inherited disorder of lipid metabolism, characterized by increased low density lipoprotein cholesterol (LDLc) levels. The main purpose of the current work was to explore alternative classification methods to traditional clinical criteria for FH diagnosis, based on several biochemical and biological indicators. Logistic regression (LR), decision tree (DT), random forest (RF) and naive Bayes (NB) algorithms were developed for this purpose, and thresholds were optimized by maximization of Youden index (YI). All models presented similar accuracy (Acc), specificity (Spec) and positive predictive values (PPV). Sensitivity (Sens) and G-mean values were significantly higher in LR and RF models, compared to the DT. When compared to Simon Broome (SB) biochemical criteria for FH diagnosis, all models presented significantly higher Acc, Spec and G-mean values (p < 0.01), and lower negative predictive value (NPV, p < 0.05). Moreover, LR and RF models presented comparable Sens values. Adjustment of the cut-off point by maximizing YI significantly increased Sens values, with no significant loss in Acc. The obtained results suggest such classification algorithms can be a viable alternative to be used as a widespread screening method. An online application has been developed to assess the performance of the LR model in a wider population.
Subject(s)
Hyperlipoproteinemia Type II/diagnosis , Models, Biological , Adolescent , Algorithms , Bayes Theorem , Child , Child, Preschool , Cholesterol, LDL/blood , Early Diagnosis , Female , Humans , Hyperlipoproteinemia Type II/blood , Male , Predictive Value of Tests , Receptors, LDL/bloodABSTRACT
BACKGROUND: Monoclonal antibodies against proprotein convertase subtilisin/kexin type 9 (PCSK9i) lower LDL-C by up to 60% and increase plasma proprotein convertase subtilisin/kexin type 9 (PCSK9) levels by 10-fold. OBJECTIVES: The authors studied the reasons behind the robust increase in plasma PCSK9 levels by testing the hypothesis that mechanisms beyond clearance via the low-density lipoprotein receptor (LDLR) contribute to the regulation of cholesterol homeostasis. METHODS: In clinical cohorts, animal models, and cell-based studies, we measured kinetic changes in PCSK9 production and clearance in response to PCSK9i. RESULTS: In a patient cohort receiving PCSK9i therapy, plasma PCSK9 levels rose 11-fold during the first 3 months and then plateaued for 15 months. In a cohort of healthy volunteers, a single injection of PCSK9i increased plasma PCSK9 levels within 12 hours; the rise continued for 9 days until it plateaued at 10-fold above baseline. We recapitulated the rapid rise in PCSK9 levels in a mouse model, but only in the presence of LDLR. In vivo turnover and in vitro pulse-chase studies identified 2 mechanisms contributing to the rapid increase in plasma PCSK9 levels in response to PCSK9i: 1) the expected delayed clearance of the antibody-bound PCSK9; and 2) the unexpected post-translational increase in PCSK9 secretion. CONCLUSIONS: PCSK9 re-entry to the liver via LDLR triggers a sensing loop regulating PCSK9 secretion. PCSK9i therapy enhances the secretion of PCSK9, an effect that contributes to the increased plasma PCSK9 levels in treated subjects.
Subject(s)
Antibodies, Monoclonal/pharmacology , Liver/metabolism , PCSK9 Inhibitors/pharmacology , Proprotein Convertase 9/blood , Adult , Aged , Animals , Antibodies, Monoclonal/therapeutic use , Female , HEK293 Cells , Healthy Volunteers , Humans , Hypercholesterolemia/drug therapy , Lipid Metabolism/drug effects , Liver/drug effects , Male , Mice, Knockout , Middle Aged , PCSK9 Inhibitors/therapeutic use , Receptors, LDL/blood , Retrospective StudiesABSTRACT
INTRODUCTION: Epidemiological data indicate that one-third of the world's population have serological markers of hepatitis B virus infection. Hepatic steatosis is often observed in patients with chronic liver diseases. The exact mechanisms of hepatic steatosis progression and the efficacy of antiviral therapy in patients with CHB and hepatic steatosis are not yet fully understood. OBJECTIVE: The aim of the study was to investigate the LDLR concentration and degree of hepatic fibrosis and hepatic steatosis in patients with chronic hepatitis B infection during tenofovir disoproxil fumarate therapy. MATERIAL AND METHODS: The study group consisted of 54 patients with CHB. The LDLR concentration, assessment of the degree of hepatic fibrosis, hepatic steatosis, total cholesterol, low density lipoprotein, high density lipoprotein and triglyceride concentrations, were assessed at the beginning of therapy, 6 months later, and 12 months after commencement of therapy. The control group consisted of 18 healthy individuals. RESULTS: The mean LDLR concentration in the studied groups was statistically significantly lower (p<0.05) than in the controls. The antiviral therapy based on TDF had no influence on the LDLR concentration and HBsAg level. CONCLUSIONS: The results indicate a statistically significant lower(p<0.05) concentration of LDLR in patients with chronic hepatitis B infection. Negative correlations between HBsAg level and LDLR concentration in patients with chronic HBV, at all stages of the study may indicate, that HBsAg protects hepatocytes from LDL accumulation.
Subject(s)
Antiviral Agents/administration & dosage , Fatty Liver/blood , Hepatitis B, Chronic/drug therapy , Liver Cirrhosis/blood , Receptors, LDL/blood , Tenofovir/administration & dosage , Adult , Aged , Fatty Liver/etiology , Fatty Liver/virology , Female , Hepatitis B Surface Antigens/blood , Hepatitis B virus/genetics , Hepatitis B virus/metabolism , Hepatitis B, Chronic/blood , Hepatitis B, Chronic/complications , Hepatitis B, Chronic/virology , Humans , Lipoproteins, HDL/blood , Liver Cirrhosis/etiology , Liver Cirrhosis/virology , Male , Middle Aged , Triglycerides/bloodABSTRACT
Rutin (R) and quercetin (Q) are two widespread dietary flavonoids. Previous studies regarding the plasma cholesterol-lowering activity of R and Q generated inconsistent results. The present study was therefore carried out to investigate the effects of R and Q on cholesterol metabolism in both HepG2 cells and hypercholesterolemia hamsters. Results from HepG2 cell experiments demonstrate that both R and Q decreased cholesterol at doses of 5 and 10 µM. R and Q up-regulated both the mRNA and protein expression of sterol regulatory element binding protein 2 (SREBP2), low-density lipoprotein receptor (LDLR), and liver X receptor alpha (LXRα). The immunofluorescence study revealed that R and Q increased the LDLR expression, while only Q improved LDL-C uptake in HepG2 cells. Results from hypercholesterolemia hamsters fed diets containing R (5.5 g/kg diet) and Q (2.5 g/kg diet) for 8 weeks demonstrate that both R and Q had no effect on plasma total cholesterol. In the liver, only Q reduced cholesterol significantly. The discrepancy between the in vitro and in vivo studies was probably due to a poor bioavailability of flavonoids in the intestine. It was therefore concluded that R and Q were effective in reducing cholesterol in HepG2 cells in vitro, whereas in vivo, the oral administration of the two flavonoids had little effect on plasma cholesterol in hamsters.
Subject(s)
Cholesterol/blood , Cholesterol/metabolism , Quercetin/pharmacology , Rutin/pharmacology , Administration, Oral , Animals , Cell Line, Tumor , Cricetinae , Flavonoids/pharmacology , Hep G2 Cells , Humans , Hypercholesterolemia/blood , Hypercholesterolemia/drug therapy , Hypercholesterolemia/metabolism , Lipid Metabolism/drug effects , Liver/drug effects , Liver/metabolism , Liver X Receptors/metabolism , Male , RNA, Messenger/metabolism , Receptors, LDL/blood , Receptors, LDL/metabolism , Sterol Regulatory Element Binding Protein 2/metabolism , Triglycerides/blood , Triglycerides/metabolism , Up-Regulation/drug effectsABSTRACT
The low-density lipoprotein receptor (LDLR) is key to cellular cholesterol uptake and is also the main receptor for the vesicular stomatitis virus glycoprotein (VSV G). Here we show that in songbirds LDLR is highly divergent and lacks domains critical for ligand binding and cellular trafficking, inconsistent with universal structure conservation and function across vertebrates. Linked to the LDLR functional domain loss, zebra finches show inefficient infectivity by lentiviruses (LVs) pseudotyped with VSV G, which can be rescued by the expression of human LDLR. Finches also show an atypical plasma lipid distribution that relies largely on high-density lipoprotein (HDL). These findings provide insights into the genetics and evolution of viral infectivity and cholesterol transport mechanisms in vertebrates.
Subject(s)
Cholesterol/genetics , Lipids/blood , Membrane Glycoproteins/genetics , Receptors, LDL/genetics , Viral Envelope Proteins/genetics , Animals , Biological Transport/genetics , Cholesterol/metabolism , Finches/blood , Finches/genetics , Gene Expression Regulation/genetics , Humans , Ligands , Receptors, LDL/bloodABSTRACT
Aim: To investigate the temporal evolution of plasma proprotein convertase subtilisin/kexin type 9 (PCSK9), low-density lipoprotein receptor (LDLR) and myeloperoxidase (MPO) in relation to clinical outcome in chronic heart failure (CHF). Methodology & results: Trimonthly blood sampling was performed during a median follow-up of 2.2 (IQR 1.4-2.5) years in 263 CHF patients. Seventy patients reached the primary end point (PE) (cardiovascular death, heart transplantation, left ventricular assist device implantation or HF-hospitalization). MPO level was independently associated with the PE; the adjusted (for clinical factors) hazard ratio (aHR) per standard deviation difference in MPO was 1.71 (95% CI: 1.23-2.43) at any time during follow-up. PCSK9 level (HR: 1.45 [1.04-2.06]) and LDLR (HR: 0.66 [0.49-0.87]) were statistical significantly associated with the PE but only in unadjusted analyses. Slope of temporal MPO evolution (aHR: 1.34 [1.12-1.76] per 0.1 standard deviation/year difference in slope) and LDLR (aHR: 0.78 [0.61-0.90]) however, were associated with PE. Conclusion: Temporal patterns of MPO and LDLR are independently associated with clinical outcome in CHF, which illustrates the importance of assessing temporal evolutions. Clinical trial registration information: registered in ClinicalTrials.gov, number NCT01851538. https://clinicaltrials.gov/ct2/show/NCT01851538.
Subject(s)
Biomarkers/blood , Heart Failure/pathology , Peroxidase/blood , Proprotein Convertase 9/blood , Receptors, LDL/blood , Aged , Female , Heart Failure/blood , Humans , Longitudinal Studies , Male , Middle Aged , Prognosis , Prospective StudiesABSTRACT
Soluble low-density lipoprotein receptor (sLDLR) is the circulating ectodomain of transmembrane LDLR. Its blood level strongly correlates with that of triglycerides (TG). This correlation has eluded satisfactory explanation. Hypertriglyceridemia and shedding of the ectodomain of many transmembrane receptors often accompany inflammatory states. The shedding mostly occurs through cleavage by a disintegrin-and-metalloproteinase-17 (ADAM-17), an enzyme activated by inflammation. It reduces the cellular uptake of TG-loaded lipoproteins, causing their accumulation in circulation; hence the correlation between plasma sLDLR and TG. Soluble LDLR could become a new surrogate marker of inflammation.
Subject(s)
Inflammation/blood , Receptors, LDL/blood , ADAM17 Protein/metabolism , Animals , Humans , Hypertriglyceridemia/blood , Hypertriglyceridemia/metabolism , Hypertriglyceridemia/pathology , Inflammation/metabolism , Inflammation/pathology , Receptors, LDL/metabolism , Triglycerides/bloodABSTRACT
Among the determinants of atherosclerotic cardiovascular disease (ASCVD), genetic and experimental evidence has provided data on a major role of angiopoietin-like proteins 3 and 4 (ANGPTL3 and ANGPTL4) in regulating the activity of lipoprotein lipase (LPL), antagonizing the hydrolysis of triglycerides (TG). Indeed, beyond low-density lipoprotein cholesterol (LDL-C), ASCVD risk is also dependent on a cluster of metabolic abnormalities characterized by elevated fasting and post-prandial levels of TG-rich lipoproteins and their remnants. In a head-to-head comparison between murine models for ANGPTL3 and ANGPTL4, the former was found to be a better pharmacological target for the treatment of hypertriglyceridemia. In humans, loss-of-function mutations of ANGPTL3 are associated with a marked reduction of plasma levels of VLDL, low-density lipoprotein (LDL) and high-density lipoprotein (HDL). Carriers of loss-of-function mutations of ANGPTL4 show instead lower TG-rich lipoproteins and a modest but significant increase of HDL. The relevance of ANGPTL3 and ANGPTL4 as new therapeutic targets is proven by the development of monoclonal antibodies or antisense oligonucleotides. Studies in animal models, including non-human primates, have demonstrated that short-term treatment with monoclonal antibodies against ANGPTL3 and ANGPTL4 induces activation of LPL and a marked reduction of plasma TG-rich-lipoproteins, apparently without any major side effects. Inhibition of both targets also partially reduces LDL-C, independent of the LDL receptor. Similar evidence has been observed with the antisense oligonucleotide ANGPTL3-LRX. The genetic studies have paved the way for the development of new ANGPTL3 and 4 antagonists for the treatment of atherogenic dyslipidemias. Conclusive data of phase 2 and 3 clinical trials are still needed in order to define their safety and efficacy profile.
Subject(s)
Angiopoietin-Like Protein 4/antagonists & inhibitors , Angiopoietin-like Proteins/antagonists & inhibitors , Atherosclerosis/drug therapy , Drug Development/methods , Dyslipidemias/drug therapy , Angiopoietin-Like Protein 3 , Angiopoietin-Like Protein 4/genetics , Angiopoietin-like Proteins/genetics , Animals , Atherosclerosis/etiology , Atherosclerosis/genetics , Biomarkers/blood , Clinical Trials as Topic , Dyslipidemias/complications , Dyslipidemias/genetics , Gene Knockdown Techniques , Humans , Lipid Metabolism/drug effects , Lipid Metabolism/genetics , Mice , Receptors, LDL/blood , Receptors, LDL/metabolism , Transcription, Genetic/drug effectsABSTRACT
OBJECTIVE: Coronary artery disease (CAD) is one of the most common causes of death worldwide. Risk factors of CAD include high LDL-C, low high-density lipoprotein (HDL), hypertension, lack of exercise, genetic factors, etc. Polymorphisms of the LDLR gene have been associated with CAD in previous studies. METHODS: The LDLR-rs72658855 C>T genotyping was detected by using allele-specific PCR (ASPCR). The association of rs2228671 and rs72658855 with CAD in a south Indian cohort (200 CAD patients and 200 matched healthy controls was studied. RESULTS: Our findings showed that rs2228671 gene variability is associated with increased susceptibility to coronary artery disease in the codominant inheritance model for variant CC vs. CT OR 3.42(1.09-10.7), with P<0.034. A non-significant association was reported in the recessive inheritance model for the variant (CC+CT) vs. TT OR 0.56(0.16-1.95), at P<0.36. and in the dominant inheritance model for variant CC vs. (CT+TT) OR 2.8(1.07-7.34), at P<0.032 .In case of allelic comparison, it was indicated that the LDLR rs2228671-T allele was associated with an increased risk of developing CAD compared to C allele OR=2.4, with 95% CI (1.05-5.64) and P< 0.036 . Our findings showed that LDLR rs72658855 C>T gene variability was associated with an increased susceptibility to coronary artery disease in the codominant inheritance model for variant CC vs. CT OR 1.7(1.1-2.6), at P<0.015 and in the dominant inheritance model for variant CC vs. (CT+TT) OR 1.66(1.07-2.58), at P<0.0.02.. In case of allelic comparison, a non-significant association was reported in LDLR rs72658855-T and C allele. CONCLUSION: We concluded that the heterozygosity in LDLR-rs72658855 and rs2228671 and T allele in LDLR rs2228671 are strongly associated with increased susceptibility to coronary artery disease. These results must be validated by future well-designed studies with larger sample sizes and different populations.
Subject(s)
Coronary Artery Disease/epidemiology , Coronary Artery Disease/genetics , Genetic Predisposition to Disease/epidemiology , Genetic Predisposition to Disease/genetics , Heterozygote , Receptors, LDL/genetics , Adult , Case-Control Studies , Cohort Studies , Coronary Artery Disease/blood , Female , Humans , India/epidemiology , Male , Middle Aged , Receptors, LDL/blood , Risk FactorsABSTRACT
AIMS: Proprotein convertase subtilisin/kexin type-9 (PCSK9), a molecular determinant of low-density lipoprotein (LDL) receptor (LDLR) fate, has emerged as a promising therapeutic target for atherosclerotic cardiovascular diseases. However, the precise mechanism by which PCSK9 regulates the internalization and lysosomal degradation of LDLR is unknown. Recently, we identified adenylyl cyclase-associated protein 1 (CAP1) as a receptor for human resistin whose globular C-terminus is structurally similar to the C-terminal cysteine-rich domain (CRD) of PCSK9. Herein, we investigated the role of CAP1 in PCSK9-mediated lysosomal degradation of LDLR and plasma LDL cholesterol (LDL-C) levels. METHODS AND RESULTS: The direct binding between PCSK9 and CAP1 was confirmed by immunoprecipitation assay, far-western blot, biomolecular fluorescence complementation, and surface plasmon resonance assay. Fine mapping revealed that the CRD of PCSK9 binds with the Src homology 3 binding domain (SH3BD) of CAP1. Two loss-of-function polymorphisms found in human PCSK9 (S668R and G670E in CRD) were attributed to a defective interaction with CAP1. siRNA against CAP1 reduced the PCSK9-mediated degradation of LDLR in vitro. We generated CAP1 knock-out mice and found that the viable heterozygous CAP1 knock-out mice had higher protein levels of LDLR and lower LDL-C levels in the liver and plasma, respectively, than the control mice. Mechanistic analysis revealed that PCSK9-induced endocytosis and lysosomal degradation of LDLR were mediated by caveolin but not by clathrin, and they were dependent on binding between CAP1 and caveolin-1. CONCLUSION: We identified CAP1 as a new binding partner of PCSK9 and a key mediator of caveolae-dependent endocytosis and lysosomal degradation of LDLR.
Subject(s)
Atherosclerosis/genetics , Carrier Proteins/genetics , Cholesterol, LDL/blood , Mutation , Proprotein Convertase 9/genetics , Receptors, LDL/blood , Animals , Atherosclerosis/metabolism , Carrier Proteins/metabolism , DNA/genetics , DNA Mutational Analysis , Disease Models, Animal , Humans , Mice , Mice, Knockout , Proprotein Convertase 9/metabolismABSTRACT
OBJECTIVE: A high level of LDL-C (low-density lipoprotein cholesterol) is a major risk factor for cardiovascular disease. The E3 ubiquitin ligase named IDOL (inducible degrader of the LDLR [LDL receptor]; also known as MYLIP [myosin regulatory light chain interacting protein]) mediates degradation of LDLR through ubiquitinating its C-terminal tail. But the expression profile of IDOL differs greatly in the livers of mice and humans. Whether IDOL is able to regulate LDL-C levels in humans remains to be determined. Approach and Results: By using whole-exome sequencing, we identified a nonsynonymous variant rs149696224 in the IDOL gene that causes a G51S (Gly-to-Ser substitution at the amino acid site 51) from a Chinese Uygur family. Large cohort analysis revealed IDOL G51S carriers (+/G51S) displayed significantly higher LDL-C levels. Mechanistically, the G51S mutation stabilized IDOL protein by inhibiting its dimerization and preventing self-ubiquitination and subsequent proteasomal degradation. IDOL(G51S) exhibited a stronger ability to promote ubiquitination and degradation of LDLR. Adeno-associated virus-mediated expression of IDOL(G51S) in mouse liver decreased hepatic LDLR and increased serum levels of LDL-C, total cholesterol, and triglyceride. CONCLUSIONS: Our study demonstrates that IDOL(G51S) is a gain-of-function variant responsible for high LDL-C in both humans and mice. These results suggest that IDOL is a key player regulating cholesterol level in humans.
Subject(s)
Cholesterol, LDL/blood , Gene Expression Regulation , Hyperlipoproteinemias/genetics , RNA/genetics , Ubiquitin-Protein Ligases/genetics , Adult , Animals , Cells, Cultured , Disease Models, Animal , Female , Humans , Hyperlipoproteinemias/blood , Male , Mice , Mice, Inbred BALB C , Middle Aged , Receptors, LDL/blood , Ubiquitin-Protein Ligases/biosynthesis , Whole Genome Sequencing/methodsABSTRACT
OBJECTIVE: Homozygous familial hypercholesterolemia is a rare disease usually caused by LDLR (low-density lipoprotein receptor) mutations. Homozygous familial hypercholesterolemia is characterized by markedly elevated LDL-C (low-density lipoprotein cholesterol) levels and an extremely high risk of premature atherosclerotic cardiovascular disease. A phase 2, proof-of-concept study (NCT02265952) demonstrated that evinacumab, a fully human monoclonal antibody to ANGPTL3 (angiopoietin-like 3 protein), reduced LDL-C levels in 9 patients with genotypically confirmed homozygous familial hypercholesterolemia and was well tolerated. The aim of this study was to analyze the effects of evinacumab on LDLR activity in lymphocytes purified from patients in the proof-of-concept study. Approach and Results: LDLR activity was assessed in patient lymphocytes before and after treatment with evinacumab and versus lymphocytes carrying wild-type LDLR, and also in an LDLR-defective Chinese hamster ovary cell line (CHO-ldlA7) transfected with plasmids encoding the LDLR variants. Overall mean peak reduction in LDL-C with evinacumab was -58±18%, occurring between Week 4 and Week 12. Mutations identified in the 9 patients were shown to be pathogenic, with loss of LDLR activity versus wild type. Two of the LDLR variants, p.(Cys681*) and p.(Ala627Profs*38), were class 2 type mutations that are retained in the endoplasmic reticulum. Six variants were class 3 type mutations with impaired LDL-C binding activity: p.(Trp87Gly), occurring in 2 patients, p.(Gln254Pro), p.(Ser177Leu), p.(Gly335Val), and p.(Ser306Leu). Evinacumab had no effect on LDLR activity. CONCLUSIONS: These results suggest that evinacumab is effective for lowering LDL-C in patients with homozygous familial hypercholesterolemia, and the inhibition of ANGPTL3 in humans lowers LDL-C in a mechanism independent of the LDLR.
Subject(s)
Angiopoietin-like Proteins/antagonists & inhibitors , Antibodies, Monoclonal/therapeutic use , Hyperlipoproteinemia Type II/blood , Hyperlipoproteinemia Type II/drug therapy , Lymphocytes/metabolism , Receptors, LDL/blood , Adolescent , Adult , Angiopoietin-Like Protein 3 , Angiopoietin-like Proteins/blood , Animals , CHO Cells , Cholesterol, LDL/blood , Cricetulus , Female , Frameshift Mutation , Humans , Hyperlipoproteinemia Type II/genetics , Male , Middle Aged , Point Mutation , Proof of Concept Study , Receptors, LDL/genetics , Young AdultABSTRACT
BACKGROUND AND OBJECTIVES: Four single nucleotide polymorphisms (SNPs); rs6921438 and rs4416670 in LOC100132354-C6orf223, rs6993770 in ZFPM2, and rs10738760 in VLDLR-KCNV2 were reported to explain up to 50% of the heritability of vascular endothelial growth factor circulating levels. These SNPs were also studied for possible associations with circulating lipid levels in supposedly healthy European individuals and in a limited number of Iranian individuals with metabolic syndrome. To go further, the association of those four SNPs with plasma lipid parameters, hypercholesterolemia and metabolic syndrome (MetS) was assessed. MATERIALS AND METHODS: A cross-sectional study was conducted on 460 individuals chosen from the general population. Demographic and clinical data were collected and DNA was extracted and genotyped using Kompetitive allele specific PCR (KASP™). A meta-analysis followed, combining our participants with the Iranian individuals (n = 336). RESULTS: Whereas rs10738760 was associated with total cholesterol (Tchol) (p = 0.01), rs6993770 showed significant associations with both Tchol and low-density lipoprotein cholesterol (LDL-C) levels (p = 0.007 and p = 0.01 respectively). Using a multivariate logistic regression model adjusted for different confounding factors, we found that rs6993770 was associated with hypercholesterolemia, specifically high Tchol (p = 0.01) and LDL-C levels (p = 0.01). Furthermore, rs10738760 was positively associated with the risk of MetS in these individuals (p = 0.02) and in the meta-analysis (OR = 1.67, p = 0.01). CONCLUSION: Our results suggest that whereas rs6993770 in ZFPM2 was positively associated with hypercholesterolemia, rs10738760 (VLDLR-KCNV2) has a possible implication in MetS in two Middle Eastern populations.
Subject(s)
Endothelial Growth Factors/genetics , Hypercholesterolemia/genetics , Metabolic Syndrome/genetics , Polymorphism, Single Nucleotide/genetics , Receptors, LDL/analysis , Adult , Cross-Sectional Studies , Female , Humans , Iran , Male , Middle Aged , Receptors, LDL/bloodABSTRACT
Individuals with elevated LDL-cholesterol levels have an increased risk for cardiovascular disease. Despite lipid lowering strategies, however, a significant cardiovascular risk remains. Bekkering et al. show that monocytes from patients with familial hypercholesterolemia have a trained immunity phenotype and that lipid lowering with statins does not revert this pro-inflammatory phenotype.
Subject(s)
Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use , Hyperlipoproteinemia Type II/metabolism , Animals , Cardiovascular Diseases/blood , Cardiovascular Diseases/drug therapy , Cardiovascular Diseases/genetics , Cholesterol, LDL/blood , Humans , Hyperlipoproteinemia Type II/blood , Hyperlipoproteinemia Type II/drug therapy , Hyperlipoproteinemia Type II/genetics , Interleukin 1 Receptor Antagonist Protein/blood , Interleukin-10/blood , Interleukin-1beta/blood , Interleukin-6/blood , Mice , Receptors, LDL/bloodABSTRACT
BACKGROUND: The incidence of premature myocardial infarction (PMI) has gradually increased in recent years. Genetics plays a central role in the development of PMI. Familial hypercholesterolemia (FH) is one of the most common genetic disorders of cholesterol metabolism leading to PMI. OBJECTIVE: This study investigated the relationship between FH-associated genes and the phenotype of PMI to clarify the genetic spectrum of PMI diseases. METHOD: This study enrolled PMI patients (n = 225) and detected the mutations in their FH-associated genes (LDLR, APOB, PCSK9, LDLRAP1) by Sanger sequencing. At the same time, patients free of PMI (non-FH patients, n = 56) were enrolled as control, and a logistic regression analysis was used to identify risk factors associated with PMI. The diagnosis of FH was confirmed using "2018 Chinese expert consensus of FH screening and diagnosis" before the prevalence and clinical features of FH were analyzed. RESULTS: Pathogenic mutations in LDLR, APOB, PCSK9 and LDLRAP1 genes were found in 17 of 225 subjects (7.6%), and all mutations were loss of function (LOF) and heterozygous. The genotype-phenotype relationship of patients carrying FH-associated mutations showed high heterogeneity. The logistic regression analysis showed that the smoking history, obesity and the family history of premature CHD were independent risk factors of PMI. In this study, a total of 19 patients (8.4%) were diagnosed as FH, and the proportion of smoking subjects in FH patients was higher than that in non-FH patients. CONCLUSIONS: FH-associated gene mutations were present in about 7.6% of Chinese patients with PMI. In addition to genetic factors, smoking history, lifestyle and other environmental factors may play a synergistic role in determining the phenotype of PMI. TRIAL REGISTRATION: Essential gene mutation of cholesterol metabolism in patients with premature myocardial infarction. ChiCTR-OCH-12002349.Registered 26 December 2014, http://www.chictr.org.cn/showproj.aspx?proj=7201 .
Subject(s)
Adaptor Proteins, Signal Transducing/genetics , Apolipoprotein B-100/genetics , Hyperlipoproteinemia Type II/diagnosis , Mutation , Myocardial Infarction/diagnosis , Proprotein Convertase 9/genetics , Receptors, LDL/genetics , Adaptor Proteins, Signal Transducing/blood , Adult , Age of Onset , Aged , Aged, 80 and over , Apolipoprotein B-100/blood , Case-Control Studies , Female , Gene Expression , Genetic Predisposition to Disease , Heterozygote , Humans , Hyperlipoproteinemia Type II/blood , Hyperlipoproteinemia Type II/complications , Hyperlipoproteinemia Type II/genetics , Inheritance Patterns , Logistic Models , Male , Middle Aged , Myocardial Infarction/blood , Myocardial Infarction/etiology , Myocardial Infarction/genetics , Obesity , Phenotype , Proprotein Convertase 9/blood , Receptors, LDL/blood , Risk Factors , Sequence Analysis, DNA , SmokingSubject(s)
Apolipoprotein B-100/genetics , Hyperlipoproteinemia Type II/genetics , Mutation , Proprotein Convertase 9/genetics , Receptors, LDL/genetics , ATP Binding Cassette Transporter, Subfamily G, Member 5/blood , ATP Binding Cassette Transporter, Subfamily G, Member 5/genetics , ATP Binding Cassette Transporter, Subfamily G, Member 8/blood , ATP Binding Cassette Transporter, Subfamily G, Member 8/genetics , Adaptor Proteins, Signal Transducing/blood , Adaptor Proteins, Signal Transducing/genetics , Apolipoprotein B-100/blood , Apolipoproteins E/blood , Apolipoproteins E/genetics , Cholesterol, LDL/blood , Databases, Genetic , Gene Expression , Genomics/methods , Humans , Hyperlipoproteinemia Type II/blood , Hyperlipoproteinemia Type II/pathology , Lipid Metabolism/genetics , Lipoproteins/blood , Lipoproteins/genetics , Proprotein Convertase 9/blood , Receptors, LDL/blood , Sterol Esterase/blood , Sterol Esterase/geneticsABSTRACT
Carob fruit extract (CFE) has shown remarkable in vitro antioxidant properties and reduces postprandial hyperglycemia and hyperlipidemia in healthy animals. Development of functional meat products that contain bioactive components are presented as a great nutritional strategy. Until now, the effect of the consumption of restructured meat enriched with CFE in a murine model of diabetes has not been investigated. The objective of this study was to evaluate the effect on glycemia, lipemia, lipoprotein profile, Ldlr, arylesterase (AE), and very low-density lipoproteins (VLDL) and liver oxidation in streptozotocin-nicotinamide (STZ-NAD) growing Wistar diabetic rats fed restructured meat in the frame of a high cholesterol/high saturated-fat diet. In the present study, three groups (D, ED and DE) were fed cholesterol-enriched (1.4% cholesterol and 0.2% cholic acid) and high saturated-fat diets (50% of total energy from fats and 20.4% from saturated fatty acids). Rats were subjected to a STZ-NAD administration at the 3rd week. Group D did not receive CFE, while ED and DE rat groups received CFE before and after the diabetic induction, respectively. After eight weeks, D rats showed hyperglycemia and hypercholesterolemia, an increased amount cholesterol-enriched VLDL (ß-VLDL), IDL and LDL particles and triglyceride-enriched HDL. ED and DE partially blocked the hypercholesterolemic induction with respect to D group (p < 0.001) and improved glycemia, cholesterol levels, lipoprotein profile, Ldlr, plasma AE activity and liver oxidation (p < 0.001). Fecal fat, moisture and excretion were higher while dietary digestibility was lower in ED and DE vs. D counterparts (p < 0.001). In conclusion, CFE-enriched meat shows, for the first time, hypoglycemic and hypolipidemic effects in STZ-NAD animals fed high cholesterol/high saturated-fat diets. Likewise, it manages to reverse possible diabetes lipoprotein alterations if CFE-enriched meat is consumed before pathology development or improves said modifications if Type 2 Diabetes Mellitus is already established.
Subject(s)
Diabetes Mellitus, Experimental/drug therapy , Diet, Atherogenic/adverse effects , Fabaceae , Lipoproteins, VLDL/blood , Meat , Plant Extracts/therapeutic use , Receptors, LDL/blood , Animals , Blood Glucose/metabolism , Carboxylic Ester Hydrolases/blood , Diabetes Mellitus, Experimental/blood , Diabetes Mellitus, Type 2/blood , Diabetes Mellitus, Type 2/drug therapy , Dietary Fats/adverse effects , Digestion , Feces , Food Handling , Fruit , Hypoglycemic Agents/pharmacology , Hypoglycemic Agents/therapeutic use , Hypolipidemic Agents/pharmacology , Hypolipidemic Agents/therapeutic use , Lipoproteins/blood , Liver/drug effects , Liver/metabolism , Male , Oxidative Stress/drug effects , Plant Extracts/pharmacology , Rats, Wistar , Triglycerides/bloodABSTRACT
Abstract Background: In menopause, there is greater cellular exposure to oxidative stress, related to the decreased antioxidative effects of estrogen. These metabolic changes favor the progression of cardiovascular diseases, such as atherosclerosis. Abnormal function of the aorta - the most important artery - is associated with many cardiovascular diseases. Collagen, especially types I and III, is one of the most important aortic wall components and it can be affected by many factors, including menopause. The 8-OHdG is one of the main markers of DNA oxidative damage induced by reactive oxygen species (ROS). Objective: We aimed to investigate effects of moderate aerobic training on the ascending aorta of LDL-knockout (LDL-KO) and ovariectomized female mice. Methods: A total of 15 C57BL/6 mice and 15 LDL-KO mice were divided into experimental groups. The thickness and volume density of types I and III collagen fibers were performed by morphoquantitative analysis, whereas the MMP-2 and MMP-9 and 8-OHdG were detected by immunohistochemistry and apoptosis was detected by the TUNEL assay. The significance level for all tests was p < 0.05. Results: Exercise causes an increase in the thickness of the aorta in LDL-KO groups, particularly accentuated in the ovariectomized groups. The type I collagen fibers showed an increase in volume density influenced by training in both Control groups and in the LDL-KO group. Type III collagen density decreased in both groups. The MMP-2 showed moderade immunostaining in the tunica media in LDL-KO groups, which did not occur in the control groups and the MMP-9 stained irregularly in all tissues. The marker 8-OhdG was stronger in the exercise training groups. Additionally, the ovariectomy, the exercise training and the LDL-KO treatments increased apoptosis. Conclusion: These results suggest that moderate-intensity aerobic exercise in ovariectomized mice associated to an increase in LDL rate possibly increases oxidative stress and apoptosis induction.
Resumo Fundamento: Na menopausa, há maior exposição celular ao estresse oxidativo, relacionada à diminuição dos efeitos antioxidantes do estrogênio. Essas alterações metabólicas favorecem a progressão das doenças cardiovasculares, como a aterosclerose. A função anormal da aorta - a artéria mais importante - está associada a muitas doenças cardiovasculares. O colágeno, especialmente os tipos I e III, é um dos mais importantes componentes da parede da aorta e pode ser afetado por muitos fatores, incluindo a menopausa. Por sua vez, 8-OHdG é um dos principais marcadores de danos oxidativos do DNA induzidos por espécies reativas de oxigênio (EROS). Objetivo: Investigar os efeitos do treinamento aeróbico moderado na aorta ascendente de camundongos fêmeas, nocaute para LDL (LDL-KO) e ovariectomizadas. Métodos: Um total de 15 animais C57BL/6 e 15 animais LDL-KO foram divididos em grupos experimentais. A espessura e a densidade de volume das fibras de colágeno tipos I e III foram realizadas por análise morfoquantitativa; MMP-2 e MMP-9 e 8-OHdG foram detectadas por imunohistoquímica; e a apoptose foi detectada pelo ensaio TUNEL. O nível de significância adotado para todos os testes realizados foi p < 0,05. Resultados: o exercício causa aumento da espessura da aorta em grupos LDL-KO, particularmente acentuada em grupos ovariectomizados. As fibras de colágeno de tipo I mostraram aumento da densidade de volume influenciado pelo treinamento em animais controle e LDL-KO. A densidade do colágeno tipo III diminuiu em ambos os grupos. A MMP-2 mostrou imunomarcação moderada na túnica média em animais LDL-KO; em grupos controle, a MMP-9 marcou irregularmente em todos os tecidos. O marcador 8-OHdG foi mais forte nos grupos de treinamento de exercícios. Além disso, a ovariectomia, o treinamento físico e os tratamentos de LDL-KO aumentaram a apoptose. Conclusão: Esses resultados sugerem que exercícios aeróbicos de intensidade moderada em camundongos ovariectomizados associados ao aumento da taxa de LDL, possivelmente, aumentam o estresse oxidativo e a indução da apoptose.
Subject(s)
Animals , Female , Rats , Aorta/metabolism , Physical Conditioning, Animal/physiology , Ovariectomy , Collagen/analysis , Matrix Metalloproteinase 2/analysis , Matrix Metalloproteinase 9/analysis , Aorta/pathology , Menopause/metabolism , Receptors, LDL/blood , Immunohistochemistry , Tunica Media/pathology , Apoptosis/physiology , Mice, Knockout , Oxidative Stress/physiology , In Situ Nick-End Labeling , Sedentary BehaviorABSTRACT
BACKGROUND: Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a serine protease and a secreted protein which increases cholesterol levels in plasma via inducing degradation of low-density lipoprotein receptor (LDLR). Cluster of differentiation 36 (CD36) is a member of a family of cell surface proteins in many cells. CD36 is known as fatty acid translocase (FAT) because it imports fatty acids inside cells and participate in triglyceride storage. It has been suggested that PCSK9 regulates CD36 in some tissues. METHODS: Data and serum levels of TSH, FT4, lipid profile and PCSK9 and the expression of CD36 on monocytes from 40 new untreated patients with subclinical hypothyroidism (SH) and 40 age- sex- and BMI-matched euthyroid controls were analyzed in a cross-sectional study. Then the relationships between these parameters were examined. RESULTS: Patients with SH had higher TSH, FT4, total cholesterol (TC) and triglyceride (TG) Low-density lipoprotein (LDL) and PCSK9 levels than controls. There were significant and positive correlations between serum TSH levels and lipid parameters except HDL-C. PCSK9 had a significant and negative correlation with FT4. No significant correlation could be found in relation to PCSK9 and CD36. CONCLUSIONS: PCSK9 inhibitors are used to reduce blood cholesterol levels as drugs. If it will be proven that PCSK9 can induce CD36 degradation, taking these drugs may have unwanted side effects. This study showed that serum PCSK9 and lipid profile levels increase in patients with subclinical hypothyroidism and there is no relationship between PCSK9 and CD36 in these patients.
Subject(s)
Biomarkers/blood , CD36 Antigens/blood , Cholesterol/blood , Hypothyroidism/blood , Lipids/blood , Monocytes/metabolism , Proprotein Convertase 9/blood , Adolescent , Adult , Case-Control Studies , Cross-Sectional Studies , Female , Follow-Up Studies , Humans , Hypothyroidism/pathology , Male , Middle Aged , Monocytes/pathology , Prognosis , Receptors, LDL/blood , Young AdultABSTRACT
PURPOSE OF REVIEW: DNA copy number variations (CNVs) are large-scale mutations that include deletions and duplications larger than 50âbp in size. In the era when single-nucleotide variations were the major focus of genetic technology and research, CNVs were largely overlooked. However, CNVs clearly underlie a substantial proportion of clinical disorders. Here, we update recent progress in identifying CNVs in dyslipidemias. RECENT FINDINGS: Until last year, only the LDLR and LPA genes were appreciated as loci within which clinically relevant CNVs contributed to familial hypercholesterolemia and variation in Lp(a) levels, respectively. Since 2017, next-generation sequencing panels have identified pathogenic CNVs in at least five more genes underlying dyslipidemias, including a PCSK9 whole-gene duplication in familial hypercholesterolemia; LPL, GPIHBP1, and APOC2 deletions in hypertriglyceridemia; and ABCA1 deletions in hypoalphalipoproteinemia. SUMMARY: CNVs are an important class of mutation that contribute to the molecular genetic heterogeneity underlying dyslipidemias. Clinical applications of next-generation sequencing technologies need to consider CNVs concurrently with familiar small-scale genetic variation, given the likely implications for improved diagnosis and treatment.