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Calcified Tissue International Feb 2024Observational studies have shown a causal association between dyslipidemia and osteoporosis, but the genetic causation and complete mechanism of which are uncertain. The...
BACKGROUND
Observational studies have shown a causal association between dyslipidemia and osteoporosis, but the genetic causation and complete mechanism of which are uncertain. The disadvantage of previous observational studies is that they are susceptible to confounding factors and bias, that makes it difficult to infer a causal link between those two diseases. Abnormal epigenetic modifications, represented by DNA methylation, are important causes of many diseases. However, there are no studies showing a bridging role for methylation modifications in blood lipid metabolism and osteoporosis.
METHODS
SNPs for lipid profile (Blood VLDL cholesterol (VLDL-C), blood LDL cholesterol (LDL-C), blood HDL cholesterol (HDL-C), blood triglycerides (TG), diagnosed pure hypercholesterolaemia, blood apolipoprotein B (Apo B), blood apolipoprotein A1(Apo A1)), and bone mineral density (BMD) in different body parts (Heel BMD, lumbar BMD, whole-body BMD, femoral neck BMD) were obtained from large meta-analyses of genome-wide association studies as instrumental variables for two-sample Mendelian randomization. Assessment of the genetic effects of lipid profile-associated methylation sites and bone mineral density was carried out using the summary-data-based Mendelian randomization (SMR) method.
RESULTS
Two-sample Mendelian randomization showed that there was a negative causal association between hypercholesterolaemia and heel BMD (p = 0.0103, OR = 0.4590), and total body BMD (p = 0.0002, OR = 0.2826). LDL-C had a negative causal association with heel BMD (p = 8.68E-05, OR = 0.9586). VLDL-C had a negative causal association with heel BMD (p = 0.035, OR = 0.9484), lumbar BMD (p = 0.0316, OR = 0.9356), and total body BMD (p = 0.0035, OR = 0.9484). HDL-C had a negative causal association with heel BMD (p = 1.25E-05, OR = 0.9548), lumbar BMD (p = 0.0129, OR = 0.9358), and total body BMD (p = 0.0399, OR = 0.9644). Apo B had a negative causal association with heel BMD (p = 0.0001, OR = 0.9647). Apo A1 had a negative causal association with heel BMD (p = 0.0132, OR = 0.9746) and lumbar BMD (p = 0.0058, OR = 0.9261). The p-values of all positive results corrected by the FDR method remained significant and sensitivity analysis showed that there was no horizontal pleiotropy in the results despite the heterogeneity in some results. SMR identified 3 methylation sites associated with lipid profiles in the presence of genetic effects on BMD: cg15707428(GREB1), cg16000331(SREBF2), cg14364472(NOTCH1).
CONCLUSION
Our study provides insights into the potential causal links and co-pathogenesis between dyslipidemia and osteoporosis. The genetic effects of dyslipidaemia on osteoporosis may be related to certain aberrant methylation genetic modifications.
Topics: Humans; Apolipoprotein A-I; Genome-Wide Association Study; Lipid Metabolism; Mendelian Randomization Analysis; Hypercholesterolemia; Multiomics; Cholesterol, LDL; Osteoporosis; Bone Density; DNA Methylation; Lipids; Apolipoproteins B; Polymorphism, Single Nucleotide
PubMed: 38071623
DOI: 10.1007/s00223-023-01160-6 -
Arteriosclerosis, Thrombosis, and... May 2024Zebrafish have become a powerful model of mammalian lipoprotein metabolism and lipid cell biology. Most key proteins involved in lipid metabolism, including cholesteryl... (Review)
Review
Zebrafish have become a powerful model of mammalian lipoprotein metabolism and lipid cell biology. Most key proteins involved in lipid metabolism, including cholesteryl ester transfer protein, are conserved in zebrafish. Consequently, zebrafish exhibit a human-like lipoprotein profile. Zebrafish with mutations in genes linked to human metabolic diseases often mimic the human phenotype. Zebrafish larvae develop rapidly and externally around the maternally deposited yolk. Recent work revealed that any disturbance of lipoprotein formation leads to the accumulation of cytoplasmic lipid droplets and an opaque yolk, providing a visible phenotype to investigate disturbances of the lipoprotein pathway, already leading to discoveries in MTTP (microsomal triglyceride transfer protein) and ApoB (apolipoprotein B). By 5 days of development, the digestive system is functional, making it possible to study fluorescently labeled lipid uptake in the transparent larvae. These and other approaches enabled the first in vivo description of the STAB (stabilin) receptors, showing lipoprotein uptake in endothelial cells. Various zebrafish models have been developed to mimic human diseases by mutating genes known to influence lipoproteins (eg, , ). This review aims to discuss the most recent research in the zebrafish ApoB-containing lipoprotein and lipid metabolism field. We also summarize new insights into lipid processing within the yolk cell and how changes in lipid flux alter yolk opacity. This curious new finding, coupled with the development of several techniques, can be deployed to identify new players in lipoprotein research directly relevant to human disease.
Topics: Zebrafish; Animals; Lipid Metabolism; Apolipoproteins B; Humans; Disease Models, Animal; Phenotype; Zebrafish Proteins; Mutation
PubMed: 38482694
DOI: 10.1161/ATVBAHA.123.318287 -
Communications Biology Feb 2024Apolipoprotein B-100 (APOB) is a component of fat- and cholesterol-transporting molecules in the bloodstream. It is the main lipoprotein in low-density lipoprotein...
Apolipoprotein B-100 (APOB) is a component of fat- and cholesterol-transporting molecules in the bloodstream. It is the main lipoprotein in low-density lipoprotein cholesterol (LDL) and has been implicated in conditions that end healthspan (the interval between birth and onset of chronic disease). However, APOB's direct relationship with healthspan remains uncertain. With Mendelian randomization, we show that higher levels of APOB and LDL shorten healthspan in humans. Multivariable Mendelian randomization of APOB and LDL on healthspan suggests that the predominant trait accounting for the relationship is APOB. In addition, we provide preliminary evidence that APOB increases risk for Alzheimer's disease, a condition that ends healthspan. If these relationships are causal, they suggest that interventions to improve healthspan in aging populations could include strategies targeting APOB. Ultimately, given that more than 44 million people currently suffer from Alzheimer's disease worldwide, such interventions are needed.
Topics: Humans; Alzheimer Disease; Mendelian Randomization Analysis; Apolipoproteins B; Cholesterol, LDL; Phenotype
PubMed: 38402277
DOI: 10.1038/s42003-024-05887-2 -
Journal of Cardiovascular Development... Jan 2024The prevention of cardiovascular (CV) disease is mandatory from childhood onwards. Among biochemical markers related to the clinical cardiovascular outcome, LDL...
RATIONALE
The prevention of cardiovascular (CV) disease is mandatory from childhood onwards. Among biochemical markers related to the clinical cardiovascular outcome, LDL cholesterol (LDL-C), non-HDL-C and apolipoprotein B (ApoB) are recognized as main target parameters. Emphasis on ApoB concentrations is growing, as representative of any class of atherogenic lipoprotein. This consideration allows checking of subjects under 18 years of age when the CV risk occurs. The aim of this study is to evaluate ApoB levels in a sample of Italian hyperlipidemic children and adolescents, and their siblings, to test any relationship with their lipid profile.
METHODS
A retrospective study, including 1877 children and adolescents (aged 0-18 years), was performed. Clinical and biochemical data were selected from a database, including the lipid profile, ApoB analysis and anthropometric parameters of any proband. Participants had been checked as potentially hyperlipidemia affected, the suspicion raised by familial CV risk or because the dyslipidemia was already known. Data from the first visit at the University Hospitals in Rome and Turin were collected. Patients affected by secondary hyperlipidemia or obesity were excluded. Blood test analysis was performed in fasting conditions by automated commercial kits. Participants were classified according to gender, age (stratified in subgroups: 0-5, 6-10, 11-14, and 15-18 years old) and anthropometric parameters, referred to as weight in Kg and height in cm, and BMI calculated. Lipid profile results were stratified in relation to acceptable, borderline, or increased levels, as indicated by NCEP, and any potential relation with ApoB established. Statistics were performed by Epi-Info 7 programs to evaluate the variance analysis. Either parent could sign the informed consent.
RESULTS
Among the whole sample n.1010 and n.867 participants were females and males, respectively. TC values acceptable (≤170 mg/dL), borderline (171-200 mg/dL) and elevated (≥201 mg/dL) were found in 411 (22%), 585 (31%) and 881 (47%) participants, respectively. The LDL-C cut-off considered was 110 mg/dL (90° percentile). Mean ApoB progressively increased from 65 to 110 mg/dL according to TC levels and resulted in significant correlation when any age subgroup and gender was considered. The highest ApoB values, TC and LDL-C related, were found in the youngest subgroup, regardless of gender.
CONCLUSION
ApoB results increase progressively and in parallel with TC and LDL-C and represent a further parameter to distinguish between normal and hyperlipidemic subjects. Serum levels are close to 70 mg/dL and to 100 mg/dL in the former and latter group, respectively.
PubMed: 38392258
DOI: 10.3390/jcdd11020044 -
JCI Insight Oct 2023Oxidized apolipoprotein B (oxLDL) and oxidized ApoA-I (oxHDL) are proatherogenic. Their prognostic value for assessing high-risk plaques by coronary computed tomography... (Observational Study)
Observational Study
BACKGROUND
Oxidized apolipoprotein B (oxLDL) and oxidized ApoA-I (oxHDL) are proatherogenic. Their prognostic value for assessing high-risk plaques by coronary computed tomography angiography (CCTA) is missing.
METHODS
In a prospective, observational study, 306 participants with cardiovascular disease (CVD) had extensive lipoprotein profiling. Proteomics analysis was performed on isolated oxHDL, and atherosclerotic plaque assessment was accomplished by quantitative CCTA.
RESULTS
Patients were predominantly White, overweight men (58.5%) on statin therapy (43.5%). Increase in LDL-C, ApoB, small dense LDL-C (P < 0.001 for all), triglycerides (P = 0.03), and lower HDL function were observed in the high oxLDL group. High oxLDL associated with necrotic burden (NB; β = 0.20; P < 0.0001) and fibrofatty burden (FFB; β = 0.15; P = 0.001) after multivariate adjustment. Low oxHDL had a significant reverse association with these plaque characteristics. Plasma oxHDL levels better predicted NB and FFB after adjustment (OR, 2.22; 95% CI, 1.27-3.88, and OR, 2.80; 95% CI, 1.71-4.58) compared with oxLDL and HDL-C. Interestingly, oxHDL associated with fibrous burden (FB) change over 3.3 years (β = 0.535; P = 0.033) when compared with oxLDL. Combined Met136 mono-oxidation and Trp132 dioxidation of HDL showed evident association with coronary artery calcium score (r = 0.786; P < 0.001) and FB (r = 0.539; P = 0.012) in high oxHDL, whereas Met136 mono-oxidation significantly associated with vulnerable plaque in low oxHDL.
CONCLUSION
Our findings suggest that the investigated oxidized lipids are associated with high-risk coronary plaque features and progression over time in patients with CVD.
CLINICALTRIALS
gov NCT01621594.
FUNDING
National Heart, Lung, and Blood Institute at the NIH Intramural Research Program.
Topics: Humans; Male; Apolipoprotein A-I; Apolipoproteins B; Cardiovascular Diseases; Cholesterol, LDL; Plaque, Atherosclerotic; Prospective Studies
PubMed: 37698922
DOI: 10.1172/jci.insight.172893 -
Atherosclerosis Nov 2023Sex-specific differences in the response to lipid-lowering therapies have been reported. Here, we assessed the effect of bempedoic acid in women and men using pooled,...
BACKGROUND AND AIMS
Sex-specific differences in the response to lipid-lowering therapies have been reported. Here, we assessed the effect of bempedoic acid in women and men using pooled, patient-level data from four phase 3 clinical trials of bempedoic acid.
METHODS
Patients were grouped into two pools: 1) atherosclerotic cardiovascular disease (ASCVD) and/or heterozygous familial hypercholesterolemia (HeFH) "on statins" and 2) "low-dose or no statin". Percent changes from baseline to at least week 12 in low-density lipoprotein cholesterol (LDL-C), non-high-density lipoprotein cholesterol (non-HDL-C), total cholesterol (TC), apolipoprotein B (Apo B), and high-sensitivity C-reactive protein (hsCRP), as well as safety, were analyzed by statin pool and sex.
RESULTS
Overall, 3623 patients were included (bempedoic acid, 2425; placebo, 1198). Significant reductions in lipid parameters and hsCRP were observed with bempedoic acid vs. placebo in both sexes in the ASCVD and/or HeFH on statins (n = 3009) and the low-dose or no statin (n = 614) pools (p ≤ 0.002). Compared with men, women had significantly greater placebo-corrected reductions in LDL-C (-21.2% vs. -17.4%; p = 0.044), non-HDL-C (-17.3% vs. -12.1%; p = 0.003), TC (-13.8% vs. -10.5%; p = 0.012), and Apo B (-16.0% vs. -11.3%; p = 0.004) in the ASCVD and/or HeFH on statins pool. Women had similar reductions to men in lipid parameters in the low-dose or no statin pool and hsCRP in both pools. The safety of bempedoic acid was comparable between sexes.
CONCLUSIONS
In this pooled analysis, women experienced significant improvements in levels of LDL-C and other lipid parameters with bempedoic acid.
Topics: Male; Humans; Female; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Cholesterol, LDL; C-Reactive Protein; Hypercholesterolemia; Fatty Acids; Dicarboxylic Acids; Cholesterol; Atherosclerosis; Apolipoproteins B; Anticholesteremic Agents; Treatment Outcome
PubMed: 37648637
DOI: 10.1016/j.atherosclerosis.2023.117192 -
Clinica E Investigacion En... 2023Primary hypocholesterolemia (or hypobetalipoproteinemia) is a rare disorder of lipoprotein metabolism that may be due to a polygenic predisposition or a monogenic...
Primary hypocholesterolemia (or hypobetalipoproteinemia) is a rare disorder of lipoprotein metabolism that may be due to a polygenic predisposition or a monogenic disease. Among these, it is possible to differentiate between symptomatic and asymptomatic forms, in which, in the absence of secondary causes, the initial clinical suspicion is plasma ApoB levels below the 5th percentile of the distribution by age and sex. Here we describe the differential diagnosis of a case of asymptomatic hypocholesterolemia. We studied proband's clinical data, the lipid profile of the proband and her relatives and the clinical data of the family relevant to carry out the differential diagnosis. We performed a genetic study as the diagnostic test. The information obtained from the differential diagnosis suggested a heterozygous hypobetalipoproteinemia due to PCSK9 loss-of-function variants. The diagnostic test revealed, in the proband, the presence of a heterozygous PCSK9 frame-shift variant of a maternal origin. Plasma levels of LDL cholesterol and PCSK9 of the patient and her relatives were compatible with the segregation of the variant revealed. In conclusion, the diagnostic test performed confirmed the suspected diagnosis of the proband as asymptomatic familial hypobetalipoproteinemia due to a loss-of-function variant in the PCSK9 gene.
Topics: Humans; Female; Proprotein Convertase 9; Hypobetalipoproteinemias; Hypolipoproteinemias; Cholesterol, LDL; Apolipoproteins B
PubMed: 37302939
DOI: 10.1016/j.arteri.2023.05.003 -
Cancer Medicine Nov 2023Plasma cell neoplasms are a group of hematologic neoplasms that often develop in the elderly population. The relationship between cholesterol levels and hematologic...
BACKGROUND
Plasma cell neoplasms are a group of hematologic neoplasms that often develop in the elderly population. The relationship between cholesterol levels and hematologic malignancy has been identified in population studies. However, it is still unclear if there is a relationship between cholesterol levels and plasma cell neoplasm in European ancestry.
METHODS
Prospective cohorts included 502,507 individuals from the UK Biobank who were followed up to 2019 and assessed total cholesterol(TC) levels, low-density lipoprotein (LDL) levels, high-density lipoprotein (HDL) levels, apolipoprotein A (ApoA) and apolipoprotein B (ApoB) as risk factors for plasma cell neoplasms with Cox proportional hazard regression and restricted cubic spline model. We also used two-sample Mendelian randomization to determine if the cholesterol level has a causal effect on developing plasma cell neoplasms.
RESULTS
We observed 1819 plasma cell neoplasm cases during 14.2 years of follow-up in the UK Biobank. We found higher blood serum cholesterol levels at baseline were associated with a lower risk of plasma cell neoplasm in our study. All lipid profiles we analyzed in this study were inversely associated with plasma cell neoplasm risk (all p <0.005) but triglycerides did not have such association. However, there was no suggestive association of genetically predicted serum LDL, HDL, and total cholesterol levels with multiple myeloma.
CONCLUSION
Low serum total cholesterol, LDL, HDL, ApoA, and ApoB levels were all associated with increasing the risk of plasma cell neoplasm.
Topics: Humans; Aged; Cohort Studies; Prospective Studies; Multiple Myeloma; Biological Specimen Banks; Cholesterol, HDL; Cholesterol, LDL; Apolipoproteins B; Risk Factors; Triglycerides; Apolipoproteins A
PubMed: 37908181
DOI: 10.1002/cam4.6649 -
Frontiers in Immunology 2023Guillain-Barre syndrome (GBS) is an immune-mediated inflammatory peripheral neuropathy. This study aimed to conduct a systematic analysis of the serum lipids profile in...
BACKGROUND
Guillain-Barre syndrome (GBS) is an immune-mediated inflammatory peripheral neuropathy. This study aimed to conduct a systematic analysis of the serum lipids profile in GBS.
METHODS
We measured the serum lipids profile in 85 GBS patients and compared it with that of 85 healthy controls matched for age and sex. Additionally, we analyzed the correlation between lipids and the severity, subtypes, precursor infections, clinical outcomes, clinical symptoms, immunotherapy, and other laboratory markers of GBS.
RESULTS
Compared to the healthy controls, GBS exhibited significantly elevated levels of Apolipoprotein B (APOB), Apolipoprotein C2 (APOC2), Apolipoprotein C3 (APOC3), Apolipoprotein E (APOE), triglycerides (TG), and residual cholesterol (RC). Conversely, Apolipoprotein A1 (APOA1), Apolipoprotein A2 (APOA2), and high-density lipoprotein (HDL) were substantially lower in GBS. Severe GBS displayed noticeably higher levels of APOC3 and total cholesterol (TC) compared to those with mild disease. Regarding different clinical outcomes, readmitted GBS demonstrated higher RC expression than those who were not readmitted. Moreover, GBS who tested positive for neuro-virus antibody IGG in cerebrospinal fluid (CSF) exhibited heightened expression of APOC3 in comparison to those who tested negative. GBS with cranial nerve damage showed significantly reduced expression of HDL and APOA1 than those without such damage. Additionally, GBS experiencing limb pain demonstrated markedly decreased HDL expression. Patients showed a significant reduction in TC after intravenous immunoglobulin therapy. We observed a significant positive correlation between lipids and inflammatory markers, including TNF-α, IL-1β, erythrocyte sedimentation rate (ESR), white blood cells, monocytes, and neutrophils in GBS. Notably, APOA1 exhibited a negative correlation with ESR. Furthermore, our findings suggest a potential association between lipids and the immune status of GBS.
CONCLUSION
The research demonstrated a strong connection between lipids and the severity, subtypes, clinical outcomes, precursor infections, clinical symptoms, immunotherapy, inflammation, and immune status of GBS. This implies that a low-fat diet or the use of lipid-lowering medications may potentially serve as an approach for managing GBS, offering a fresh viewpoint for clinical treatment of this condition.
Topics: Humans; Guillain-Barre Syndrome; Lipids; Triglycerides; Cholesterol; Apolipoproteins B
PubMed: 38143756
DOI: 10.3389/fimmu.2023.1301577 -
European Review For Medical and... Dec 2023Patients with pancreatic diseases are at increased risk of cardiovascular events. Investigating various apolipoprotein forms as important atherogenesis components may...
OBJECTIVE
Patients with pancreatic diseases are at increased risk of cardiovascular events. Investigating various apolipoprotein forms as important atherogenesis components may improve cardiovascular risk (CVR) prediction. This study aimed to investigate CVR factors in patients with chronic pancreatitis.
PATIENTS AND METHODS
The study enrolled 70 patients (40 males and 30 females, mean age 55.2 years) with chronic pancreatitis and treated pancreatic exocrine insufficiency. We assessed CVR by apolipoproteins A-I, A-II, B, and C-III, lipid profile; score systems [SCORE risk chart and Framingham Risk Score (FRS)], diabetes mellitus; chronic pancreatitis by M-ANNHEIM classification. Statistics were performed via SPSS v. 22.
RESULTS
Low apolipoprotein A-I and high apolipoprotein B levels with increased atherogenic potential were observed in 37 and 26 patients. 45.71% demonstrated a high risk of myocardial infarction with high apolipoprotein B/apolipoprotein A-I ratio. Men are at higher CVR risk. Apolipoproteins A-I and A-II correlated with the cardioprotective high-density lipoprotein (HDL) in contrast to apolipoproteins B and C-III, which correlated strongly with low-density lipoprotein (LDL), total cholesterol (TC), and triglycerides (TG). Increased CVR assessed by FRS correlated with significantly lower apolipoprotein A-I and higher apolipoprotein B and apolipoprotein B/apolipoprotein A-I ratio. With the increase in chronic pancreatitis severity, we observed decreased apolipoproteins and increased apolipoprotein B/apolipoprotein A-I ratio.
CONCLUSIONS
Apolipoproteins are valuable CVR indicators. Further studies are required to establish a CVR screening panel in this population.
Topics: Male; Female; Humans; Middle Aged; Apolipoprotein A-I; Cardiovascular Diseases; Risk Factors; Apolipoproteins; Apolipoproteins B; Triglycerides; Atherosclerosis; Heart Disease Risk Factors; Pancreatitis, Chronic; Cholesterol, HDL
PubMed: 38164866
DOI: 10.26355/eurrev_202312_34802