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European Journal of Preventive... Sep 2023Studies have linked gut microbiome and heart failure (HF). However, their causal relationships and potential mediating factors have not been well defined. To investigate... (Meta-Analysis)
Meta-Analysis
AIMS
Studies have linked gut microbiome and heart failure (HF). However, their causal relationships and potential mediating factors have not been well defined. To investigate the causal relationships between the gut microbiome and HF and the mediating effect of potential blood lipids by using genetics.
METHODS AND RESULTS
We performed a bidirectional and mediation Mendelian randomization (MR) study using summary statistics from the genome-wide association studies of gut microbial taxa (Dutch Microbiome Project, n = 7738), blood lipids (UK Biobank, n = 115 078), and a meta-analysis of HF (115 150 cases and 1550 331 controls). We applied the inverse-variance weighted estimation method as the primary method, with several other estimators as complementary methods. The multivariable MR approach based on Bayesian model averaging (MR-BMA) was used to prioritize the most likely causal lipids. Six microbial taxa are suggestively associated with HF causally. The most significant taxon was the species Bacteroides dorei [odds ratio = 1.059, 95% confidence interval (CI) = 1.022-1.097, P-value = 0.0017]. The MR-BMA analysis showed that apolipoprotein B (ApoB) was the most likely causal lipid for HF (the marginal inclusion probability = 0.717, P-value = 0.005). The mediation MR analysis showed that ApoB mediated the causal effects of species B. dorei on HF (proportion mediated = 10.1%, 95% CI = 0.2-21.6%, P-value = 0.031).
CONCLUSION
The study suggested a causal relationship between specific gut microbial taxa and HF and that ApoB might mediate this relationship as the primary lipid determinant of HF.
Topics: Humans; Gastrointestinal Microbiome; Mendelian Randomization Analysis; Bayes Theorem; Genome-Wide Association Study; Heart Failure; Apolipoproteins B; Lipids; Polymorphism, Single Nucleotide
PubMed: 37195998
DOI: 10.1093/eurjpc/zwad171 -
Nature Medicine Nov 2023Nonalcoholic steatohepatitis (NASH) is a progressive liver disease with no approved treatment. MAESTRO-NAFLD-1 was a 52-week randomized, double-blind, placebo-controlled... (Randomized Controlled Trial)
Randomized Controlled Trial
Nonalcoholic steatohepatitis (NASH) is a progressive liver disease with no approved treatment. MAESTRO-NAFLD-1 was a 52-week randomized, double-blind, placebo-controlled phase 3 trial evaluating the safety of resmetirom in adults with nonalcoholic fatty liver disease and presumed NASH. Patients were randomized to three double-blind arms (100 mg resmetirom (n = 325), 80 mg resmetirom (n = 327) or placebo (n = 320)) or open-label 100 mg resmetirom (n = 171). The primary end point was incidence of treatment-emergent adverse events (TEAEs) over 52 weeks and key secondary end points were LDL-C, apoB, triglycerides (over 24 weeks), hepatic fat (over 16 and 52 weeks) and liver stiffness (over 52 weeks). Resmetirom was safe and well tolerated. TEAEs occurred in 86.5% (open-label 100 mg resmetirom), 86.1% (100 mg resmetirom), 88.4% (80 mg resmetirom) and 81.8% (placebo) of patients. TEAEs in excess of placebo included diarrhea and nausea at the initiation of treatment. Key secondary end points included least square means difference from placebo at 80 mg, 100 mg resmetirom: LDL-C (-11.1%, -12.6%), apoB (-15.6%, -18.0%), triglycerides (-15.4%, -20.4%), 16-week hepatic fat (-34.9%, -38.6%), (P < 0.0001) and liver stiffness (-1.02, -1.70) and 52-week hepatic fat (-28.8, -33.9). These findings demonstrate resmetirom was safe and well tolerated in adults with presumed NASH, supporting a role for further clinical development. (ClinicalTrials.gov identifier NCT04197479 ).
Topics: Adult; Humans; Apolipoproteins B; Cholesterol, LDL; Double-Blind Method; Liver; Non-alcoholic Fatty Liver Disease; Treatment Outcome; Triglycerides
PubMed: 37845512
DOI: 10.1038/s41591-023-02603-1 -
Journal of the American Heart... Oct 2022In 2019, the European Society of Cardiology/European Atherosclerosis Society stated that apolipoprotein B (apoB) was a more accurate marker of cardiovascular risk than... (Review)
Review
Physiological Bases for the Superiority of Apolipoprotein B Over Low-Density Lipoprotein Cholesterol and Non-High-Density Lipoprotein Cholesterol as a Marker of Cardiovascular Risk.
In 2019, the European Society of Cardiology/European Atherosclerosis Society stated that apolipoprotein B (apoB) was a more accurate marker of cardiovascular risk than low-density lipoprotein cholesterol (LDL-C) and non-high-density lipoprotein cholesterol. Since then, the evidence has continued to mount in favor of apoB. This review explicates the physiological mechanisms responsible for the superiority of apoB as a marker of the cardiovascular risk attributable to the atherogenic apoB lipoprotein particles chylomicron remnants, very low-density lipoprotein, and low-density lipoprotein particles. First, the nature and relative numbers of these different apoB particles will be outlined. This will make clear why low-density lipoprotein particles are almost always the major determinants of cardiovascular risk and why the concentrations of triglycerides and LDL-C may obscure this relation. Next, the mechanisms that govern the number of very low-density lipoprotein and low-density lipoprotein particles will be outlined because, except for dysbetalipoproteinemia, the total number of apoB particles determines cardiovascular risk, Then, the mechanisms that govern the cholesterol mass within very low-density lipoprotein and low-density lipoprotein particles will be reviewed because these are responsible for the discordance between the mass of cholesterol within apoB particles, measured either as LDL-C or non-high-density lipoprotein cholesterol, and the number of apoB particles measured as apoB, which creates the superior predictive power of apoB over LDL-C and non-high-density lipoprotein cholesterol. Finally, the major apoB dyslipoproteinemias will be briefly outlined. Our objective is to provide a physiological framework for health care givers to understand why apoB is a more accurate marker of cardiovascular risk than LDL-C or non-high-density lipoprotein cholesterol.
Topics: Humans; Cholesterol, LDL; Chylomicron Remnants; Cardiovascular Diseases; Risk Factors; Apolipoproteins B; Cholesterol; Lipoproteins; Biomarkers; Triglycerides; Heart Disease Risk Factors; Atherosclerosis; Lipoproteins, VLDL; Apolipoprotein B-100
PubMed: 36216435
DOI: 10.1161/JAHA.122.025858 -
Advanced Science (Weinheim,... Jul 2022Dysfunctional triglyceride-very low-density lipoprotein (TG-VLDL) metabolism is linked to metabolic-associated fatty liver disease (MAFLD); however, the underlying cause...
Dysfunctional triglyceride-very low-density lipoprotein (TG-VLDL) metabolism is linked to metabolic-associated fatty liver disease (MAFLD); however, the underlying cause remains unclear. The study shows that hepatic E3 ubiquitin ligase murine double minute 2 (MDM2) controls MAFLD by blocking TG-VLDL secretion. A remarkable upregulation of MDM2 is observed in the livers of human and mouse models with different levels of severity of MAFLD. Hepatocyte-specific deletion of MDM2 protects against high-fat high-cholesterol diet-induced hepatic steatosis and inflammation, accompanied by a significant elevation in TG-VLDL secretion. As an E3 ubiquitin ligase, MDM2 targets apolipoprotein B (ApoB) for proteasomal degradation through direct protein-protein interaction, which leads to reduced TG-VLDL secretion in hepatocytes. Pharmacological blockage of the MDM2-ApoB interaction alleviates dietary-induced hepatic steatohepatitis and fibrosis by inducing hepatic ApoB expression and subsequent TG-VLDL secretion. The effect of MDM2 on VLDL metabolism is p53-independent. Collectively, these findings suggest that MDM2 acts as a negative regulator of hepatic ApoB levels and TG-VLDL secretion in MAFLD. Inhibition of the MDM2-ApoB interaction may represent a potential therapeutic approach for MAFLD treatment.
Topics: Animals; Apolipoproteins B; Fatty Liver; Humans; Lipoproteins, VLDL; Liver; Mice; Obesity; Proteolysis; Proto-Oncogene Proteins c-mdm2; Triglycerides
PubMed: 35524581
DOI: 10.1002/advs.202200742 -
European Heart Journal Oct 2023The strength of the relationship of triglyceride-rich lipoproteins (TRL) with risk of coronary heart disease (CHD) compared with low-density lipoprotein (LDL) is yet to...
AIMS
The strength of the relationship of triglyceride-rich lipoproteins (TRL) with risk of coronary heart disease (CHD) compared with low-density lipoprotein (LDL) is yet to be resolved.
METHODS AND RESULTS
Single-nucleotide polymorphisms (SNPs) associated with TRL/remnant cholesterol (TRL/remnant-C) and LDL cholesterol (LDL-C) were identified in the UK Biobank population. In a multivariable Mendelian randomization analysis, TRL/remnant-C was strongly and independently associated with CHD in a model adjusted for apolipoprotein B (apoB). Likewise, in a multivariable model, TRL/remnant-C and LDL-C also exhibited independent associations with CHD with odds ratios per 1 mmol/L higher cholesterol of 2.59 [95% confidence interval (CI): 1.99-3.36] and 1.37 [95% CI: 1.27-1.48], respectively. To examine the per-particle atherogenicity of TRL/remnants and LDL, SNPs were categorized into two clusters with differing effects on TRL/remnant-C and LDL-C. Cluster 1 contained SNPs in genes related to receptor-mediated lipoprotein removal that affected LDL-C more than TRL/remnant-C, whereas cluster 2 contained SNPs in genes related to lipolysis that had a much greater effect on TRL/remnant-C. The CHD odds ratio per standard deviation (Sd) higher apoB for cluster 2 (with the higher TRL/remnant to LDL ratio) was 1.76 (95% CI: 1.58-1.96), which was significantly greater than the CHD odds ratio per Sd higher apoB in cluster 1 [1.33 (95% CI: 1.26-1.40)]. A concordant result was obtained by using polygenic scores for each cluster to relate apoB to CHD risk.
CONCLUSION
Distinct SNP clusters appear to impact differentially on remnant particles and LDL. Our findings are consistent with TRL/remnants having a substantially greater atherogenicity per particle than LDL.
Topics: Humans; Cholesterol, LDL; Biological Specimen Banks; Triglycerides; Lipoproteins; Cholesterol; Apolipoproteins B; Coronary Disease; United Kingdom
PubMed: 37358553
DOI: 10.1093/eurheartj/ehad337 -
Current Opinion in Endocrinology,... Apr 2022Elevated fasting and postprandial plasma triglyceride concentrations are associated with an increased risk for atherosclerotic cardiovascular disease in patients on and... (Review)
Review
PURPOSE OF REVIEW
Elevated fasting and postprandial plasma triglyceride concentrations are associated with an increased risk for atherosclerotic cardiovascular disease in patients on and off low-density lipoprotein (LDL) lowering therapy.
RECENT FINDINGS
This association is not mediated by triglycerides directly. Other components of triglyceride rich lipoproteins, such as cholesterol and apolipoproteins B and -CIII can directly induce and enhance atherosclerosis. In addition, an elevated concentration of triglyceride rich lipoproteins affects the concentration, composition, function, and metabolism of LDL and high-density lipoprotein (HDL), which contributes to the risk. Especially in patients with hypertriglyceridemia, apolipoprotein B and non-HDL-cholesterol (encompassing cholesterol of all atherogenic lipoproteins) predict risk better than LDL-cholesterol and/or triglycerides. Therefore, current guidelines have stated secondary goals relating to non-HDL-cholesterol and apolipoprotein B (in addition to the primary goal relating to LDL-cholesterol). These secondary goals can be achieved by further reducing LDL-cholesterol or by decreasing triglyceride rich lipoproteins. However, only further LDL reduction has so far proven to be beneficial in outcome trials. In addition, high dose eicosapentaenoic acid (EPA) can reduce atherosclerotic cardio-vascular disease risk in patients with hypertriglyceridemia, although benefit is not (or not only) related to apolipoprotein B or non-HDL-cholesterol reduction.
SUMMARY
Non-HDL-cholesterol and apoB represent novel targets for patients with hypertriglyceridemia, but achieving LDL-cholesterol targets remains the first step for cardio-vascular risk reduction.
Topics: Apolipoproteins B; Atherosclerosis; Cholesterol; Cholesterol, LDL; Humans; Hyperlipidemias; Hypertriglyceridemia; Lipoproteins; Triglycerides
PubMed: 35045528
DOI: 10.1097/MED.0000000000000714 -
Current Opinion in Lipidology Aug 2022In recent years, there has been interest for the development of simplified diagnosis algorithms of dysbetalipoproteinemia (DBL) in order to avoid the complex testing... (Review)
Review
PURPOSE OF REVIEW
In recent years, there has been interest for the development of simplified diagnosis algorithms of dysbetalipoproteinemia (DBL) in order to avoid the complex testing associated with the Fredrickson criteria (reference method). The purpose of this review is to present recent advances in the field of DBL with a focus on screening and diagnosis.
RECENT FINDINGS
Recently, two different multi-step algorithms for the diagnosis of DBL have been published and their performance has been compared to the Fredrickson criteria. Furthermore, a recent large study demonstrated that only a minority (38%) of DBL patients are carriers of the E2/E2 genotype and that these individuals presented a more severe phenotype.
SUMMARY
The current literature supports the fact that the DBL phenotype is more heterogeneous and complex than previously thought. Indeed, DBL patients can present with either mild or more severe phenotypes that can be distinguished as multifactorial remnant cholesterol disease and genetic apolipoprotein B deficiency. Measurement of apolipoprotein B as well as APOE gene testing are both essential elements in the diagnosis of DBL.
Topics: Apolipoprotein B-100; Apolipoproteins B; Apolipoproteins E; Cholesterol; Genotype; Humans; Hyperlipidemias; Hyperlipoproteinemia Type III
PubMed: 35942808
DOI: 10.1097/MOL.0000000000000831 -
JAMA Cardiology Mar 2022
Apolipoprotein B vs Low-Density Lipoprotein Cholesterol and Non-High-Density Lipoprotein Cholesterol as the Primary Measure of Apolipoprotein B Lipoprotein-Related Risk: The Debate Is Over.
Topics: Apolipoproteins B; Atherosclerosis; Cholesterol; Cholesterol, LDL; Humans; Lipoproteins; Myocardial Infarction
PubMed: 34773457
DOI: 10.1001/jamacardio.2021.5080 -
Cancer Research Aug 2023Long noncoding RNAs (lncRNA) regulate a number of aspects of cancer biology. Recent research has shown that lncRNAs can encode micropeptides that mediate their functions...
UNLABELLED
Long noncoding RNAs (lncRNA) regulate a number of aspects of cancer biology. Recent research has shown that lncRNAs can encode micropeptides that mediate their functions in tumors. Here, we revealed that the liver-specific putative lncRNA, AC115619, is expressed at low levels in hepatocellular carcinoma (HCC) and encodes a micropeptide, designated as AC115619-22aa. AC115619 played a crucial role in the regulation of tumor progression and was a prognostic indicator in HCC. The encoded micropeptide AC115619-22aa inhibited the progression of HCC by binding to WTAP and impeding the assembly of the N6-methyladenosine (m6A) methyltransferase complex, which regulates the expression of tumor-associated genes, such as SOCS2 and ATG14. AC115619 was cotranscribed with the adjacent upstream coding gene APOB, and hypoxia induced transcriptional repression of both APOB and AC115619 by controlling HIF1A/HDAC3 and HNF4A signaling. In animal and patient-derived models, AC115619-22aa reduced global m6A levels and suppressed tumor growth. In conclusion, this study establishes AC115619 and its encoded micropeptide as potential prognostic markers and therapeutic targets for patients with HCC.
SIGNIFICANCE
A micropeptide encoded by lncRNA AC115619 impedes formation of the m6A methylation complex to lower m6A levels and reduce the growth of hepatocellular carcinoma.
Topics: Animals; Apolipoproteins B; Carcinoma, Hepatocellular; Gene Expression Regulation, Neoplastic; Hypoxia; Liver Neoplasms; RNA, Long Noncoding; Humans; Micropeptides
PubMed: 37326474
DOI: 10.1158/0008-5472.CAN-23-0337 -
Journal of the American College of... Jan 2024Lipoprotein(a) (Lp(a)) is recognized as a causal factor for coronary heart disease (CHD) but its atherogenicity relative to that of low-density lipoprotein (LDL) on a...
BACKGROUND
Lipoprotein(a) (Lp(a)) is recognized as a causal factor for coronary heart disease (CHD) but its atherogenicity relative to that of low-density lipoprotein (LDL) on a per-particle basis is indeterminate.
OBJECTIVES
The authors addressed this issue in a genetic analysis based on the fact that Lp(a) and LDL both contain 1 apolipoprotein B (apoB) per particle.
METHODS
Genome-wide association studies using the UK Biobank population identified 2 clusters of single nucleotide polymorphisms: one comprising 107 variants linked to Lp(a) mass concentration, the other with 143 variants linked to LDL concentration. In these Lp(a) and LDL clusters, the relationship of genetically predicted variation in apoB with CHD risk was assessed.
RESULTS
The Mendelian randomization-derived OR for CHD for a 50 nmol/L higher Lp(a)-apoB was 1.28 (95% CI: 1.24-1.33) compared with 1.04 (95% CI: 1.03-1.05) for the same increment in LDL-apoB. Likewise, use of polygenic scores to rank subjects according to difference in Lp(a)-apoB vs difference in LDL-apoB revealed a greater HR for CHD per 50 nmol/L apoB for the Lp(a) cluster (1.47; 95% CI: 1.36-1.58) compared with the LDL cluster (1.04; 95% CI: 1.02-1.05). From these data, we estimate that the atherogenicity of Lp(a) is approximately 6-fold (point estimate of 6.6; 95% CI: 5.1-8.8) greater than that of LDL on a per-particle basis.
CONCLUSIONS
We conclude that the atherogenicity of Lp(a) (CHD risk quotient per unit increase in particle number) is substantially greater than that of LDL. Therefore, Lp(a) represents a key target for drug-based intervention in a significant proportion of the at-risk population.
Topics: Humans; Lipoprotein(a); Genome-Wide Association Study; Cholesterol, LDL; Apolipoproteins B; Coronary Disease; Risk Factors
PubMed: 38233012
DOI: 10.1016/j.jacc.2023.10.039