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Olezarsen is a hepatocyte-targeted, GalNAc-modified antisense oligonucleotide that decreases plasma levels of apolipoprotein C-III (apoC-III) and triglyceride-rich lipoproteins (TRLs).To define the effect of olezarsen on NMR-derived lipoprotein particle size and concentration.Patients (n=114) with or at risk for atherosclerotic cardiovascular disease and fasting triglycerides ≥200 and500 mg/dL received olezarsen (10 or 50 mg every 4 weeks, 15 mg every 2 weeks, or 10 mg every week) or saline placebo subcutaneously for 6-12 months. NMR LipoProfile® analysis was performed in frozen EDTA plasma samples collected at baseline and at the primary analysis timepoint (PAT) at 6 months.A dose-dependent relationship was generally noted with increasing cumulative doses of olezarsen in TRL particle (TRLP), LDL particle (LDL-P) and HDL (HDL-P) particle concentrations. In the 50 mg every 4 weeks dose, compared to placebo, olezarsen resulted in a significant reduction in total TRL-P (51%, P0.0001) with largest reductions in large-size (68%, P0.0001) and medium-size (63%, P0.0001) TRL-P. Total LDL-P concentration was not changed, but large LDL-P increased by 186% (p=0.0034), and small LDL-P decreased by 39% (p=0.0713). Total HDL-P concentration increased by 15% (P=0.0006), driven primarily by a 32% increase in small HDL subspecies (diameters8.3 nm) (P=0.0008).Olezarsen results in favorable changes in lipoprotein concentration and particle size, primarily manifested by reduction in TRLs, remodeling to larger LDL particles, and increase in small HDL-P. These findings suggest that apoC-III inhibition improves the overall atherogenic risk profile.

Background: Mutations in genes encoding lipoprotein lipase (LPL) or its regulators can cause severe hypertriglyceridemia (HTG). Thus far, the effect of genetic HTG on the lipid profile has been mainly determined via conventional techniques. Objective: To show detailed differences in the (apo)lipoprotein profile of patients with genetic HTG by combining LC-MS and NMR techniques. Methods: Fasted serum from 7 patients with genetic HTG and 10 normolipidemic controls was used to measure the concentration of a spectrum of apolipoproteins by LC-MS, and to estimate the concentration and size of lipoprotein subclasses and class-specific lipid composition using NMR spectroscopy. Results: Patients with genetic HTG compared to normolipidemic controls had higher levels of apoB48 (fold change [FC] 11.3, P, P, P=0.007), apoC-III (FC 3.4, P, Pi.e., chylomicrons and very low-density lipoproteins [VLDL]; FC 3.0, Pi.e., chylomicrons, VLDL), explaining high levels of apoC-I, apoC-II, apoC-III and apoE, whereas small atherogenic LDL particles are absent. The presence of chylomicrons in patients with HTG weakens the accuracy of the NMR-based model as it was designed for normolipidemic fasted individuals.

Familial celiac disease syndrome (FCS) is a form of hypertriglyceridemia (HTG) caused by the accumulation of celiac particles. Currently, volanesorsen is considered to be used to treat patients with FCS and HTG to improve symptoms. To evaluate the effect of volanesorsen on lipid metabolism in patients with FCS, we performed a systematic evaluation and meta-analysis.A systematic search of PubMed, Embase, ClinicalTrials.gov, and the Cochrane Library was conducted, and the bibliographies of original articles were checked manually. The quality of the studies was assessed using the Cochrane Risk of Bias tool.Four randomized, controlled trials involving 246 patients were analyzed in this study. Patients treated with volanesorsen showed (MD = -78.85%; 95% CI = -96.04 to -61.65, P = 0.67, I

Triglyceride-rich lipoproteins (TRL: chylomicrons and VLDL) are a key component of diabetes dyslipoproteinemia and cardiovascular risk. We have shown that it is already prevalent in obese adolescents in association with lipoprotein lipase (LPL) dysregulation. Insulin resistance (IR) suffices to produce TRL dyslipoproteinemia and LPL dysfunction even in the absence of obesity.This cross-sectional study included euglycemic adolescents between 15 and 19 y, classified in 4 groups according to BMI, HOMA-IR and fasting lipid as: metabolically healthy lean (MHL, n = 30), metabolically unhealthy lean (MUL, n = 25), metabolically healthy obese (MHO, = 30), and metabolically unhealthy obese (MUO, n = 42).As compared to MHL, MUL participants showed 73% higher concentrations of ApoB-48; 84% of ApoC-III; 24% ANGPTL-3; 200% of TG; 218% of VLDL-C and 238% of TG/HDL-CEuglycemic lean adolescents with IR display TRL dyslipoproteinemia with increased inhibition of LPL as highlighted by higher concentrations of ANGPTL-3, ApoC-III and fasting chylomicron remnants (ApoB-48).

To review the currently available data on the effect of Glucagon-like peptide 1 receptor agonists (GLP-1 RAs) on postprandial lipaemia.Out of the available studies that examined the respective lipid parameter, exenatide reduced postprandial triacyglycerol (TAG) in 4/6, apolipoprotein B-48 in 3/3, non-esterified fatty acids in 2/2, and apolipoprotein C-III and very low-density lipoprotein cholesterol (VLDL-C) in 1/1 studies. Liraglutide reduced postprandial TAG in 2/2, apolipoprotein B-48 in 3/3 and apolipoprotein C-III, chylomicron-TAG and VLDL

Alcohol consumption increases circulating high-density lipoprotein cholesterol (HDL-C), but HDL protein cargo may better reflect HDL function. This study examined the associations between alcohol intake and HDL subspecies containing or lacking apoC3, apoE, and apoJ in a well-phenotyped cohort. We performed a cross-sectional analysis of 2092 Cardiovascular Health Study participants aged 70 or older with HDL subspecies measured in stored specimens from 1998 to 1999. Associations between alcohol intake and apoA1 defined HDL subspecies lacking or containing apoC3, apoE, and apoJ, and circulating levels of total apoA1, apoC3, apoE, and apoJ were examined. HDL subspecies lacking and containing apoC3, apoE, and apoJ were all positively associated with alcohol intake, with ∼1% per additional drink per week or ∼7% per additional drink per day (subspecies without the apolipoproteins, P ≤ 2 × 10−9, subspecies with the apolipoproteins, P ≤ 3 × 10−5). Total apoA1 was also directly associated with alcohol consumption, with a 1% increase per additional drink per week (P = 1 × 10−14). Total apoC3 blood levels were 0.5% higher per additional drink per week (P = 0.01), but the association was driven by a few heavily drinking men. Alcohol intake was positively associated with HDL subspecies lacking and containing apoC3, apoE, or apoJ, and with total plasma apoA1. ApoC3 was directly, albeit not as robustly associated with alcohol intake. HDL protein cargo is crucial for its anti-atherosclerotic functions, but it remains to be determined whether HDL subspecies play a role in the putative association between limited alcohol intake and lower risk of coronary heart disease.

Supplemental Digital Content is available in the text., Objective: Plasma total HDL (high-density lipoprotein) is a heterogeneous mix of many protein-based subspecies whose functions and associations with coronary heart disease vary. We hypothesize that increasing HDL by CETP (cholesteryl ester transfer protein) inhibition failed to reduce cardiovascular disease risk, in part, because it increased dysfunctional subspecies associated with higher risk such as HDL that contains apoC3. Approach and Results: We studied participants in 2 randomized, double-blind, placebo-controlled trials of a CETP inhibitor on a background of atorvastatin treatment: ACCENTUATE (The Addition of Evacetrapib to Atorvastatin Compared to Placebo, High Intensity Atorvastatin, and Atorvastatin With Ezetimibe to Evaluate LDL-C Lowering in Patients With Primary Hyperlipidemia; 130 mg evacetrapib; n=126) and ILLUMINATE (Phase 3 Multi Center, Double Blind, Randomized, Parallel Group Evaluation of the Fixed Combination Torcetrapib/Atorvastatin, Administered Orally, Once Daily [Qd], Compared With Atorvastatin Alone, on the Occurrence of Major Cardiovascular Events in Subjects With Coronary Heart Disease or Risk Equivalents; 60 mg torcetrapib; n=80). We measured the concentration of apoA1 in total plasma and 17 protein-based HDL subspecies at baseline and 3 months. Both CETP inhibitors increased apoA1 in HDL that contains apoC3 the most of all HDL subspecies (median placebo-adjusted percent increase: evacetrapib 99% and torcetrapib 50%). They also increased apoA1 in other HDL subspecies associated with higher coronary heart disease risk such as those involved in inflammation (α-2-macroglobulin and complement C3) or hemostasis (plasminogen), and in HDL that contains both apoE and apoC3, a complex subspecies associated with higher coronary heart disease risk. ApoA1 in HDL that contains apoC1, associated with lower risk, increased 71% and 40%, respectively. Only HDL that contains apoL1 showed no response to either drug. Conclusions: CETP inhibitors evacetrapib and torcetrapib increase apoA1 in HDL subspecies that contain apoC3 and other HDL subspecies associated with higher risk of coronary heart disease. Subspecies-specific effects shift HDL subspecies concentrations toward a profile associated with higher risk, which may contribute to lack of clinical benefit from raising HDL by pharmaceutical CETP inhibition.

Supplemental Digital Content is available in the text., Rationale: PCSK9 (proprotein convertase subtilisin/kexin type 9) circulates in a free and lipoprotein-bound form, yet the functional consequence of the association between PCSK9 and HDL (high-density lipoprotein) remains unexplored. Objective: This study sought to interrogate the novel relationship between PCSK9 and HDL in humans. Methods and Results: Comparing lipoprotein and apolipoprotein profiles by nuclear magnetic resonance spectroscopy and targeted mass spectrometry measurements with PCSK9 levels in the community-based Bruneck study (n=656) revealed a positive association of plasma PCSK9 with small HDL, alongside a highly significant positive correlation between plasma levels of PCSK9 and apolipoprotein C3 (apoC3), an inhibitor of lipoprotein lipase. The latter association was replicated in an independent cohort, the SAPHIR study (Salzburg Atherosclerosis Prevention Program in Subjects at High Individual Risk; n=270). Thus, PCSK9-HDL association was determined during the postprandial response in two dietary studies (n=20 participants each, 8 time points). Peak triglyceride levels coincided with an attenuation of the PCSK9-HDL association, a loss of apoC3 from HDL, and lower levels of small HDL as measured by nuclear magnetic resonance spectroscopy. Crosslinking mass spectrometry upon isolated HDL identified PCSK9 as a potential HDL-binding partner. PCSK9 association with HDL was confirmed through size-exclusion chromatography and immuno-isolation. Quantitative proteomics upon HDL isolated from patients with coronary artery disease (n=172) returned PCSK9 as a core member of the HDL proteome. Combined interrogation of the HDL proteome and lipidome revealed a distinct cluster of PCSK9, phospholipid transfer protein, clusterin, and apolipoprotein E within the HDL proteome that was altered by sex and positively correlated with sphingomyelin content. Mechanistically, HDL facilitated PCSK9-mediated low-density lipoprotein receptor degradation and reduced low-density lipoprotein uptake through the modulation of PCSK9 internalization and multimerization. Conclusions: This study reports HDL as a binder of PCSK9 and regulator of its function. The combination of -omic technologies revealed postprandial lipemia as a driver of PCSK9 and apoC3 release from HDL. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03191513; URL: https://www.isrctn.com; Unique identifier: ISRCTN20774126.

Background Dyslipidemia is a major risk factor for cardiovascular disease, and diabetes impacts the lipid metabolism through multiple pathways. In addition to the standard lipid measurements, apolipoprotein concentrations provide added awareness of the burden of circulating lipoproteins. While common genetic variants modestly affect the serum lipid concentrations, rare genetic mutations can cause monogenic forms of hypercholesterolemia and other genetic disorders of lipid metabolism. We aimed to identify low-frequency protein-altering variants (PAVs) affecting lipoprotein and lipid traits. Methods We analyzed whole-exome (WES) and whole-genome sequencing (WGS) data of 481 and 474 individuals with type 1 diabetes, respectively. The phenotypic data consisted of 79 serum lipid and apolipoprotein phenotypes obtained with clinical laboratory measurements and nuclear magnetic resonance spectroscopy. Results The single-variant analysis identified an association between the LIPC p.Thr405Met (rs113298164) and serum apolipoprotein A1 concentrations (p=7.8×10−8). The burden of PAVs was significantly associated with lipid phenotypes in LIPC, RBM47, TRMT5, GTF3C5, MARCHF10, and RYR3 (p−6). The RBM47 gene is required for apolipoprotein B post-translational modifications, and in our data, the association between RBM47 and apolipoprotein C-III concentrations was due to a rare 21 base pair p.Ala496-Ala502 deletion; in replication, the burden of rare deleterious variants in RBM47 was associated with lower triglyceride concentrations in WES of >170,000 individuals from multiple ancestries (p=0.0013). Two PAVs in GTF3C5 were highly enriched in the Finnish population and associated with cardiovascular phenotypes in the general population. In the previously known APOB gene, we identified novel associations at two protein-truncating variants resulting in lower serum non-HDL cholesterol (p=4.8×10−4), apolipoprotein B (p=5.6×10−4), and LDL cholesterol (p=9.5×10−4) concentrations. Conclusions We identified lipid and apolipoprotein-associated variants in the previously known LIPC and APOB genes, as well as PAVs in GTF3C5 associated with LDLC, and in RBM47 associated with apolipoprotein C-III concentrations, implicated as an independent CVD risk factor. Identification of rare loss-of-function variants has previously revealed genes that can be targeted to prevent CVD, such as the LDL cholesterol-lowering loss-of-function variants in the PCSK9 gene. Thus, this study suggests novel putative therapeutic targets for the prevention of CVD.

Background High triglyceride levels are associated with increased cardiovascular risk, but whether reductions in these levels would lower the incidence of cardiovascular events is uncertain. Pemafibrate, a selective peroxisome proliferator-activated receptor α modulator, reduces triglyceride levels and improves other lipid levels. Methods In a multinational, double-blind, randomized, controlled trial, we assigned patients with type 2 diabetes, mild-to-moderate hypertriglyceridemia (triglyceride level, 200 to 499 mg per deciliter), and high-density lipoprotein (HDL) cholesterol levels of 40 mg per deciliter or lower to receive pemafibrate (0.2-mg tablets twice daily) or matching placebo. Eligible patients were receiving guideline-directed lipid-lowering therapy or could not receive statin therapy without adverse effects and had low-density lipoprotein (LDL) cholesterol levels of 100 mg per deciliter or lower. The primary efficacy end point was a composite of nonfatal myocardial infarction, ischemic stroke, coronary revascularization, or death from cardiovascular causes. Results Among 10,497 patients (66.9% with previous cardiovascular disease), the median baseline fasting triglyceride level was 271 mg per deciliter, HDL cholesterol level 33 mg per deciliter, and LDL cholesterol level 78 mg per deciliter. The median follow-up was 3.4 years. As compared with placebo, the effects of pemafibrate on lipid levels at 4 months were -26.2% for triglycerides, -25.8% for very-low-density lipoprotein (VLDL) cholesterol, -25.6% for remnant cholesterol (cholesterol transported in triglyceride-rich lipoproteins after lipolysis and lipoprotein remodeling), -27.6% for apolipoprotein C-III, and 4.8% for apolipoprotein B. A primary end-point event occurred in 572 patients in the pemafibrate group and in 560 of those in the placebo group (hazard ratio, 1.03; 95% confidence interval, 0.91 to 1.15), with no apparent effect modification in any prespecified subgroup. The overall incidence of serious adverse events did not differ significantly between the groups, but pemafibrate was associated with a higher incidence of adverse renal events and venous thromboembolism and a lower incidence of nonalcoholic fatty liver disease. Conclusions Among patients with type 2 diabetes, mild-to-moderate hypertriglyceridemia, and low HDL and LDL cholesterol levels, the incidence of cardiovascular events was not lower among those who received pemafibrate than among those who received placebo, although pemafibrate lowered triglyceride, VLDL cholesterol, remnant cholesterol, and apolipoprotein C-III levels. (Funded by the Kowa Research Institute; PROMINENT ClinicalTrials.gov number, NCT03071692.)

Hypertriglyceridemia may be implicated in the high atherosclerotic cardiovascular disease (ASCVD) risk experienced by patients with end-stage renal disease (ESRD). In this post-hoc analysis of the "Die Deutsche Diabetes Dialyse Studie (4D)" clinical trial, we examined incident ASCVD events, defined as myocardial infarction, ischemic stroke, or a coronary revascularization procedure, among 1255 participants with type 2 diabetes and ESRD treated with hemodialysis. Cox-regression methods were used to evaluate the association of triglycerides, very-low density lipoprotein cholesterol (VLDL-C), and apolipoproteins B (Apo B) and C-III (Apo C-III) with ASCVD. During a median follow-up time of 2.3 years, 340 (27%) participants experienced an ASCVD event. Higher concentrations of triglycerides were not associated with ASCVD risk: Hazard ratio (HR) 0.95; 95% CI (0.83, 1.10) per doubling concentration. Similarly, VLDL-C HR 1.01; 95% CI (0.90, 1.13); Apo B HR 1.04; 95% CI (0.93, 1.16); and Apo C-III HR 0.97; 95% CI (0.86, 1.09) (per one standard deviation higher concentrations), were not associated with ASCVD events. These associations did not differ by allocation to treatment to atorvastatin or by concentrations of markers of inflammation or malnutrition. In conclusion, we found no evidence that triglycerides, triglyceride-rich lipoproteins, or apolipoproteins B or C-III were associated with risk of ASCVD events among patients with type 2 diabetes and ESRD on hemodialysis. These results suggest that lowering triglycerides may not decrease atherosclerotic cardiovascular risk in this population.

International audience; We identified three cases of congenital disorders of glycosylation (CDG) with Golgi homeostasis disruption, one ATP6V0A2-CDG and two COG4-CDG, with normal transferrin screening analyses. Patient 1 (P1) presented at birth with cutis laxa. Patient 2 (P2) and patient 3 (P3) are adult siblings and presented with severe symptoms evocative of inborn errors of metabolism. Targeted gene sequencing in P1 revealed pathogenic ATP6V0A2 variants, shared by her affected older brother. In P2 and P3, whole exome sequencing revealed a homozygous COG4 variant of unknown significance. In all affected individuals, transferrin analysis was normal. Mass-spectrometry based serum N-glycome analysis and two-dimensional electrophoresis (2-DE) of haptoglobin and of mucin core 1 O-glycosylated apolipoprotein C-III (apoC-III) were performed. All results of second-line N-glycosylation analyses were initially normal. However, apoC-III 2-DE revealed characteristic "apoC-III1" pattern in P1 and specific "apoC-III0" patterns in P2 and P3. In P2 and P3, this allowed reclassifying the variant as likely pathogenic according to ACMG guidelines. These cases highlight the existence of normal transferrin patterns in CDG with Golgi homeostasis disruption, putting the clinicians at risk of misdiagnosing patients. Furthermore, they show the potential of apoC-III 2-DE in diagnosing this type of CDG, with highly specific patterns in COG-CDG.

Lymph node metastasis is associated with poor prognosis of oral squamous cell carcinoma (OSCC), and few studies have explored the relevance of postoperative lymphatic drainage (PLD) in metastatic OSCC. Alpha-enolase (ENO1) is a metabolic enzyme, which is related to lymphatic metastasis of OSCC. However, the role of ENO1 in PLD in metastatic OSCC has not been elucidated. Herein, we collected lymphatic drainage after lymphadenectomy between metastatic and non-metastatic lymph nodes in OSCC patients to investigate the relationship between ENO1 expression and metastasis, and to identify the proteins which interacted with ENO1 in PLD of patients with metastatic OSCC by MS/GST pulldown assay. Results revealed that the metabolic protein apolipoprotein C-III (ApoC3) was a novel partner of ENO1. The ENO1 bound to ApoC3 in OSCC cells and elicited the production of interleukin (IL)-8, as demonstrated through a cytokine antibody assay. We also studied the function of IL-8 on Jurkat T cells co-cultured with OSCC cells in vitro. Western blot analysis was applied to quantitate STAT3 (signal transducer and activator of transcription 3) and p-STAT3 levels. Mechanistically, OSCC cells activated the STAT3 signaling pathway on Jurkat T cells through IL-8 secretion, promoted apoptosis, and inhibited the proliferation of Jurkat T cells. Collectively, these findings illuminate the molecular mechanisms underlying the function of ENO1 in metastasis OSCC and provide new strategies for targeting ENO1 for OSCC treatment.

BackgroundApolipoprotein C-III (apoC-III) is a regulator of triglyceride (TG) metabolism, and due to its association with risk of cardiovascular disease, is an emergent target for pharmacological intervention. The impact of substantially lowering apoC-III on lipoprotein metabolism is not clear.MethodsWe investigated the kinetics of apolipoproteins B48 and B100 (apoB48 and apoB100) in chylomicrons, VLDL1, VLDL2, IDL, and LDL in patients heterozygous for a loss-of-function (LOF) mutation in the APOC3 gene. Studies were conducted in the postprandial state to provide a more comprehensive view of the influence of this protein on TG transport.ResultsCompared with non-LOF variant participants, a genetically determined decrease in apoC-III resulted in marked acceleration of lipolysis of TG-rich lipoproteins (TRLs), increased removal of VLDL remnants from the bloodstream, and substantial decrease in circulating levels of VLDL1, VLDL2, and IDL particles. Production rates for apoB48-containing chylomicrons and apoB100-containing VLDL1 and VLDL2 were not different between LOF carriers and noncarriers. Likewise, the rate of production of LDL was not affected by the lower apoC-III level, nor were the concentration and clearance rate of LDL-apoB100.ConclusionThese findings indicate that apoC-III lowering will have a marked effect on TRL and remnant metabolism, with possibly significant consequences for cardiovascular disease prevention.Trial registrationClinicalTrials.gov NCT04209816 and NCT01445730.FundingSwedish Heart-Lung Foundation, Swedish Research Council, ALF grant from the Sahlgrenska University Hospital, Novo Nordisk Foundation, Sigrid Juselius Foundation, Helsinki University Hospital Government Research funds, Finnish Heart Foundation, and Finnish Diabetes Research Foundation.

This review will briefly revise the evidence concerning the pharmacological inhibition of Apolipoprotein CIII (ApoCIII) in patients with hypertriglyceridemia.ApoCIII is a plasma apolipoprotein playing a major role in the metabolism of triglyceride-rich lipoproteins, namely chylomicrons and very-low-density lipoproteins as well as in the pathological processes involved in atherosclerosis. Therefore, ApoCIII is a potential new target for reducing plasma levels of TRLs and, thereby, cardiovascular risk. In recent years, there have been extensive preclinical and clinical pharmacological studies aimed at testing drugs directed against ApoCIII.In this review, firstly we will summarize the molecular function of ApoCIII in lipoprotein metabolism. Then, we will examine the lipid-lowering potential of the pharmacological inhibition of ApoCIII based on the results of clinical trial employing Volansesorsen, the first approved antisense therapeutic oligonucleotide against ApoCIII mRNA. The future perspectives for ApoCIII inhibition will be also revised.

We aimed to clarify the relationship between apolipoprotein C3 (apo-C3) and the vascular composition of lesion plaque in stable coronary disease (SCD) before percutaneous coronary intervention (PCI), and to investigate major adverse cardiovascular events (MACEs) within 4 years. Data of 98 consecutive patients with SCD who underwent PCI between November 1, 2012, and March 10, 2015, were analyzed. Laboratory and virtual histology-intravascular ultrasound (VH-IVUS) examinations of culprit lesions were conducted before PCI. Patients were divided according to median apo-C3 into low apo-C3 (≤ 8.5 mg/dL) and high apo-C3 (> 8.5 mg/dL) groups. VH-IVUS data indicated that the percentage of necrotic core volume (%NC) was significantly higher in the high apo-C3 group than in the low apo-C3 group. Moreover, the %NC significantly correlated with the apo-C3 level (R = 0.2109, P = 0.037). Kaplan–Meier curve analysis revealed that freedom from MACEs exhibited a greater decrease in the high apo-C3 group than in the low apo-C3 group, and in the high %NC group than in the low %NC group. Multivariate Cox hazards analysis showed that the %NC and high apo-C3 were independent predictors of 4 year MACEs. Apo-C3 may be a useful marker of future MACEs in patients with SCD after PCI and contribute to %NC growth.

Patients with severe hypertriglyceridaemia (sHTG) are often refractory to lipid-lowering therapy. Apolipoprotein (Apo) CIII inhibition could be promising to treat subjects with sHTG. The antisense oligonucleotide against APOC3 mRNA volanesorsen was recently introduced to treat sHTG. We performed a systematic review and meta-analysis of RCTs on the efficacy and safety of volanesorsen as compared to placebo treatment in patients with severe HTG.Studies were systematically searched in the PubMed, Web of Science and Scopus databases according to PRISMA guidelines. The last search was performed on 7 February 2022.Four studies showed significant reduction in TG after 3 months of treatment with volanesorsen as compared with placebo (MD: -73.9%; 95%CI: -93.5%, -54.2; p .001 IIn patients with severe HTG, volanesorsen is associated with a significant reduction in TG, VLDL-C, Apo-B48 and non-HDL-C and increment of HDL-C as compared to placebo. Documented efficacy is accompanied by an acceptable safety profile.

Low-density lipoprotein (LDL) cholesterol (LDL-C) is a causal risk factor for cardiovascular complications. A target value is set according to risk, guideline-based and individual basis. We now have the means to lower LDL‑C levels to ranges that are even associated with plaque volume regression. Moreover, lipid treatment is an example of how pharmacotherapy has evolved from classical selective inhibition of enzymes by drugs (e.g. statins) to targeted neutralization of proteins by antibodies. The reduction of atherogenic lipoproteins by specific inhibition or reduction of mRNA of target proteins, e.g. PCSK‑9, ANGPLT3, ApoC-III or Apo (a), and possibly one day by vaccination or even CRISP-based gene therapy will in the long term lead to new concepts in the treatment and prevention of dyslipidemia and cardiovascular complications. The cumulative exposure of atherogenic lipoproteins to the vessel wall is determined by the time-averaged LDL‑C level. This essentially depends on patient adherence and prescribed treatment intensity by physicians. Therefore, it is likely that treatment adherence influences the cumulative benefit of treatment. Accordingly, the new therapeutic strategies mentioned above with presumably higher adherence rates could help to optimize cardiovascular prevention. Early and effective LDL‑C lowering could drastically reduce the incidence of cardiovascular complications in the long term and help to maintain the health of our patients.LDL(„low-density lipoprotein“)-Cholesterin (LDL-C) ist ein kausaler Risikofaktor für kardiovaskuläre Komplikationen. Ein Zielwert wird risikobezogen, leitlinienbasiert und individualisiert festgelegt. Wir haben heutzutage die Möglichkeiten, LDL-C-Werte in Bereiche zu senken, die sogar mit einer Regression des Plaquevolumens verbunden sind. Zudem ist die Lipidtherapie ein Beispiel, wie sich die Pharmakotherapie von klassischen selektiven Hemmungen von Enzymen durch Medikamente (z. B. Statine) zur gezielten Neutralisierung von Proteinen durch Antikörper entwickelt hat. Die Reduktion atherogener Lipoproteine durch spezifische Hemmung oder Verminderung der mRNA von Zielproteinen (z. B. PCSK9, ANGPLT3, ApoC-III oder Apolipoprotein[a]) sowie eventuell eines Tages durch Impfung oder auch CRISP-basierte Gentherapie wird langfristig zu neuen Konzepten in der Therapie und Prävention von Fettstoffwechselstörungen und kardiovaskulären Komplikationen führen. Die kumulative Exposition atherogener Lipoproteine für die Gefäßwand wird durch den zeitlich gemittelten LDL-C-Wert bestimmt. Dieser hängt wesentlich von der Adhärenz des Patienten und der verordneten Behandlungsintensität durch Ärzte ab. Daher ist es wahrscheinlich, dass die Therapietreue den kumulativen Nutzen der Therapie beeinflusst. Entsprechend könnten die neuen, o. a. Therapiestrategien mit vermutlich höheren Adhärenzraten dazu beitragen, die kardiovaskuläre Prävention zu optimieren. Eine frühzeitige und effektive LDL-C-Senkung könnte langfristig das Auftreten kardiovaskulärer Komplikationen drastisch reduzieren und dazu beitragen, die Gesundheit unserer Patienten zu erhalten.

Cholesterol levels have been repeatedly linked to Alzheimer's Disease (AD), suggesting that high levels could be detrimental, but this effect is likely attributed to Low-Density Lipoprotein (LDL) cholesterol. On the other hand, High-Density Lipoproteins (HDL) cholesterol levels have been associated with reduced brain amyloidosis and improved cognitive function. However, recent findings have suggested that HDL-functionality, which depends upon the HDL-cargo proteins associated with HDL, rather than HDL levels, appears to be the key factor, suggesting a quality over quantity status. In this report, we have assessed the HDL-cargo (Cholesterol, ApoA-I, ApoA-II, ApoC-I, ApoC-III, ApoD, ApoE, ApoH, ApoJ, CRP, and SAA) in stable healthy control (HC), healthy controls who will convert to MCI/AD (HC-Conv) and AD patients (AD). Compared to HC we observed an increased cholesterol/ApoA-I ratio in AD and HC-Conv, as well as an increased ApoD/ApoA-I ratio and a decreased ApoA-II/ApoA-I ratio in AD. Higher cholesterol/ApoA-I ratio was also associated with lower cortical grey matter volume and higher ventricular volume, while higher ApoA-II/ApoA-I and ApoJ/ApoA-I ratios were associated with greater cortical grey matter volume (and for ApoA-II also with greater hippocampal volume) and smaller ventricular volume. Additionally, in a clinical status-independent manner, the ApoE/ApoA-I ratio was significantly lower in APOE ε4 carriers and lowest in APOE ε4 homozygous. Together, these data indicate that in AD patients the composition of HDL is altered, which may affect HDL functionality, and such changes are associated with altered regional brain volumetric data.

Primary chylomicronemia is characterized by pathological accumulation of chylomicrons in the plasma causing severe hypertriglyceridemia, typically10 mmol/L (875 mg/dL). Patients with the ultra-rare familial chylomicronemia syndrome (FCS) subtype completely lack lipolytic capacity and respond minimally to traditional triglyceride-lowering therapies. The mainstay of treatment is a low-fat diet, which is difficult to follow and compromises quality of life. New therapies are being developed primarily to prevent episodes of life-threatening acute pancreatitis.Antagonists of apolipoprotein (apo) C-III, such as the antisense oligonucleotide (ASO) volanesorsen, significantly reduce triglyceride levels in chylomicronemia. However, approval of and access to volanesorsen are restricted since a substantial proportion of treated FCS patients developed thrombocytopenia. Newer apo C-III antagonists, namely, the ASO olezarsen (formerly AKCEA-APOCIII-LRx) and short interfering RNA (siRNA) ARO-APOC3, appear to show efficacy with less risk of thrombocytopenia. Potential utility of antagonists of angiopoietin-like protein 3 (ANGPTL3) such as evinacumab and the siRNA ARO-ANG3 in subtypes of chylomicronemia remains to be defined.Emerging pharmacologic therapies for chylomicronemia show promise, particularly apo C-III antagonists. However, these treatments are still investigational. Further study of their efficacy and safety in patients with both rare FCS and more common multifactorial chylomicronemia is needed.

BackgroundAlthough traditional lipid parameters and coronary imaging techniques are valuable for cardiovascular disease (CVD) risk prediction, better diagnostic tests are still needed.MethodsIn a prospective, observational study, 795 individuals had extensive cardiometabolic profiling, including emerging biomarkers, such as apolipoprotein E-containing HDL-cholesterol (ApoE-HDL-C). Coronary artery calcium (CAC) score was assessed in the entire cohort, and quantitative coronary computed tomography angiography (CCTA) characterization of total burden, noncalcified burden (NCB), and fibrous plaque burden (FB) was performed in a subcohort (n = 300) of patients stratified by concentration of ApoE-HDL-C. Total and HDL-containing apolipoprotein C-III (ApoC-III) were also measured.ResultsMost patients had a clinical diagnosis of coronary artery disease (CAD) (n = 80.4% of 795), with mean age of 59 years, a majority being male (57%), and about half on statin treatment. The low ApoE-HDL-C group had more severe stenosis (11% vs. 2%, overall P0.001), with higher CAC as compared with high ApoE-HDL-C. On quantitative CCTA, the high ApoE-HDL-C group had lower NCB (β = -0.24, P = 0.0001), which tended to be significant in a fully adjusted model (β = -0.32, P = 0.001) and altered by ApoC-III in HDL levels. Low ApoE-HDL-C was significantly associated with LDL particle number (β = 0.31; P = 0.0001). Finally, when stratified by FB, ApoC-III in HDL showed a more robust predictive value of CAD over ApoE-HDL-C (AUC: 0.705, P = 0.0001) in a fully adjusted model.ConclusionApoE-containing HDL-C showed a significant association with early coronary plaque characteristics and is affected by the presence of ApoC-III, indicating that low ApoE-HDL-C and high ApoC-III may be important markers of CVD severity.Trial RegistrationClinicalTrials.gov: NCT01621594.FundingThis work was supported by the NHLBI at the NIH Intramural Research Program.

Background: Elevated triglycerides or triglyceride-rich lipoproteins are an additional cause of cardiovascular (CV) disease. Given that patients with systemic lupus erythematosus (SLE) have a high prevalence of premature CV disease and show an altered lipid profile, our objective was to study whether three molecules that play a central role in the triglyceride metabolism: apolipoprotein C-III (ApoC3), angiopoietin-like protein 4 (ANGPLT4), and lipoprotein lipase (LPL) differ between SLE patients and controls, and how they are related to disease characteristics, including disease damage. Methods: Cross-sectional study that included 347 women, 185 of them diagnosed with SLE and 162 age-matched controls. ANGPTL4, ApoC3 and LPL, and standard lipid profiles were analyzed in SLE patients and controls. A multivariable analysis was performed to assess whether ANGPTL4, ApoC3 and LPL molecules differ between patients and controls and to study their relationship with SLE disease damage. Results: After fully multivariable analysis that included classic CV risk factors, and the modifications that the disease itself produces over the lipid profile, it was found that ApoC3 was significantly lower (beta coef. -1.2 [95%CI -1.6- -0.8) mg/dl

Background Insulin resistance and beta-cell dysfunction are manifestations of rheumatoid arthritis (RA). Apolipoprotein C-III (ApoC3) has been associated with such insulin resistance and beta-cell dysfunction in the general population. Our purpose was to study whether ApoC3 is also related to the insulin resistance and beta-cell dysfunction that are present in patients with RA. Methods Three hundred thirty-eight non-diabetic patients with RA who had a glycemia lower than 110 mg/dl were recruited. Insulin, C-peptide, and ApoC3 were assessed. Insulin resistance and beta-cell function were calculated using the Homeostasis Model Assessment (HOMA2) indices. A multivariable regression analysis was performed to study the relationship of ApoC3 with those molecules and indices adjusting for classic factors associated with insulin resistance that included glucocorticoids. Results ApoC3 was related to significant higher levels of circulating insulin (beta coef. 0.37 [95%CI 0.01–0.73] µU/ml, p = 0.044) and C-peptide (beta coef. 0.13 [95%CI 0.05–0.22] ng/ml, p = 0.003), and higher insulin resistance —HOMA2-IR— (beta coef. 0.05 [95%CI 0.00–0.09], p = 0.041) and beta-cell dysfunction —HOMA2-%B— (beta coef. 2.94 [95%CI 0.07–5.80], p = 0.044) indices. This was found after a fully multivariable analysis that included, among others, prednisone intake and the classic factors associated with carbohydrate metabolism such as triglycerides, waist circumference, and obesity. Conclusion ApoC3, insulin resistance, and beta-cell dysfunction are independently associated in patients RA.

Cardiovascular diseases (CVD) have overtaken infectious diseases and are currently the world's top killer. A quite strong linkage between this type of ailments and elevated plasma levels of triglycerides (TG) has been always noticed. Notably, this risk factor is mired in deep confusion, since its role in atherosclerosis is uncertain. One of the explanations that aim to decipher this persistent enigma was provided by apolipoprotein C-III (apoC-III), a small protein historically recognized as an important regulator of TG metabolism. Preeminently, hundreds of studies have been carried out in order to explore the APOC3 genetic background, as well as to establish a correlation between its variants and dyslipidemia-related disorders, pointing to an earnest predictive power for future outcomes. Among several polymorphisms reported within the APOC3, the SstI site in its 3'-untranslated region (3'-UTR) was the most consistently and robustly associated with an increased CVD risk. As more genetic data supporting its importance in cardiovascular events aggregate, it was declared, correspondingly, that apoC-III exerts various atherogenic effects, either by intervening in the function and catabolism of many lipoproteins, or by inducing endothelial inflammation and smooth muscle cells (SMC) proliferation. This review was designed to shed the light on the structural and functional aspects of the APOC3 gene, the existing association between its SstI polymorphism and CVD, and the specific molecular mechanisms that underlie apoC-III pathological implications. In addition, the translation of all these gathered knowledges into preventive and therapeutic benefits will be detailed too.

Triglyceride hydrolysis by lipoprotein lipase (LPL), regulated by apolipoproteins C-II (apoC-II) and C-III (apoC-III), is essential for maintaining normal lipid homeostasis. During triglyceride lipolysis, the apoCs are known to be transferred from very low-density lipoprotein (VLDL) to high-density lipoprotein (HDL), but the detailed mechanisms of this transfer remain unclear. In this study, we investigated the extent of the apoC transfers and their distribution in HDL subfractions, HDL2 and HDL3. Each HDL subfraction was incubated with VLDL or biotin-labeled VLDL, and apolipoproteins and lipids in the re-isolated HDL were quantified using western blotting and high-performance liquid chromatography (HPLC). In consequence, incubation with VLDL showed the increase of net amount of apoC-II and apoC-III in the HDL. HPLC analysis revealed that the biotin-labeled apolipoproteins, including apoCs and apolipoprotein E, were preferably transferred to the larger HDL3. No effect of cholesteryl ester transfer protein inhibitor on the apoC transfers was observed. Quantification of apoCs levels in HDL2 and HDL3 from healthy subjects (n = 8) showed large individual differences between apoC-II and apoC-III levels. These results suggest that both apoC-II and apoC-III transfer disproportionately from VLDL to HDL2 and the larger HDL3, and these transfers might be involved in individual triglyceride metabolism.

Background and Aim: The apolipoprotein C3 (APOC3) polymorphism has been reported to predispose to non-alcoholic fatty liver disease (NAFLD). However, the results remain inconclusive. This meta-analysis aimed to provide insights into the association between APOC3 polymorphisms and NAFLD risk. Methods: Studies with terms “NALFD” and “APOC3” were retrieved from PubMed, Web of Science, CNKI and Wan- fang databases up to August 1, 2019. Pooled odds ratio (OR) and 95% confidence interval (95% CI) for the association of APOC3 polymorphisms and NAFLD risk were calculated using fixed and random-effects models. Results: A total of twelve studies from eleven articles were included. Of them, eight studies (1750 cases and 2181 controls) reported the strong association of variant rs2854116 with NAFLD and six studies (1523 cases and 1568 controls) found the association of rs2854117 polymorphism with NAFLD. Overall, a statistically significant association between rs2854116 pol- ymorphism of APOC3 gene and NAFLD risk was found only under dominant model. However, association of rs2854117 polymorphism with NAFLD risk was not detected under all four genetic models. In sub-group analysis of NAFLD subjects based on country, no association among them in China was detected. Besides, four studies analyze the association between the two polymorphisms and clinical characteristics in all subjects or NAFLD patients, and we also failed detect any associa- tion between the wild carriers and variant carriers. Conclusion: The meta-analyses suggests that the rs2854116 polymorphism but not rs2854117 polymorphism in APOC3 gene might be a risk factor for NAFLD among Asians. That is, individuals with CT+CC genotype have higher risk of devel- oping NAFLD. However, studies with sufficient sample size are needed for the further validation. Keywords: Apolipoprotein C3; polymorphism; non-alcoholic fatty liver disease; meta-analysis.

The unusual chromosome 11q23.3 harboring the apolipoprotein (APO) gene cluster has been well documented for its essential roles in plasma lipid-related traits and atherosclerotic cardiovascular diseases. However, its genetic architecture and the potential biological mechanisms underlying complex phenotypes have not been well assessed. We conducted a study for this target region in a Han Chinese population through a stepwise forward framework based on massive parallel sequencing, association analyses, genetic fine mapping, and functional interpretation. The present study identified new meaningful genetic associations that were not simply determined by statistical significance. In addition to the APOA5 gene, we found robust evidence of the genetic commitments of APOC3 and APOA1 to blood lipids. Several variants with high confidence were prioritized along with the potential biological mechanism interpretations in the wake of adaptive fine-mapping analyses. rs2849174 in the APOC3 enhancer was discovered with an unrivaled posterior probability of causality for triglyceride levels and could mediate APOC3 expression through enhancer activity modulated by a combination of histone modifications and transcription factor accessibility. Similarly, multiple lines of evidence converged in favor of rs3741297 as a causal variant influencing high-density lipoprotein cholesterol. Our findings provided novel insights into this genomic locus in the Chinese population.

ObjectiveApolipoproteins are amphipathic molecules and the major components of plasma lipoproteins. This study aims to investigate the effects of dysregulated apolipoprotein (apo) profiles and their ratios on type 2 diabetes mellitus (T2DM) and diabetic retinopathy (DR) further to test the hypothesis that altered serum level of apolipoproteins is strong biomarkers for DR.Research Design and MethodsThis case-control study consists of 157 patients with T2DM including DM without DR, non-proliferative DR (NPDR), and proliferative DR (PDR). Fifty-eight age- and sex-matched healthy subjects were enrolled as normal controls. Blood biochemistry profile including serum levels of glucose, glycated hemoglobin (HbA1c), lipid profile [total cholesterol (TC), Triglycerides (TG), high and low-density lipoprotein (HDL-C and LDL-C)] was estimated. Apolipoproteins (apos, A-I, A-II, B, C-II, C-III, and E) was evaluated by protein chips (Luminex technology). Apolipoprotein ratios and arteriosclerosis-associated plasma indices were calculated. The Kruskal–Wallis test, independent sample t-test or Mann–Whitney U test, and multivariate regression analysis were performed to investigate the association of serum lipid biomarkers and the DR severity.ResultsSerum level of apoA-I was negatively correlated with TC-(HDL-C)/HDL-C (p < 0.001), fasting glucose (p < 0.001), HbA1c (p < 0.001), and (pp < 0.001). Single variable logistic analysis results showed that body mass index (BMI) (p = 0.023), DM duration (p < 0.001), apoE (p < 0.001), apoC-II/apo C-III (p < 0.001), apoE/apoC-II (p < 0.001), atherogenic index (p = 0.013), fasting glucose (p < 0.001), HbA1c (p < 0.001), LPA (p = 0.001), and LDL-C/HDL-C (p = 0.031) were risk factors for the occurrence and severity of DR. Multivariate logistic regression mode showed that apoC-II/apoC-III and apoB/non–HDL-C (p < 0.001) as well as apoE/apoC-II (p = 0.001) were the independent risk factors for the occurrence and severity of DR—apopA-I and apoA-II are protective factors for DR—after controlling for the duration of DM, HbA1c, fasting glucose, and LPA.ConclusionsapoE, apoC-II/apoC-III, apoE/apoC-II, and apoB/non–HDL-C could be used as novel biomarkers for occurrence and severity of DR, whereas apoA-I and apoA-II resulted as protective factors for DR.

Aims Hypertriglyceridaemia is associated with increased risk of cardiovascular events. This clinical trial evaluated olezarsen, an N-acetyl-galactosamine-conjugated antisense oligonucleotide targeted to hepatic APOC3 mRNA to inhibit apolipoprotein C-III (apoC-III) production, in lowering triglyceride levels in patients at high risk for or with established cardiovascular disease. Methods and results A randomized, double-blind, placebo-controlled, dose-ranging study was conducted in 114 patients with fasting serum triglycerides 200–500 mg/dL (2.26–5.65 mmol/L). Patients received olezarsen (10 or 50 mg every 4 weeks, 15 mg every 2 weeks, or 10 mg every week) or saline placebo subcutaneously for 6–12 months. The primary endpoint was the percent change in fasting triglyceride levels from baseline to Month 6 of exposure. Baseline median (interquartile range) fasting triglyceride levels were 262 (222–329) mg/dL [2.96 (2.51–3.71) mmol/L]. Treatment with olezarsen resulted in mean percent triglyceride reductions of 23% with 10 mg every 4 weeks, 56% with 15 mg every 2 weeks, 60% with 10 mg every week, and 60% with 50 mg every 4 weeks, compared with increase by 6% for the pooled placebo group (P-values ranged from 0.0042 to Conclusion Olezarsen significantly reduced apoC-III, triglycerides, and atherogenic lipoproteins in patients with moderate hypertriglyceridaemia and at high risk for or with established cardiovascular disease. Trial registration number NCT03385239.

Patients with hypertriglyceridemia ( 150 mg/dl) have an increased risk for atherosclerotic cardiovascular disease, and those with severe hypertriglyceridemia ( 880 mg/dl) also for pancreatitis. The currently available medications to decrease triglyceride levels, such as fibrates, statins, and omega‑3 fatty acids, are in many cases not able to achieve normal triglyceride levels. Therefore, new drugs are in development to address this unmet need. Recently, icosapent ethyl, a purified formulation of the omega-3-fatty acid eicosapentaenoic acid, was approved in Germany for the reduction of cardiovascular events in patients with hypertriglyceridemia and established cardiovascular disease or with diabetes and other risk factors on top of statins. Other new drugs in development are the more selective peroxisome proliferator-activated receptor α (PPARα) modulator, pemafibrate, already approved for the treatment of hypertriglyceridemia in Japan, and inhibitors of ApoC-III and angiopoietin-like 3 (ANGPTL3) in the form of antisense oligonucleotides or siRNAs or fully human monoclonal binding antibodies. Apolipoprotein C-III and ANGPTL3 protein seem to be quite promising targets based on solid genetic data. Larger studies of long duration, many of them currently ongoing, are needed to establish the role these medications will play in the treatment of hypertriglyceridemia in clinical practice.Patienten mit Hypertriglyzeridämie ( 150 mg/dl) haben ein erhöhtes Risiko für atherosklerotische Herz-Kreislauf-Erkrankungen und Patienten mit schwerer Hypertriglyzeridämie ( 880 mg/dl) auch für das Auftreten einer Pankreatitis. Die derzeit verfügbaren Medikamente zur Senkung des Triglyzeridspiegels, wie Fibrate, Statine und Omega-3-Fettsäuren, sind in vielen Fällen nicht in der Lage, die Triglyzeridspiegel zu normalisieren. Daher werden derzeit neue Medikamente entwickelt, um diesen „unmet need“ zu decken. Kürzlich wurde in Deutschland Icosapent-Ethyl, eine gereinigte Formulierung der Omega-3-Fettsäure Eicosapentaensäure, zur Verringerung kardiovaskulärer Ereignisse bei Patienten mit Hypertriglyzeridämie und diagnostizierter kardiovaskulärer Erkrankung oder mit Diabetes und anderen Risikofaktoren zusätzlich zu Statinen zugelassen. Weitere neue Medikamente in der Entwicklung sind der selektivere Modulator des „peroxisome proliferator-activated receptor α“ (PPARα) Pemafibrat, der in Japan bereits für die Behandlung einer Hypertriglyzeridämie zugelassen ist, sowie Inhibitoren von Apolipoprotein C-III (ApoC-III) und des angiopoetinähnlichen Protein 3 (ANGPTL3) in Form von Antisense-Oligonukleotiden, „small interfering RNA“ (siRNA) oder vollständig humanen monoklonalen bindenden Antikörpern. ApoC-III und ANGPTL3 scheinen auf der Grundlage solider genetischer Daten recht vielversprechende therapeutische Zielstrukturen zu sein. Größere Langzeitstudien, von denen viele derzeit laufen, sind erforderlich, um zu ermitteln, welche Rolle diese Medikamente bei der Behandlung der Hypertriglyzeridämie in der klinischen Praxis spielen werden.