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Aging Dec 2023Despite the widespread use of statins, newer lipid-lowering drugs have been emerging. It remains unclear how the long-term use of novel lipid-lowering drugs affects the...
BACKGROUND
Despite the widespread use of statins, newer lipid-lowering drugs have been emerging. It remains unclear how the long-term use of novel lipid-lowering drugs affects the occurrence of cancers and age-related diseases.
METHODS
A drug-target Mendelian randomization study was performed. Genetic variants of nine lipid-lowering drug-target genes (, and ) were extracted as exposures from the summary data of Global Lipids Genetics Consortium Genome-Wide Association Studies (GWAS). GWAS summary data of cancers and noncancerous diseases were used as outcomes. The inverse-variance weighted method was applied as the main statistical approach. Sensitivity tests were conducted to evaluate the robustness, pleiotropy, and heterogeneity of the results.
RESULTS
In addition to marked effects on decreased risks of atherosclerotic cardiovascular diseases, genetically proxied lipid-lowering variants of , , , , and were associated with longer human lifespans (). Lipid-lowering variants of and were associated with reduced risks of colorectal cancer, and was also associated with lower risks of gastric cancer (). Lipid-lowering variants were associated with decreased risks of hypertension, type 2 diabetes, nonalcoholic fatty liver disease, and bladder cancer (). Lipid-lowering variants of and were associated with decreased risks of osteoporosis (). Lipid-lowering variants were associated with a decreased risk of thyroid cancer ().
CONCLUSIONS
Our study provides genetic evidence that newer nonstatin lipid-lowering agents have causal effects on decreased risks of several common cancers and cardiometabolic diseases. These data provide genetic insights into the potential benefits of newer nonstatin therapies.
Topics: Humans; Diabetes Mellitus, Type 2; Genome-Wide Association Study; Mendelian Randomization Analysis; Cholesterol, LDL; Hypolipidemic Agents; Neoplasms; Aging; Apolipoproteins B; Polymorphism, Single Nucleotide; Angiopoietin-Like Protein 3
PubMed: 38127052
DOI: 10.18632/aging.205347 -
Lipids in Health and Disease Dec 2023It remains controversial whether the long-term use of statins or newer nonstatin drugs has a positive effect on human longevity. Therefore, this study aimed to...
BACKGROUND
It remains controversial whether the long-term use of statins or newer nonstatin drugs has a positive effect on human longevity. Therefore, this study aimed to investigate the genetic associations between different lipid-lowering therapeutic gene targets and human longevity.
METHODS
Two-sample Mendelian randomization analyses were conducted. The exposures comprised genetic variants that proxy nine drug target genes mimicking lipid-lowering effects (LDLR, HMGCR, PCKS9, NPC1L1, APOB, CETP, LPL, APOC3, and ANGPTL3). Two large-scale genome-wide association study (GWAS) summary datasets of human lifespan, including up to 500,193 European individuals, were used as outcomes. The inverse-variance weighting method was applied as the main approach. Sensitivity tests were conducted to evaluate the robustness, heterogeneity, and pleiotropy of the results. Causal effects were further validated using expression quantitative trait locus (eQTL) data.
RESULTS
Genetically proxied LDLR variants, which mimic the effects of lowering low-density lipoprotein cholesterol (LDL-C), were associated with extended lifespan. This association was replicated in the validation set and was further confirmed in the eQTL summary data of blood and liver tissues. Mediation analysis revealed that the genetic mimicry of LDLR enhancement extended lifespan by reducing the risk of major coronary heart disease, accounting for 22.8% of the mediation effect. The genetically proxied CETP and APOC3 inhibitions also showed causal effects on increased life expectancy in both outcome datasets. The lipid-lowering variants of HMGCR, PCKS9, LPL, and APOB were associated with longer lifespans but did not causally increase extreme longevity. No statistical evidence was detected to support an association between NPC1L1 and lifespan.
CONCLUSION
This study suggests that LDLR is a promising genetic target for human longevity. Lipid-related gene targets, such as PCSK9, CETP, and APOC3, might potentially regulate human lifespan, thus offering promising prospects for developing newer nonstatin therapies.
Topics: Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Proprotein Convertase 9; Longevity; Mendelian Randomization Analysis; Genome-Wide Association Study; Cholesterol, LDL; Apolipoproteins B; Angiopoietin-Like Protein 3
PubMed: 38082436
DOI: 10.1186/s12944-023-01983-0 -
Diabetologia Dec 2023This study explored the hypothesis that significant abnormalities in the metabolism of intestinally derived lipoproteins are present in individuals with type 2 diabetes...
AIMS/HYPOTHESIS
This study explored the hypothesis that significant abnormalities in the metabolism of intestinally derived lipoproteins are present in individuals with type 2 diabetes on statin therapy. These abnormalities may contribute to residual CVD risk.
METHODS
To investigate the kinetics of ApoB-48- and ApoB-100-containing lipoproteins, we performed a secondary analysis of 11 overweight/obese individuals with type 2 diabetes who were treated with lifestyle counselling and on a stable dose of metformin who were from an earlier clinical study, and compared these with 11 control participants frequency-matched for age, BMI and sex. Participants in both groups were on a similar statin regimen during the study. Stable isotope tracers were used to determine the kinetics of the following in response to a standard fat-rich meal: (1) apolipoprotein (Apo)B-48 in chylomicrons and VLDL; (2) ApoB-100 in VLDL, intermediate-density lipoprotein (IDL) and LDL; and (3) triglyceride (TG) in VLDL.
RESULTS
The fasting lipid profile did not differ significantly between the two groups. Compared with control participants, in individuals with type 2 diabetes, chylomicron TG and ApoB-48 levels exhibited an approximately twofold higher response to the fat-rich meal, and a twofold higher increment was observed in ApoB-48 particles in the VLDL and VLDL density ranges (all p < 0.05). Again comparing control participants with individuals with type 2 diabetes, in the latter, total ApoB-48 production was 25% higher (556 ± 57 vs 446 ± 57 mg/day; p < 0.001), conversion (fractional transfer rate) of chylomicrons to VLDL was around 40% lower (35 ± 25 vs 82 ± 58 pools/day; p=0.034) and direct clearance of chylomicrons was 5.6-fold higher (5.6 ± 2.2 vs 1.0 ± 1.8 pools/day; p < 0.001). During the postprandial period, ApoB-48 particles accounted for a higher proportion of total VLDL in individuals with type 2 diabetes (44%) compared with control participants (25%), and these ApoB-48 VLDL particles exhibited a fivefold longer residence time in the circulation (p < 0.01). No between-group differences were seen in the kinetics of ApoB-100 and TG in VLDL, or in LDL ApoB-100 production, pool size and clearance rate. As compared with control participants, the IDL ApoB-100 pool in individuals with type 2 diabetes was higher due to increased conversion from VLDL.
CONCLUSIONS/INTERPRETATION
Abnormalities in the metabolism of intestinally derived ApoB-48-containing lipoproteins in individuals with type 2 diabetes on statins may help to explain the residual risk of CVD and may be suitable targets for interventions.
TRIAL REGISTRATION
ClinicalTrials.gov NCT02948777.
Topics: Humans; Apolipoprotein B-100; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Apolipoprotein B-48; Diabetes Mellitus, Type 2; Cardiovascular Diseases; Lipoproteins, VLDL; Apolipoproteins B; Lipoproteins; Triglycerides; Lipoproteins, IDL; Chylomicrons
PubMed: 37775612
DOI: 10.1007/s00125-023-06008-0 -
Atherosclerosis Jun 2024The PROMINENT trial, a cardiovascular outcome trial of the triglyceride- and remnant cholesterol-lowering agent pemafibrate, has shown neutral results despite reduction... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND AND AIMS
The PROMINENT trial, a cardiovascular outcome trial of the triglyceride- and remnant cholesterol-lowering agent pemafibrate, has shown neutral results despite reduction in plasma triglycerides and remnant cholesterol. We tested the hypothesis that absolute mass changes in remnant cholesterol, LDL cholesterol, and apolipoprotein B explain the results of the PROMINENT trial.
METHODS
Among 108,431 individuals from the Copenhagen General Population Study (CGPS), those who met the key inclusion criteria of the PROMINENT trial were analyzed to mimic the trial design. Endpoint atherosclerotic cardiovascular disease (ASCVD) was cardiovascular death, myocardial infarction, ischemic stroke, and coronary revascularization as defined in PROMINENT.
RESULTS
In the PROMINENT trial, treatment with pemafibrate resulted in -7 mg/dL (-0.18 mmol/L; -18 %) change in remnant cholesterol, +10 mg/dL (+0.26 mmol/L; +12 %) LDL cholesterol, and +5 mg/dL (+0.05 g/L; +5 %) apolipoprotein B. In the CGPS mimicking PROMINENT, the estimated hazard ratios for ASCVD were 0.97 (95 % confidence interval: 0.94-0.99) for a -7 mg/dL (-0.18 mmol/L) change in remnant cholesterol, 1.04 (1.01-1.07) for a +10 mg/dL (+0.26 mmol/L) change in LDL cholesterol, and 1.02 (1.01-1.03) for a +5 mg/dL (+0.05 g/L) change in apolipoprotein B. When combining absolute changes in remnant cholesterol, LDL cholesterol, and apolipoprotein B, the estimated hazard ratio for ASCVD was 1.05 (0.96-1.14) in the CGPS mimicking PROMINENT compared to 1.03 (0.91-1.15) in the PROMINENT trial.
CONCLUSIONS
Absolute mass changes in remnant cholesterol, LDL cholesterol, and apolipoprotein B can explain results of the PROMINENT trial. The 3 mg/dL (0.08 mmol/L) higher total atherogenic cholesterol together with 5 mg/dL (0.05 g/L) higher apolipoprotein B seem to explain the trend toward more ASCVD in the pemafibrate arm.
Topics: Humans; Cholesterol, LDL; Female; Male; Middle Aged; Cholesterol; Aged; Triglycerides; Treatment Outcome; Denmark; Biomarkers; Apolipoprotein B-100; Cardiovascular Diseases; Atherosclerosis; Apolipoproteins B; Adult; Hypolipidemic Agents; Benzoxazoles; Butyrates; Lipoproteins
PubMed: 38678642
DOI: 10.1016/j.atherosclerosis.2024.117556 -
Atherosclerosis Nov 2023Despite increased clinical interest in lipoprotein(a) (Lp(a)), many questions remain about the molecular mechanisms by which it contributes to atherosclerotic...
BACKGROUND AND AIMS
Despite increased clinical interest in lipoprotein(a) (Lp(a)), many questions remain about the molecular mechanisms by which it contributes to atherosclerotic cardiovascular disease. Existing murine transgenic (Tg) Lp(a) models are limited by low plasma levels of Lp(a) and have not consistently shown a pro-atherosclerotic effect of Lp(a).
METHODS
We generated Tg mice expressing both human apolipoprotein(a) (apo(a)) and human apoB-100, with pathogenic levels of plasma Lp(a) (range 87-250 mg/dL). Female and male Lp(a) Tg mice (Tg(LPA;APOB)) and human apoB-100-only controls (Tg(APOB)) (n = 10-13/group) were fed a high-fat, high-cholesterol diet for 12 weeks, with Ldlr knocked down using an antisense oligonucleotide. FPLC was used to characterize plasma lipoprotein profiles. Plaque area and necrotic core size were quantified and immunohistochemical assessment of lesions using a variety of cellular and protein markers was performed.
RESULTS
Male and female Tg(LPA;APOB) and Tg(APOB) mice exhibited proatherogenic lipoprotein profiles with increased cholesterol-rich VLDL and LDL-sized particles and no difference in plasma total cholesterol between genotypes. Complex lesions developed in the aortic sinus of all mice. Plaque area (+22%), necrotic core size (+25%), and calcified area (+65%) were all significantly increased in female Tg(LPA;APOB) mice compared to female Tg(APOB) mice. Immunohistochemistry of lesions demonstrated that apo(a) deposited in a similar pattern as apoB-100 in Tg(LPA;APOB) mice. Furthermore, female Tg(LPA;APOB) mice exhibited less organized collagen deposition as well as 42% higher staining for oxidized phospholipids (OxPL) compared to female Tg(APOB) mice. Tg(LPA;APOB) mice had dramatically higher levels of plasma OxPL-apo(a) and OxPL-apoB compared to Tg(APOB) mice, and female Tg(LPA;APOB) mice had higher plasma levels of the proinflammatory cytokine MCP-1 (+3.1-fold) compared to female Tg(APOB) mice.
CONCLUSIONS
These data suggest a pro-inflammatory phenotype exhibited by female Tg mice expressing Lp(a) that appears to contribute to the development of more severe lesions with greater vulnerable features.
Topics: Male; Humans; Female; Mice; Animals; Lipoprotein(a); Apolipoprotein B-100; Mice, Transgenic; Atherosclerosis; Apolipoproteins B; Apolipoproteins A; Apoprotein(a); Cholesterol
PubMed: 37290980
DOI: 10.1016/j.atherosclerosis.2023.05.019 -
Metabolism: Clinical and Experimental Jan 2024Epidemiological evidence links the proprotein convertase subtilisin/kexin 7 (PCSK7) to triglyceride (TG) metabolism. We associated the known PCSK7 gain-of-function...
BACKGROUND
Epidemiological evidence links the proprotein convertase subtilisin/kexin 7 (PCSK7) to triglyceride (TG) metabolism. We associated the known PCSK7 gain-of-function non-coding SNP rs236918 with higher levels of plasma apolipoprotein B (apoB) and the loss-of-function coding variant p.Pro777Leu (SNP rs201598301) with lower apoB and TG. Herein, we aimed to unravel the in vivo role of liver PCSK7.
METHODS
We biochemically defined the functional role of PCSK7 in lipid metabolism using hepatic cell lines and Pcsk7 mice. Our findings were validated following subcutaneous administration of hepatocyte-targeted N-acetylgalactosamine (GalNAc)-antisense oligonucleotides (ASOs) against Pcsk7.
RESULTS
Independent of its proteolytic activity, membrane-bound PCSK7 binds apoB100 in the endoplasmic reticulum and enhances its secretion. Mechanistically, the loss of PCSK7/Pcsk7 leads to apoB100 degradation, triggering an unfolded protein response, autophagy, and β-oxidation, eventually reducing lipid accumulation in hepatocytes. Non-alcoholic fatty liver disease (NAFLD) was induced by a 12-week high fat/fructose/cholesterol diet in wild type (WT) and Pcsk7 mice that were then allowed to recover on a 4-week control diet. Pcsk7 mice recovered more effectively than WT mice from all NAFLD-related liver phenotypes. Finally, subcutaneous administration of GalNAc-ASOs targeting hepatic Pcsk7 to WT mice validated the above results.
CONCLUSIONS
Our data reveal hepatic PCSK7 as one of the major regulators of apoB, and its absence reduces apoB secretion from hepatocytes favoring its ubiquitination and degradation by the proteasome. This results in a cascade of events, eventually reducing hepatic lipid accumulation, thus supporting the notion of silencing PCSK7 mRNA in hepatocytes for targeting NAFLD.
Topics: Mice; Animals; Non-alcoholic Fatty Liver Disease; Subtilisin; Triglycerides; Liver; Apolipoproteins B; Proprotein Convertases; Apolipoprotein B-100
PubMed: 37967646
DOI: 10.1016/j.metabol.2023.155736 -
Lipids in Health and Disease Jul 2023Generally, low-density lipoprotein (LDL) particle size can be inferred from the LDL cholesterol concentration to total apolipoprotein B concentration ratio (LDL-C/ApoB...
BACKGROUND
Generally, low-density lipoprotein (LDL) particle size can be inferred from the LDL cholesterol concentration to total apolipoprotein B concentration ratio (LDL-C/ApoB ratio, hereinafter called LAR), which is a good predictor of cardiovascular disease. However, the predictive ability of LAR for mortality risk in the general population is still unclear. This study aimed to explore the association between LAR and cardiovascular as well as all-cause mortality among American adults.
METHODS
The present study was a secondary analysis of existing data from the National Health and Nutrition Examination Survey (NHANES). The final analysis included 12,440 participants from 2005 to 2014. Survival differences between groups were visualized using Kaplan‒Meier curves and the log-rank test. The association of LAR with cardiovascular and all-cause mortality was evaluated using multivariate Cox regression and restricted cubic spline analysis. Age, sex, coronary artery disease, diabetes, lipid-lowering medication use and hypertriglyceridemia were analyzed in subgroup analyses.
RESULTS
The median age in the study cohort was 46.0 years [interquartile range (IQR): 31.0-62.0], and 6,034 (48.5%) participants were male. During the follow-up period, there were 872 (7.0%) all-cause deaths and 150 (1.2%) cardiovascular deaths. Compared with individuals without cardiovascular events, those who experienced cardiovascular deaths had a lower LAR (1.13 vs. 1.25) (P < 0.001). The adjusted Cox regression model indicated that lower LAR was an independent risk factor for both cardiovascular [hazard ratio (HR) = 0.304, 95% confidence interval (CI): 0.114-0.812] and all-cause mortality (HR = 0.408, 95% CI: 0.270-0.617). Moreover, a significant age interaction was observed (P for interaction < 0.05), and there was a strong association between LAR and mortality among participants over 65 years of age. Further analysis showed an inverse association between LAR and both cardiovascular and all-cause mortality.
CONCLUSIONS
LAR can independently predict cardiovascular and all-cause mortality in the general population.
Topics: Adult; Humans; Male; Middle Aged; Female; Apolipoproteins B; Cholesterol, LDL; Nutrition Surveys; Coronary Artery Disease; Cardiovascular Diseases
PubMed: 37480052
DOI: 10.1186/s12944-023-01869-1 -
Gene Nov 2023The contribution of insulin to acne is that it stimulates the synthesis of androgenic hormones, which are important in the development of excess sebum,...
BACKGROUND
The contribution of insulin to acne is that it stimulates the synthesis of androgenic hormones, which are important in the development of excess sebum, hyperkeratinization, and sebaceous gland cell growth.
OBJECTIVE
To ascertain whether the lipid profile abnomalies seen in acne vulgaris are genetically induced, we also seek to establish a link between insulin resistance and lipid profiles.
METHODS
An analytical cross-sectional study with case-control design research investigation of 72 individuals with acne vulgaris and 72 healthy volunteers was carried out. Both groups' medical histories were taken, as were the severity and duration of the disease among acne sufferers, as well as demographic data. Anthropometry tests were performed on both groups, including their weights, height, and circumference of waist, as well as the profile of lipids, blood glucose levels after a fast, insulin levels during fasting, resistance to insulin, and Apo B-48 folding change.
RESULTS
Severe acne vulgaris patients showed significantly increased TG, TC, LDL-C, blood glucose levels after a fast, fasting insulin, and resistance to insulin levels. P = 0.005 showed that Apo B-48 expression increased in patients compared to healthy people. Apo B-48 folding change and insulin resistance were found to have a substantial positive simple linear association. Acne vulgaris, whether mild, moderate, or severe, has a significant positive linear connection with insulin resistance.
CONCLUSION
Acne patients had an abnormal in lipid profile. Acne individuals with severe form are more inclined to acquire resistance to insulin as well as higher glucose and insulin levels. Apo B-48 gene expression is elevated in acne individuals with severe form who have lipid abnormalities. This illustrating the importance of genetic variables in acne, insulin resistance, lipid profile modifications as well as Isotretinoin, a standard acne medication, can also cause lipid irregularities.
Topics: Humans; Insulin Resistance; Apolipoprotein B-48; Blood Glucose; Cross-Sectional Studies; Insulin; Acne Vulgaris; Cholesterol, LDL; Gene Expression
PubMed: 37572798
DOI: 10.1016/j.gene.2023.147703 -
International Journal of Cardiology Nov 2023The study compared the distribution of serum LDL-C, non-HDL-C, and apolipoprotein B (apoB) among participants of the NATPOL 2011 survey and analysed...
Concordance/discordance between serum apolipoprotein B, low density lipoprotein cholesterol and non-high density lipoprotein cholesterol in NATPOL 2011 participants - An epidemiological perspective.
BACKGROUND
The study compared the distribution of serum LDL-C, non-HDL-C, and apolipoprotein B (apoB) among participants of the NATPOL 2011 survey and analysed concordance/discordance of results in the context of the risk for atherosclerotic cardiovascular disease (ASCVD).
METHODS
Serum levels of apoB, LDL-C, non-HDL-C and small dense LDL-C were measured/calculated in 2067-2098 survey participants. The results were compared between women and men, age groups and in relation to body mass index (BMI), fasting glucose and TG levels, and the presence of CVD. Percentile distribution of lipid levels and concordance/discordance analysis were based on medians and ESC/EAS 2019 target thresholds for ASCVD risk and on comparison of measured apoB levels and levels calculated from linear regression equations with serum LDL- C and non-HDL-C as independent variables.
RESULTS
Serum apoB, LDL-C and non-HDL-C were similarly related to sex, age, BMI, visceral obesity, cardiovascular disease, and fasting glucose and triglyceride levels. Serum apoB, LDL-C and non-HDL-C very high- and moderate- target thresholds were exceeded in 83%, 99% and 96.9% and in 41%, 75% and 63.7% of subjects, respectively. The incidence of the discordances between the results depended on the dividing values used and ranged from 0.2% to 45.2% of the respondents. Subjects with high apoB / low LDL-C/non-HDL-C discordance had features of metabolic syndrome.
CONCLUSIONS
Diagnostic discordances between apoB and LDL-C/non-HDL-C indicate limitations of serum LDL-C/non-HDL-C in ASCVD risk management. Due to the high apoB/low LDL-C/non-HDL-C discordance, obese/metabolic syndrome patients may benefit from replacing LDL-C/non-HDL-C by apoB in ASCVD risk assessment and lipid-lowering therapy.
Topics: Male; Humans; Female; Cholesterol, LDL; Metabolic Syndrome; Cardiovascular Diseases; Apolipoproteins B; Atherosclerosis; Cholesterol, HDL
PubMed: 37429441
DOI: 10.1016/j.ijcard.2023.131150 -
The British Journal of Nutrition Apr 2024Niacin has been investigated for its potential impact on lipid metabolism and cardiovascular health. This meta-analysis aims to systematically evaluate the effects of... (Meta-Analysis)
Meta-Analysis Review
Niacin has been investigated for its potential impact on lipid metabolism and cardiovascular health. This meta-analysis aims to systematically evaluate the effects of niacin interventions on apo A1 and apo B levels, key regulators of lipoprotein metabolism and markers of cardiovascular risk. A comprehensive search of the literature was performed on five databases of PubMed, Scopus, Web of Science, Embase and Cochrane library, from inception up to 15 July 2023. This search identified 1452 publications, from which twelve randomised controlled trials met the inclusion criteria. The intervention dosages ranged from 500 to 3000 mg/d, and the study durations spanned from 6 to 102·8 weeks. The niacin intervention demonstrated a significant reduction in apo B levels (weighted mean differences (WMD): -24·37 mg/dl, = 0·01). Subgroup analyses indicated that intervention duration played a role, with trials of ≤ 16 weeks showing a greater reduction in apo B. Regarding apo A1, niacin significantly increased its levels (WMD: 8·23 mg/dl, < 0·001). Subgroup analyses revealed that the beneficial effects of niacin on apo A1 were observed at a dosage of > 1500 mg/d ( < 0·001), and extended-release niacin was more effective compared with other forms ( < 0·001). According to the Begg's regression test, no publication bias was observed in this systematic review and meta-analysis. This meta-analysis highlights niacin's potential role in improving lipid profiles and cardiovascular health. Further well-designed clinical trials are needed to elucidate and confirm optimal dosages and durations of niacin interventions for influencing apo A1 and B.
Topics: Niacin; Apolipoprotein A-I; Apolipoproteins B; Randomized Controlled Trials as Topic
PubMed: 38112076
DOI: 10.1017/S000711452300288X