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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 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 -
Nature Reviews. Cardiology Mar 2024Prolonged or excessive exposure to oxidized phospholipids (OxPLs) generates chronic inflammation. OxPLs are present in atherosclerotic lesions and can be detected in... (Review)
Review
Prolonged or excessive exposure to oxidized phospholipids (OxPLs) generates chronic inflammation. OxPLs are present in atherosclerotic lesions and can be detected in plasma on apolipoprotein B (apoB)-containing lipoproteins. When initially conceptualized, OxPL-apoB measurement in plasma was expected to reflect the concentration of minimally oxidized LDL, but, surprisingly, it correlated more strongly with plasma lipoprotein(a) (Lp(a)) levels. Indeed, experimental and clinical studies show that Lp(a) particles carry the largest fraction of OxPLs among apoB-containing lipoproteins. Plasma OxPL-apoB levels provide diagnostic information on the presence and extent of atherosclerosis and improve the prognostication of peripheral artery disease and first and recurrent myocardial infarction and stroke. The addition of OxPL-apoB measurements to traditional cardiovascular risk factors improves risk reclassification, particularly in patients in intermediate risk categories, for whom improving decision-making is most impactful. Moreover, plasma OxPL-apoB levels predict cardiovascular events with similar or greater accuracy than plasma Lp(a) levels, probably because this measurement reflects both the genetics of elevated Lp(a) levels and the generalized or localized oxidation that modifies apoB-containing lipoproteins and leads to inflammation. Plasma OxPL-apoB levels are reduced by Lp(a)-lowering therapy with antisense oligonucleotides and by lipoprotein apheresis, niacin therapy and bariatric surgery. In this Review, we discuss the role of role OxPLs in the pathophysiology of atherosclerosis and Lp(a) atherogenicity, and the use of OxPL-apoB measurement for improving prognosis, risk reclassification and therapeutic interventions.
Topics: Humans; Cardiovascular Diseases; Phospholipids; Apolipoproteins B; Atherosclerosis; Lipoprotein(a); Inflammation
PubMed: 37848630
DOI: 10.1038/s41569-023-00937-4 -
Journal of Atherosclerosis and... May 2022Familial hypercholesterolemia (FH) is underdiagnosed in most countries. The genetic heterogeneity of FH requires an algorithm to efficiently integrate genetic testing...
AIM
Familial hypercholesterolemia (FH) is underdiagnosed in most countries. The genetic heterogeneity of FH requires an algorithm to efficiently integrate genetic testing into clinical practice. We aimed to report the spectrum of genetic mutations from patients with clinically diagnosed FH in Taiwan.
METHODS
Patients with LDL-C>190 mg/dL or those with probable or definite FH according to the Taiwan Lipid Guidelines underwent genetic testing. Samples from 750 index patients from the Taiwan FH registry were screened using custom-made mass spectrometry, followed by targeted next generation sequencing (NGS) and/or multiplex ligation-dependent probe amplification (MLPA) if found negative.
RESULTS
The mean age of the patients was 52.4±15.1 years and 40.9% were male. Mutations were detected in 445 patients (59.3%). The distribution of mutations was as follows: LDLR (n=395), APOB (n=58), PCSK9 (n=0), and ABCG5 (n=3). The most common mutations were APOB c.10579 C>T (p.R3527W) (12.6%), LDLR c.986 G>A (p.C329Y) (11.5%), and LDLR c.1747 C>T (p.H583Y) (10.8%). LDLR c.1187-10 G>A (IVS 8-10) and APOB c.10580 G>A (p.R3527Q) were detected using targeted NGS in Taiwan for the first time. Four novel mutations were identified, including LDLR c.1060+2 T>C (IVS 7+2), LDLR c.1139 A>C (p.E380A), LDLR c.1322 T>C (p.A431T)+c.1867 A>G (p.I623V), and ABCG5 c.1337 G>A (p.R447Q).
CONCLUSION
LDLR and APOB, but not PCSK9, mutations were the major genetic causes of FH. Four novel mutations in LDLR or ABCG5 were identified. This genetic screening method using mass spectrometry, targeted NGS, and MLPA analysis provided an efficient algorithm for genetic testing for clinically diagnosed FH in Taiwan.
Topics: Adult; Aged; Apolipoproteins B; DNA Mutational Analysis; Female; Genetic Testing; Humans; Hyperlipoproteinemia Type II; Male; Middle Aged; Mutation; Phenotype; Proprotein Convertase 9; Receptors, LDL
PubMed: 33994402
DOI: 10.5551/jat.62773 -
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 -
Expert Review of Endocrinology &... May 2023Hypocholesterolemia results from genetic - both monogenic and polygenic - and non-genetic causes and can sometimes be a source of clinical concern. We review etiologies... (Review)
Review
INTRODUCTION
Hypocholesterolemia results from genetic - both monogenic and polygenic - and non-genetic causes and can sometimes be a source of clinical concern. We review etiologies and sequelae of hypocholesterolemia and therapeutics inspired from genetic hypocholesterolemia.
AREAS COVERED
Monogenic hypocholesterolemia disorders caused by the complete absence of apolipoprotein (apo) B-containing lipoproteins (abetalipoproteinemia and homozygous hypobetalipoproteinemia) or an isolated absence of apo B-48 lipoproteinemia (chylomicron retention disease) lead to clinical sequelae. These include gastrointestinal disturbances and severe vitamin deficiencies that affect multiple body systems, i.e. neurological, musculoskeletal, ophthalmological, and hematological. Monogenic hypocholesterolemia disorders with reduced but not absent levels of apo B lipoproteins have a milder clinical presentation and patients are protected against atherosclerotic cardiovascular disease. Patients with heterozygous hypobetalipoproteinemia have somewhat increased risk of hepatic disease, while patients with PCSK9 deficiency, ANGPTL3 deficiency, and polygenic hypocholesterolemia typically have anunremarkable clinical presentation.
EXPERT OPINION
In patients with severe monogenic hypocholesterolemia, early initiation of high-dose vitamin therapy and a low-fat diet are essential for optimal prognosis. The molecular basis of monogenic hypocholesterolemia has inspired novel therapeutics to help patients with the opposite phenotype - i.e. elevated apo B-containing lipoproteins. In particular, inhibitors of PCSK9 and ANGPTL3 show important clinical impact.
Topics: Humans; Proprotein Convertase 9; Hypobetalipoproteinemias; Apolipoproteins B; Lipoproteins; Cholesterol; Angiopoietin-Like Protein 3
PubMed: 37089071
DOI: 10.1080/17446651.2023.2204932 -
Current Opinion in Lipidology Dec 2019Determine if evidence supports interventions to prevent development of atherosclerosis and atherosclerotic cardiovascular disease (ASCVD) events and death. (Review)
Review
PURPOSE OF REVIEW
Determine if evidence supports interventions to prevent development of atherosclerosis and atherosclerotic cardiovascular disease (ASCVD) events and death.
RECENT FINDINGS
An extensive body of evidence supports the fundamental causal role of apolipoprotein B lipoproteins in the development of atherosclerosis. Recent epidemiologic studies have shown that LDL-cholesterol (LDL-C) and non-HDL-cholesterol levels in early adults are associated with accelerated subclinical atherosclerosis and an excess of atherosclerotic cardiovascular events later in life. Animal and human data have shown that intensive LDL-C lowering can regress earlier stages of atherosclerosis.
SUMMARY
The next research priority is evaluating the impact of lowering LDL-C earlier in life to regress early atherosclerosis, followed by trials to demonstrate this approach will eradicate later-life ASCVD events and death. This approach of curing atherosclerosis will likely be the most effective strategy for reducing the huge global burden of atherosclerosis.
Topics: Animals; Apolipoproteins B; Atherosclerosis; Cholesterol, LDL; Humans; Lipoproteins, HDL
PubMed: 31592794
DOI: 10.1097/MOL.0000000000000644 -
The American Journal of Clinical... Apr 2024Apolipoproteins (APOs) have emerged as significant players in lipid metabolism that affects the risk of chronic disease. However, the impact of circulating APO...
BACKGROUND
Apolipoproteins (APOs) have emerged as significant players in lipid metabolism that affects the risk of chronic disease. However, the impact of circulating APO concentrations on premature death remains undetermined.
OBJECTIVES
This study aimed to investigate the associations of serum APOs with all-cause, cardiovascular disease (CVD)-related, and cancer-related mortality.
METHODS
We included 340,737 participants who had serum APO measurements from the UK Biobank. Restricted cubic splines and multivariable Cox regression models were used to assess the associations between APOs and all-cause and cause-specific mortality by computing hazard ratios (HRs) and 95% confidence intervals (CIs). Based on 1-sample Mendelian randomization (MR) design, including 398,457 participants of White ancestry who had genotyping data from the UK Biobank, we performed instrumental variable analysis with 2-stage least squares regression to assess the association between genetically predicted APOs and mortality.
RESULTS
After adjusting for potential confounders including high-density and low-density lipoprotein particles, we observed nonlinear inverse relationships of APOA1 with all-cause, CVD-related, and cancer-related mortality (P-nonlinear < 0.001). By contrast, positive relationships were observed for APOB and all-cause (P-nonlinear < 0.001), CVD-related (P-linear < 0.001), and cancer-related (P-linear = 0.03) mortality. MR analysis showed consistent results, except that the association between APOB and cancer mortality was null. Furthermore, both observational and MR analyses found an inverse association between APOA1 and lung cancer-related mortality (HR comparing extreme deciles: 0.46; 95% CI: 0.26, 0.80; and HR: 0.78; 95% CI: 0.63, 0.97, respectively).
CONCLUSIONS
Our findings indicate that circulating APOA1 has potential beneficial effects on all-cause, CVD-related, and lung cancer-related death risk, whereas APOB may confer detrimental effects on all-cause and CVD-related death risk.
Topics: Humans; Mendelian Randomization Analysis; Risk Factors; Apolipoproteins; Cardiovascular Diseases; Apolipoproteins B; Lung Neoplasms
PubMed: 38211689
DOI: 10.1016/j.ajcnut.2024.01.002