-
Environmental Research Aug 2023Dyslipidemia, an imbalance of lipids and a major risk factor for cardiovascular disease, has been associated with elevated blood and urine levels of several heavy...
Dyslipidemia, an imbalance of lipids and a major risk factor for cardiovascular disease, has been associated with elevated blood and urine levels of several heavy metals. Using data from a Canadian Health Measures Survey (CHMS), we tested associations between blood levels of cadmium, copper, mercury, lead, manganese, molybdenum, nickel, selenium, and zinc, and the lipids triglycerides (TG), total cholesterol (TC), low density lipoproteins (LDL), high density lipoproteins (HDL) and apolipoproteins A1 (APO A1), and B (APO B). All adjusted associations between single metals and lipids were positive and significant, except for APO A1 and HDL. The joint effect of an interquartile range increase in heavy metals was positively associated with percentage increases of TC, LDL and APO B of 8.82% (95%CI: 7.06, 10.57), 7.01% (95%CI: 2.51, 11.51) and 7.15% (95%CI: 0.51, 13.78), respectively. Future studies are warranted to determine if reducing environmental exposure to heavy metals favorably influences lipid profiles and the risk of cardiovascular disease.
Topics: Humans; Lipoproteins; Lipids; Apolipoprotein A-I; Cardiovascular Diseases; Cross-Sectional Studies; Canada; Apolipoproteins B; Triglycerides; Cholesterol, HDL
PubMed: 37187310
DOI: 10.1016/j.envres.2023.116107 -
Hepatology (Baltimore, Md.) Nov 2023The assembly and secretion of VLDL from the liver, a pathway that affects hepatic and plasma lipids, remains incompletely understood. We set out to identify players in...
BACKGROUND AND AIMS
The assembly and secretion of VLDL from the liver, a pathway that affects hepatic and plasma lipids, remains incompletely understood. We set out to identify players in the VLDL biogenesis pathway by identifying genes that are co-expressed with the MTTP gene that encodes for microsomal triglyceride transfer protein, key to the lipidation of apolipoprotein B, the core protein of VLDL. Using human and murine transcriptomic data sets, we identified small leucine-rich protein 1 ( SMLR1 ), encoding for small leucine-rich protein 1, a protein of unknown function that is exclusively expressed in liver and small intestine.
APPROACH AND RESULTS
To assess the role of SMLR1 in the liver, we used somatic CRISPR/CRISPR-associated protein 9 gene editing to silence murine Smlr1 in hepatocytes ( Smlr1 -LKO). When fed a chow diet, male and female mice show hepatic steatosis, reduced plasma apolipoprotein B and triglycerides, and reduced VLDL secretion without affecting microsomal triglyceride transfer protein activity. Immunofluorescence studies show that SMLR1 is in the endoplasmic reticulum and Cis-Golgi complex. The loss of hepatic SMLR1 in female mice protects against diet-induced hyperlipidemia and atherosclerosis but causes NASH. On a high-fat, high-cholesterol diet, insulin and glucose tolerance tests did not reveal differences in male Smlr1 -LKO mice versus controls.
CONCLUSIONS
We propose a role for SMLR1 in the trafficking of VLDL from the endoplasmic reticulum to the Cis-Golgi complex. While this study uncovers SMLR1 as a player in the VLDL assembly, trafficking, and secretion pathway, it also shows that NASH can occur with undisturbed glucose homeostasis and atheroprotection.
Topics: Animals; Female; Humans; Male; Mice; Apolipoproteins B; Atherosclerosis; Leucine; Lipoproteins, VLDL; Liver; Non-alcoholic Fatty Liver Disease; Small Leucine-Rich Proteoglycans; Triglycerides
PubMed: 36053190
DOI: 10.1002/hep.32709 -
JAMA Network Open Jan 2024Apolipoprotein B (apoB), low-density lipoprotein cholesterol (LDL-C), and triglycerides (TG) are associated with coronary artery disease (CAD). However, trial evidence...
IMPORTANCE
Apolipoprotein B (apoB), low-density lipoprotein cholesterol (LDL-C), and triglycerides (TG) are associated with coronary artery disease (CAD). However, trial evidence for the association of intensive LDL-C lowering and TG lowering with mortality is less definitive.
OBJECTIVES
To investigate the associations of apoB, LDL-C, and TG with CAD and mortality, both overall and by sex and age, and to characterize the shapes of these associations.
DESIGN, SETTING, AND PARTICIPANTS
This genetic association study used linear and nonlinear mendelian randomization (MR) to analyze a population-based cohort of individuals of European ancestry from the UK Biobank, which recruited participants from 2006 to 2010 with follow-up information updated until September 2021. Data analysis occurred from December 2022 to November 2023.
EXPOSURES
Genetically predicted apoB, LDL-C, and TG.
MAIN OUTCOMES AND MEASURES
The primary outcomes were CAD, all-cause mortality, and cause-specific mortality. Genetic associations with CAD were calculated using logistic regression, associations with all-cause mortality using Cox proportional hazards regression, and associations with cause-specific mortality using cause-specific Cox proportional hazards regression with censoring for other causes of mortality.
RESULTS
This study included 347 797 participants (mean [SD] age, 57.2 [8.0] years; 188 330 female [54.1%]). There were 23 818 people who developed CAD and 23 848 people who died. Genetically predicted apoB was positively associated with risk of CAD (odds ratio [OR], 1.65 per SD increase; 95% CI 1.57-1.73), all-cause mortality (hazard ratio [HR], 1.11; 95% CI, 1.06-1.16), and cardiovascular mortality (HR, 1.36; 95% CI, 1.24-1.50), with some evidence for larger associations in male participants than female participants. Findings were similar for LDL-C. Genetically predicted TG was positively associated with CAD (OR, 1.60; 95% CI 1.52-1.69), all-cause mortality (HR, 1.08; 95% CI, 1.03-1.13), and cardiovascular mortality (HR, 1.21; 95% CI, 1.09-1.34); however, sensitivity analyses suggested evidence of pleiotropy. The association of genetically predicted TG with CAD persisted but it was no longer associated with mortality outcomes after controlling for apoB. Nonlinear MR suggested that all these associations were monotonically increasing across the whole observed distribution of each lipid trait, with no diminution at low lipid levels. Such patterns were observed irrespective of sex or age.
CONCLUSIONS AND RELEVANCE
In this genetic association study, apoB (or, equivalently, LDL-C) was associated with increased CAD risk, all-cause mortality, and cardiovascular mortality, all in a dose-dependent way. TG may increase CAD risk independent of apoB, although the possible presence of pleiotropy is a limitation. These insights highlight the importance of apoB (or, equivalently, LDL-C) lowering for reducing cardiovascular morbidity and mortality across its whole distribution.
Topics: Humans; Male; Female; Middle Aged; Coronary Artery Disease; Cholesterol, LDL; Risk Factors; Apolipoproteins B; Triglycerides
PubMed: 38241044
DOI: 10.1001/jamanetworkopen.2023.52572 -
BMC Medical Genomics Dec 2023In response to the controversy surrounding observational studies of the association between lipid profiles and the risk of insomnia, the aim of this study was to analyze...
OBJECTIVES
In response to the controversy surrounding observational studies of the association between lipid profiles and the risk of insomnia, the aim of this study was to analyze lipid profiles, including triglycerides (TG), apolipoprotein A-1 (ApoA-1), apolipoprotein B (ApoB) and lipoprotein A (LPA), in a European population to further assess the causal relationship between these lipid types and insomnia.
MATERIALS AND METHODS
This study explores the causal effect of lipid profiles on insomnia based on a genome-wide association study (GWAS)-derived public dataset using two-sample and multivariate Mendelian randomization (MVMR) analysis. The main MR analyses used inverse variance weighting (IVW) odds ratio (OR), and the sensitivity analyses included weighted median (WM) and MR‒Egger.
RESULTS
Both MR and MVMR showed that lowering ApoA-1 and LPA levels had causal effects on the risk of insomnia [MR: per 10 units, ApoA-1: OR: 0.7546, 95% CI: 0.6075-0.9372, P = 0.011; LPA: OR: 0.8392, 95% CI: 0.7202-0.9778, P = 0.025; MVMR: per 10 units, ApoA-1: OR: 0.7600, 95% CI: 0.6362-0.9079, P = 0.002; LPA, OR: 0.903, 95% CI: 0.8283-0.9845, P = 0.021]. There were no causal effects of TG or ApoB on insomnia (all P > 0.05). The MR‒Egger intercept test, funnel plot, and IVW methods all suggested an absence of strong directional pleiotropy, and leave-one-out permutation analysis did not detect any single single-nucleotide polymorphism that had a strong influence on the results.
CONCLUSION
Elevated levels of ApoA-1 and LPA were independently and causally associated with the risk of insomnia, suggesting that elevated ApoA-1 and LPA levels may contribute to a reduced risk of insomnia.
Topics: Humans; Apolipoprotein A-I; Apolipoproteins B; Genome-Wide Association Study; Mendelian Randomization Analysis; Polymorphism, Single Nucleotide; Sleep Initiation and Maintenance Disorders; Triglycerides
PubMed: 38087303
DOI: 10.1186/s12920-023-01761-y -
Environment International Jan 2024Per- and polyfluoroalkyl substances (PFAS) can disrupt liver homeostasis. Studies have shown that a single exposure to PFAS may provoke abnormal liver function; however,...
Per- and polyfluoroalkyl substances (PFAS) can disrupt liver homeostasis. Studies have shown that a single exposure to PFAS may provoke abnormal liver function; however, few studies have investigated the overall effect of PFAS mixtures. We aimed to investigate associations between exposure to PFAS mixtures and liver function indices and explore the relevant mechanisms. This study included 278 adult males from Guangzhou, China. Serum metabolite profiles were analyzed using untargeted metabolomics. We applied weighted quantile sum (WQS) regression as well as Bayesian kernel machine regression (BKMR) to analyze the association of nine PFAS mixtures with 14 liver function indices. PFAS mixtures were positively associated with apolipoprotein B (APOB) and gamma-glutamyltransferase (GGT) and negatively associated with direct bilirubin (DBIL) and total bilirubin (TBIL) in both the WQS and BKMR analyses. In addition, Spearman's correlation test showed individual PFAS correlated with APOB, GGT, TBIL, and DBIL, while there's little correlation between individual PFAS and other liver function indices. In linear regression analysis, PFHxS, PFOS, PFHpS, PFNA, PFDA, and PFUdA were associated with APOB; PFOA, PFDA, PFOS, PFNA, and PFUdA were associated with GGT. Subsequently, a metabolome-wide association study and mediation analysis were combined to explore metabolites that mediate these associations. The mechanisms linking PFAS to APOB and GGT are mainly related with amino acid and glycerophospholipid metabolism. High-dimensional mediation analysis showed that glycerophospholipids are the main markers of the association between PFAS and APOB, and that (R)-dihydromaleimide, Ile Leu, (R)-(+)-2-pyrrolidone-5-carboxylic acid, and L-glutamate are the main markers of the association between PFAS and GGT. In summary, overall associations between PFAS and specific indices of liver function were found using two statistical methods; the metabolic pathways and markers identified here may serve to prompt more detailed study in animal-based systems, as well as a similar detailed analysis in other populations.
Topics: Animals; Male; Bayes Theorem; Apolipoproteins B; Bilirubin; Liver; Fluorocarbons; Environmental Pollutants; Alkanesulfonic Acids
PubMed: 38163401
DOI: 10.1016/j.envint.2023.108405 -
Frontiers in Endocrinology 2023Research has shown that the disordered serum lipid profile may be associated with the risk of differentiated thyroid cancer (DTC). Whether this association reflect...
BACKGROUND
Research has shown that the disordered serum lipid profile may be associated with the risk of differentiated thyroid cancer (DTC). Whether this association reflect causal effect is still unclear. The aim of this study was to evaluate the causality of circulating lipoprotein lipids on DTC.
METHODS
Mendelian randomization (MR) analysis was conducted to evaluate the relationship between the circulating lipoprotein lipids and DTC risk using single-nucleotide polymorphisms (SNPs) from a genome-wide association (GWA) study containing a high-incidence Italian population of 690 cases samples with DTC and 497 controls.
RESULTS
Univariate and multivariate mendelian randomization analysis demonstrated that 'total cholesterol', 'HDL cholesterol', 'apolipoprotein B' and 'ratio of apolipoprotein B to apolipoprotein A1' were correlated with DTC. According to sensitivity analysis, our results were reliable. Furthermore, multivariate analysis revealed that there is no causative association between DTC and any of the many cause factors when they interact with one another, suggesting that there was a deep interaction between the four factors, which could affect each other. Finally, the mechanism of the related effects each other as well as the target genes with significant SNP regulatory effects in DTC was explored by conducting functional enrichment analysis and constructing the regulatory networks.
CONCLUSIONS
We obtained four exposure factors (total cholesterol, HDL cholesterol, apolipoprotein B and ratio of apolipoprotein B to apolipoprotein A1) closely related to DTC, which laid a theoretical foundation for the treatment of DTC.
Topics: Humans; Apolipoprotein A-I; Genome-Wide Association Study; Mendelian Randomization Analysis; Adenocarcinoma; Apolipoproteins B; Cholesterol, HDL; Lipid Metabolism Disorders; Thyroid Neoplasms
PubMed: 38189054
DOI: 10.3389/fendo.2023.1291445 -
European Review For Medical and... Jul 2023Berberine is a plant alkaloid known to exert positive metabolic effects. Human studies have confirmed its ability to improve the lipid and glycemic profile. This study... (Randomized Controlled Trial)
Randomized Controlled Trial
Berberine phospholipid exerts a positive effect on the glycemic profile of overweight subjects with impaired fasting blood glucose (IFG): a randomized double-blind placebo-controlled clinical trial.
OBJECTIVE
Berberine is a plant alkaloid known to exert positive metabolic effects. Human studies have confirmed its ability to improve the lipid and glycemic profile. This study aimed to evaluate the potential benefit of oral supplementation of Berberine PhytosomeTM (2 tablets/day, 550 mg/tablet) on the metabolic profile of subjects with impaired fasting blood glucose (IFG).
PATIENTS AND METHODS
A total of 49 overweight subjects, 28 females and 21 males, were randomly assigned to either the supplemented group (n=24) or placebo (n=25). We considered glycemia as the primary endpoint and total cholesterol, high-density lipoprotein (HDL), total cholesterol/HLD, low-density lipoprotein (LDL), LDL/HDL, triglycerides, insulin, glycated hemoglobin, Homeostasis Model Assessment (HOMA), ApoA, ApoB, ApoB/ApoA, androgen suppression treatment (AST), alternative lengthening of telomeres (ALT), gamma-glutamyl transferase (GGT), creatinine, and body composition by dual-energy X-ray absorptiometry (DXA) as secondary endpoints. These parameters have been assessed at baseline, after 30 days, and after 60 days.
RESULTS
After two months of treatment, through the use of linear mixed effect models, a statistically significant difference between supplemented and placebo groups was observed for glycemia [β=-0.2495% C.I. (-0.47; -0.06), p=0.004], total cholesterol [β=-0.25, 95% C.I. (-0.45; -0.04), p=0.05], total cholesterol/HDL [β=-0.25, 95% C.I. (-0.43; -0.06), p=0.04], triglycerides [β=-0.14, 95% C.I. (-0.25; -0.02), p=0.05], insulin [β=-1.78, 95% C.I. (-2.87; -0.66), p=0.009], ApoB/ApoA [β=-0.08, 95% C.I. (-0.13; -03), p=0.004], Visceral adipose tissue (VAT) [β=-91.50, 95% C.I. (-132.60; -48.19), p<0.0001] and fat mass [β=-945.56, 95% C.I. (-1,424.42; -441.57), p=0.004].
CONCLUSIONS
The use of berberine had no adverse events, supporting its use as a natural alternative to pharmacological therapies in the case of IFG.
Topics: Male; Female; Humans; Overweight; Blood Glucose; Berberine; Phospholipids; Triglycerides; Insulin; Lipoproteins, HDL; Cholesterol; Apolipoproteins A; Apolipoproteins B; Fasting; Double-Blind Method
PubMed: 37522683
DOI: 10.26355/eurrev_202307_33142 -
Frontiers in Endocrinology 2023Previous findings have indicated that elevated low-density lipoprotein cholesterol (LDL-C) and remnant cholesterol (RC) are associated with hypertension. We aim to...
BACKGROUND
Previous findings have indicated that elevated low-density lipoprotein cholesterol (LDL-C) and remnant cholesterol (RC) are associated with hypertension. We aim to explore whether higher RC levels may be associated with hypertension beyond LDL-C in the general US adult population.
METHODS
This study included 10,842 adults from the National Health and Nutrition Examination Survey (NHANES) 1999-2018. Weighted multivariable logistic regression models were used to estimate the odds ratios (ORs) of hypertension for LDL-C and RC. We also performed analyses examining the association between hypertension and LDL-C vs. RC concordant/discordant groups.
RESULTS
A total of 4,963 (41.54%, weighted) individuals had hypertension. The weighted median levels were LDL-C: 118mg/dL, RC: 20mg/dL. At lower LDL-C clinical cut-point, the proportion of discordantly high RC dramatically increased. After multivariable adjustment, log RC was associated with higher prevalence of hypertension [OR 2.54, 95% confidence interval (CI) 2.17-2.99]. Participants with the highest tertile of RC were more likely to have hypertension (OR 2.18; 95% CI 1.89-2.52) compared with those with the lowest tertile of RC. This association remained marked after including body mass index (BMI), LDL-C, high-density lipoprotein cholesterol (HDL-C) or triglycerides. The association between LDL-C and hypertension was absent after adjusting for BMI, RC or triglycerides. Compared with low LDL-C/low RC group, the discordant low LDL-C/high RC group was associated with hypertension (OR 2.04; 95% CI 1.72-2.42), whereas the high LDL-C/low RC group was not, regardless of BMI, HDL-C or triglycerides. Similar results were observed when examining discordance among different clinical cut-points, except for the cut-point of LDL-C 70 mg/dL and RC 13 mg/dL. To better understand the association, we performed an additional analysis, which showed that among participants with apolipoprotein B < median (92mg/dL), those with discordant RC ≥ median (20mg/dL) had significantly higher odds of having hypertension (OR 1.73; 95% CI 1.38-2.17).
CONCLUSION
RC was associated with hypertension beyond LDL-C in the general US adult population. This association went beyond increased triglycerides levels, and lipoproteins other than apoB may be involved.
Topics: Adult; Humans; Cholesterol, LDL; Nutrition Surveys; Cholesterol; Cholesterol, HDL; Triglycerides; Hypertension; Apolipoproteins B; Hyperlipidemias
PubMed: 37842298
DOI: 10.3389/fendo.2023.1260764 -
Ecotoxicology and Environmental Safety Dec 2023Neonicotinoid insecticides (NNIs) are widely used in agriculture, horticulture, forestry, and household environment, but their potential impact on human health remains a...
Neonicotinoid insecticides (NNIs) are widely used in agriculture, horticulture, forestry, and household environment, but their potential impact on human health remains a subject of concern. This study aimed to investigate the relationship between NNIs and their metabolites in urine with serum lipid profiles in adults using data from the National Health and Nutrition Examination Survey (NHANES) 2015-2016. The study included 1192 participants aged over 20 years with urinary NNIs levels, serum lipid parameter levels and potential confounders. Urinary concentrations of NNIs, including imidacloprid, acetamiprid, clothianidin, thiacloprid, N-desmethyl-acetamiprid, and 5-hydroxy-imidacloprid, were quantified. Serum lipids profiles, such as total cholesterol (TC), triglyceride (TG), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C) and apolipoprotein B (Apo-B), were assessed. Considering the effects of lipid-lowering medications, the censored normal regression model was used to explore the associations between urinary NNIs and TC, TG, HDL-C, LDL-C and Apo-B levels. The results revealed a significant increase of 9.0 mg/dL (95%CI: 2.0, 16.1) in TC levels among participants with detectable N-desmethyl-acetamiprid compared to those with undetectable levels. Stratified analysis indicated that the association between N-desmethyl-acetamiprid and HDL-C levels was more pronounced among participants aged ≥ 46 years compared to those aged between 20 and 45 years with undetectable N-desmethyl-acetamiprid (p=0.044). Additionally, there were marginal effect modification of BMI on the association between N-desmethyl-acetamiprid and LDL-C (p=0.097) and Apo-B (p=0.052) levels. Specifically, participants with BMI ≥ 25 kg/m² and detectable N-desmethyl-acetamiprid tended to have higher LDL-C and Apo-B levels compared to those with BMI < 25 kg/m² and undetectable N-desmethyl-acetamiprid. However, no significant associations were observed between other NNIs and lipid profiles in the present study. To validate these findings, further longitudinal studies with larger sample sizes should be conducted, particularly within populations characterized by a high detection rate of NNIs.
Topics: Adult; Humans; Young Adult; Middle Aged; Insecticides; Nutrition Surveys; Cholesterol, LDL; Cross-Sectional Studies; Neonicotinoids; Triglycerides; Cholesterol, HDL; Apolipoproteins B
PubMed: 37992647
DOI: 10.1016/j.ecoenv.2023.115724 -
Journal of Lipid Research Feb 2024Angiopoietin-like protein (ANGPTL) complexes 3/8 and 4/8 are established inhibitors of LPL and novel therapeutic targets for dyslipidemia. However, the effects of...
Angiopoietin-like protein (ANGPTL) complexes 3/8 and 4/8 are established inhibitors of LPL and novel therapeutic targets for dyslipidemia. However, the effects of regular exercise on ANGPTL3/8 and ANGPTL4/8 are unknown. We characterized ANGPTL3/8 and ANGPTL4/8 and their relationship with in vivo measurements of lipase activities and cardiometabolic traits before and after a 5-month endurance exercise training intervention in 642 adults from the HERITAGE (HEalth, RIsk factors, exercise Training And GEnetics) Family Study. At baseline, higher levels of both ANGPTL3/8 and ANGPTL4/8 were associated with a worse lipid, lipoprotein, and cardiometabolic profile, with only ANGPTL3/8 associated with postheparin LPL and HL activities. ANGPTL3/8 significantly decreased with exercise training, which corresponded with increases in LPL activity and decreases in HL activity, plasma triglycerides, apoB, visceral fat, and fasting insulin (all P < 5.1 × 10). Exercise-induced changes in ANGPTL4/8 were directly correlated to concomitant changes in total cholesterol, LDL-C, apoB, and HDL-triglycerides and inversely related to change in insulin sensitivity index (all P < 7.0 × 10). In conclusion, exercise-induced decreases in ANGPTL3/8 and ANGPTL4/8 were related to concomitant improvements in lipase activity, lipid profile, and cardiometabolic risk factors. These findings reveal the ANGPTL3-4-8 model as a potential molecular mechanism contributing to adaptations in lipid metabolism in response to exercise training.
Topics: Adult; Humans; Angiopoietin-like Proteins; Angiopoietin-Like Protein 3; Triglycerides; Lipase; Exercise; Cardiovascular Diseases; Apolipoproteins B; Lipoprotein Lipase; Angiopoietin-Like Protein 4
PubMed: 38160757
DOI: 10.1016/j.jlr.2023.100495