Apolipoprotein C-III Research Articles

Apolipoprotein CIII Reduction Protects White Adipose Tissues against Obesity-Induced Inflammation and Insulin Resistance in Mice.

Apolipoprotein CIII (apoCIII) is proinflammatory and increases in high-fat diet (HFD)-induced obesity and insulin resistance. We have previously shown that reducing apoCIII improves insulin sensitivity in vivo by complex mechanisms involving liver and brown adipose tissue. In this study the focus was on subcutaneous (SAT) and visceral (VAT) white adipose tissue (WAT). Mice were either given HFD for 14 weeks and directly from start also treated with antisense oligonucleotide (ASO) against apoCIII or given HFD for 10 weeks and HFD+ASO for an additional 14 weeks. Both groups had animals treated with inactive (Scr) ASO as controls and in parallel chow-fed mice were injected with saline. Preventing an increase or lowering apoCIII in the HFD-fed mice decreased adipocytes’ size, reduced expression of inflammatory cytokines and increased expression of genes related to thermogenesis and beiging. Isolated adipocytes from both VAT and SAT from the ASO-treated mice had normal insulin-induced inhibition of lipolysis compared to cells from Scr-treated mice. In conclusion, the HFD-induced metabolic derangements in WATs can be prevented and reversed by lowering apoCIII.

Serum PCSK9 Correlates with PTX3 and Apolipoproteins B, A1, and C3 Concentrations in Patients with Type 2 Diabetes.

Proprotein convertase subtilisin/kexin type 9 (PCSK9) is involved in the regulation of LDL metabolism. There is evidence that circulating PCSK9 is a cardiovascular risk factor. In this study, we determined factors associated with circulating PCSK9 in a group of patients with type 2 diabetes mellitus (DM2). Material included 116 consecutive patients with DM2 from outpatient diabetes clinic. Circulating PCSK9, PTX3, apolipoprotein (apo) B100, apo B48, and apo C3 levels were determined by ELISA, apo A1 by immunoturbidimetry. The mean (sd) age of patients was 59.1 (11.1) years, the mean (sd) values of serum PCSK9 were 255.4 (106.97) ng/ml. Circulating PCSK9 correlated negatively with age (r = −0.21, p < 0.05) and HbA1c (r = −0.21, p < 0.05) and positively with BMI (r = 0.21, p < 0.05), total cholesterol (r = 0.59), LDL-cholesterol (r = 0.50), triglyceride (r = 0.35), apo B100 (r = 0.43), apo A1 (r = 0.43) (p < 0.001 for all), apo C3 (r = 0.29, p < 0.01), and apo B48 (r = 0.25, p < 0.01) concentration and FLI (r = 0.26, p < 0.01). Strong correlation between PTX3 and PCSK9 levels was observed (r = 0.47, p < 0.001). Multiple stepwise backward regression analysis with PCSK9 as dependent variable revealed that PTX3, apo B100, apo A1, apo B48, and BMI were significantly positive and the presence of NAFLD and HbA1c negatively associated with PCSK9 concentrations. These variables together explain 57% of PCSK9 variability; the strongest relationship was observed between PCSK9 and PTX3 and apo B100. Our results indicate that circulating PCSK9 is significantly associated with inflammation marker PTX3 as well as atherogenic lipids and apolipoproteins C3, B100, and B48, which might be of value in understanding interactions between development of atherosclerosis and inflammatory state in DM2 patients.

The Apolipoprotein C1 is involved in breast cancer progression via EMT and MAPK/JNK pathway

Apolipoprotein C1 (APOC1) is a member of the apolipoprotein family. In recent years, more and more studies have shown that APOC1 participates in the occurrence and development of cancer. However, there is no systematic study about the specific functions and underlying mechanisms of APOC1 in breast carcinogenesis. The APOC1 was found significantly over-expressed in breast cancer tissues. The correlation of APOC1 expression with the prognosis and the clinicopathological characteristics were subsequently analyzed. APOC1 overexpression was correlated with higher TNM stage and positive lymph node metastasis. APOC1 enhanced the proliferation, invasion, and migration ability of breast cancer cell lines (MDA-MB-231 and MCF-7) in vitro. APOC1 inhibited E-cadherin expression and promoted Vimentin’s expression, which suggested that APOC1 played a crucial role in the epithelial-mesenchymal transition (EMT) process of the breast cancer cell. Moreover, APOC1 participated in the progression of breast cancer by regulating the JNK/MAPK pathway. Thus, our results demonstrated that APOC1 might be used as a novel biomarker for prognosis and diagnostic in breast cancer patients.

Study of Morphofunctional Parameters of Blood Cells in Ischemic Stroke Using a Genome-wide Research

Biomarkers can play many useful roles in modern neurology. Early diagnosis and immediate therapy are important factors for reducing the degree of brain tissue damage in ischemic stroke, reduces the risk of death from stroke. In the current study, apolipoprotein CIII (ApoCIII), a biomarker of ischemic stroke, was found.

Association of the lipoprotein lipase and Apolipoprotein C-II gene polymorphisms with risk of dyslipidemia in smokers and non-smokers male

ObjectiveDyslipidaemia is considered a metabolic abnormality andan important risk factor that leads to atherogenic cardiovascular diseases. Cigarette smoking is associated with dyslipidaemia. This study aimed to demonstrate whether lipoprotein lipase enzyme (LPL) and Apolipoprotein CII (APOCII) gene polymorphisms can be considered as independent genetic risk factors for dyslipidaemia among smokers with various smoking durations. MethodsA total of 185 males (90 smokers and 95 non-smokers)were included in this study, Lipid profiles were measured and DNA was isolated. The LPL-Hind III and APO CII-Ava II polymorphisms were determined using the polymerase reaction-restriction fragment length polymorphisms (RFLP) technique. ResultsFor the LPL-Hind IIIpolymorphism H+H+ genotype group, the triglycerides TG and very-low-density lipoprotein cholesterol VLDL-C concentrations were significantly higher and the high-density lipoprotein cholesterol HDL-C concentration was significantly lower than those of the H–H- genotype. ForAPO CII-Ava II polymorphisms, compared with those of the A2A2 genotype group, the total cholesterol TC, TG, low-density lipoprotein cholesterol LDL-C and VLDL-C concentrations were significantly increased in the A1A2 genotype group, while the HDL-C concentration was significantly decreased. ConclusionsThe study revealed that the H+H+ or H + H-genotype of the LPL-Hind III polymorphism and the A1A1or A1A2 genotype of the APOCII-Ava II polymorphism were at higher risk of developing dyslipidaemia compared to the H–H- genotype of the LPL-Hind III polymorphism and A2A2 genotype of the APOCII-Ava II polymorphism.

Dietary fat and carbohydrate affect the metabolism of protein-based high-density lipoprotein subspecies.

Purpose of reviewDietary fat compared to carbohydrate increases the plasma concentration of high-density lipoprotein (HDL)-cholesterol. However, neither the mechanism nor its connection to cardiovascular disease is known.Recent findingsProtein-based subspecies of HDL, especially those containing apolipoprotein E (apoE) or apolipoprotein C3 (apoC3), offer a glimpse of a vast metabolic system related to atherogenicity, coronary heart disease (CHD) and other diseases. ApoE stimulates several processes that define reverse cholesterol transport through HDL, specifically secretion of active HDL subspecies, cholesterol efflux to HDL from macrophages involved in atherogenesis, size enlargement of HDL with cholesterol ester, and rapid clearance from the circulation. Dietary unsaturated fat stimulates the flux of HDL that contains apoE through these protective pathways. Effective reverse cholesterol transport may lessen atherogenesis and prevent disease. In contrast, apoC3 abrogates the benefit of apoE on reverse cholesterol transport, which may account for the association of HDL that contains apoC3 with dyslipidemia, obesity and CHD.SummaryDietary unsaturated fat and carbohydrate affect the metabolism of protein-defined HDL subspecies containing apoE or apoC3 accelerating or retarding reverse cholesterol transport, thus demonstrating new mechanisms that may link diet to HDL and to CHD.

Disease activity in patients with rheumatoid arthritis increases serum levels of apolipoprotein C-III.

Rheumatoid arthritis (RA) has been unequivocally associated with an increased burden of accelerated atherosclerosis, which, at least in part, is a consequence of the inflammation present in the disease. Apolipoprotein C-III (ApoC3) is a key molecule in triglycerides metabolism that has been linked to cardiovascular (CV) disease. Our objective was to study how ApoC3 is related to the characteristics of RA, paying special attention to its relationship with the inflammatory activity of the disease. Cross-sectional study that included 430 patients with RA. In these patients, data related to the disease, classic CV risk factors, complete lipid profile, and serum ApoC3 levels were evaluated. A multivariable regression analysis was performed to study the relationship of the characteristics of RA with ApoC3. Abdominal circumference, obesity, type 2 diabetes, and circulating triglycerides were significantly associated with higher ApoC3 serum levels. Furthermore, C-reactive protein and erythrocyte sedimentation rate, as well as the disease activity score -DAS28- were significantly related to a higher circulating ApoC3 after multivariable analysis. Patients included in the moderate or high disease activity groups had higher ApoC3 serum levels compared to those in remission (beta coefficient 1.28 [95% confidence interval 0.16-2.39] mg/dl, p=0.025) when adjusting for confounders. The use of prednisone, disease-modifying anti-rheumatic drugs and anti-tumour necrosis factor therapies was associated with lower values of ApoC3. The activity of the disease in patients with RA is independently associated with higher serum levels of ApoC3.

New Therapies for Primary Hyperlipidemia.

Primary hyperlipidemias include a heterogeneous set of monogenic and polygenic conditions characterized by a strong family aggregation, severe forms of hypercholesterolemia and/or hypertriglyceridemia, appearance early on life, and a high risk of cardiovascular events and/or recurrent pancreatitis. In real life, a small proportion of the primary hyperlipidemia cases is recognized and treated properly. Our goal is to present an update of current and upcoming therapies for patients with primary hyperlipidemia. Recently, new lipid-lowering medications have obtained authorization from the U.S. Food and Drug Administration and the European Medicines Agency. These drugs target metabolic pathways, including (adenosine 5'-triphosphates)-citrate lyase (bempedoic acid), proprotein convertase subtilisin/kexin 9 (inclisiran), apolipoprotein CIII (volanesorsen), and angiopoietin-like 3 (volanesorsen), that have additive effects with the actions of the currently available therapies (i.e., statins, ezetimibe or fibrates). We discuss the potential clinical indications for the novel medications. To conclude, the addition of these new medications to the therapeutic options for primary hyperlipidemia patients may increase the likelihood of achieving the treatment targets. Also, it could be a safer alternative for patients with side effects for the currently available drugs.

The Differential Effects of HDL Subpopulations on Lipoprotein Lipase (LPL)-Mediated VLDL Catabolism.

High-density lipoprotein (HDL) subpopulations functional assessment is more relevant for HDL anti-atherogenic activity than cholesterol level. The aim of the study was to assess the impact of HDL-2 and HDL-3 on lipoprotein lipase (LPL)-mediated very-low-density lipoprotein (VLDL) catabolism related to hypertriglyceridemia development. VLDL and HDLs were isolated from serum by ultracentrifugation. VLDL was incubated with LPL in the absence and presence of total HDL or HDL subpopulations. Next, VLDL remnants were separated, and their composition and electrophoretic mobility was assessed. Both HDL subpopulations increased the efficiency of triglyceride lipolysis and apolipoprotein CII and CIII removal from VLDL up to ~90%. HDL-3 exerted significantly greater impact than HDL-2 on apolipoprotein E (43% vs. 18%, p < 0.001), free cholesterol (26% vs. 18%, p < 0.05) and phospholipids (53% vs. 43%, p < 0.05) removal from VLDL and VLDL remnant electrophoretic mobility (0.18 vs. 0.20, p < 0.01). A greater release of these components was also observed in the presence of total HDL with a low HDL-2/HDL-3 cholesterol ratio. Both HDL subpopulations affect VLDL composition during lipolysis, but HDL-3 exhibited a greater effect on this process. Altered composition of HDL related to significant changes in the distribution between HDL-2 and HDL-3 can influence the VLDL remnant features, affecting atherosclerosis progression.

CRISPR/Cas9-mediated knockout of APOC3 stabilizes plasma lipids and inhibits atherosclerosis in rabbits

BackgroundHigh levels of apolipoprotein C3 (APOC3) can lead to hypertriglyceridemia, which increases the risk of cardiovascular disease. We aim to create APOC3-knockout (KO) rabbits and explore the effects of APOC3 deletion on the occurrence and development of atherosclerosis.MethodsAn sgRNA anchored to exon 2 of APOC3 was designed to edit embryo genomes using the CRISPR/Cas9 system. The founder rabbits were sequenced, and their lipid profile, inflammatory cytokines, and atherosclerotic plaques were analyzed.ResultsWhen given a normal chow (NC) diet, all APOC3-KO rabbits had 50% lower triglyceride (TG) levels than those of the matched age control group. Additionally, their plasma lipoprotein lipase increased. When fed a high-fat diet, APOC3 deficiency was observed to be more conducive to the maintenance of plasma TG, total cholesterol, and low-density lipoprotein cholesterol levels, and the inhibition of the inflammatory response and the protection against atherosclerosis in rabbits.ConclusionAPOC3 deficiency can delay the formation of atherosclerosis-induced HFD in rabbits, indicating this is a novel therapeutic target to treat atherosclerosis.

Apolipoprotein C-III predicts cardiovascular events and mortality in individuals with type 1 diabetes and albuminuria.

ObjectivesWe studied apolipoprotein C‐III (apoC‐III) in relation to diabetic kidney disease (DKD), cardiovascular outcomes, and mortality in type 1 diabetes.MethodsThe cohort comprised 3966 participants from the prospective observational Finnish Diabetic Nephropathy Study. Progression of DKD was determined from medical records. A major adverse cardiac event (MACE) was defined as acute myocardial infarction, coronary revascularization, stroke, or cardiovascular mortality through 2017. Cardiovascular and mortality data were retrieved from national registries.ResultsApoC‐III predicted DKD progression independent of sex, diabetes duration, blood pressure, HbA1c, smoking, LDL‐cholesterol, lipid‐lowering medication, DKD category, and remnant cholesterol (hazard ratio [HR] 1.43 [95% confidence interval 1.05–1.94], p = 0.02). ApoC‐III also predicted the MACE in a multivariable regression analysis; however, it was not independent of remnant cholesterol (HR 1.05 [0.81–1.36, p = 0.71] with remnant cholesterol; 1.30 [1.03–1.64, p = 0.03] without). DKD‐specific analyses revealed that the association was driven by individuals with albuminuria, as no link between apoC‐III and the outcome was observed in the normal albumin excretion or kidney failure categories. The same was observed for mortality: Individuals with albuminuria had an adjusted HR of 1.49 (1.03–2.16, p = 0.03) for premature death, while no association was found in the other groups. The highest apoC‐III quartile displayed a markedly higher risk of MACE and death than the lower quartiles; however, this nonlinear relationship flattened after adjustment.ConclusionsThe impact of apoC‐III on MACE risk and mortality is restricted to those with albuminuria among individuals with type 1 diabetes. This study also revealed that apoC‐III predicts DKD progression, independent of the initial DKD category.

Advances in the care of lipodystrophies.

Lipodystrophies are a group of rare, heterogeneous disorders characterized by a lack or maldistribution of adipose tissue. Treatment focusses on the management of complications, including hypertriglyceridemia, which can be severe. Patients are predisposed to early atherosclerotic cardiovascular disease and acute pancreatitis. This review summarizes the recent advances in the treatment of lipodystrophies, with a particular focus on the treatment of hypertriglyceridemia in familial partial lipodystrophy (FPLD). Treatment of dyslipidemia in FPLD requires management of secondary exacerbating factors, particularly insulin resistance and diabetes, together with modification of atherosclerotic cardiovascular disease risk factors. In addition, specific lipid-lowering therapies are usually needed, starting with statins and fibrates. Leptin therapy improves triglycerides. Several emerging treatments for hypertriglyceridemia include apo C-III antagonists (volanesorsen, AKCEA-APOCIII-LRx and ARO-APOC3) and angiopoietin-like 3 antagonists (evinacumab, vupanorsen and ARO-ANG3); efficacy observed in clinical trials of these agents in nonlipodystrophic patients with severe hypertriglyceridemia suggests that they may also be helpful in lipodystrophy. Emerging therapies for dyslipidemia show promise in advancing the care of patients with lipodystrophy. However, these treatments are not yet approved for use in lipodystrophy. Further study of their efficacy and safety in this patient population is needed.

Abstract 10357: ARO-APOC3, an Investigational RNAi Therapeutic, Shows Similar Efficacy and Safety in Genetically Confirmed FCS and Non-FCS Participants with Severe Hypertriglyceridemia

Background: Familial chylomicronemia syndrome (FCS) is an ultrarare condition caused by biallelic pathogenic DNA variants in lipolysis-associated genes, resulting in severe hypertriglyceridemia (HTG) and associated with high risk of acute pancreatitis with few therapeutic options. In a 16-week Phase 1 study (NCT03783377), subcutaneously administered ARO-APOC3 reduced serum apolipoprotein C3 (APOC3) and TG in healthy volunteers and participants (pts) with HTG and was well tolerated. Purpose: To report on the safety/pharmacodynamic (PD) effects of ARO-APOC3 in both FCS pts with biallelic pathogenic variants and pts with severely elevated TG at screening (&gt;880 mg/dL) but without biallelic pathogenic variants (chylomicronemia (MCM)). Methods: Four genetically confirmed FCS pts received 50 mg ARO-APOC3 and 26 MCM pts received 10, 25, 50, or 100 mg ARO-APOC3 on Days 1 and 29. Since similar PD responses were observed among MCM pts, results were pooled across dose levels. Safety and PD responses were examined. Maximal mean/median changes from baseline for APOC3, TG, non-HDL-C, and HDL-C were reported. Results: Baseline/demographics were comparable between groups, except for mean BMI (22.1 [FCS] and 30.5 [MCM] kg/m 2 ), and mean baseline HDL-C , which were lower in FCS pts (Table 1) (p&lt;0.0001 for both). Mean APOC3 was reduced by 98% and 96% in FCS and MCM pts, respectively. Both groups also showed similar maximum median reductions in TG of 91% and 90%, respectively. Similar to the full study, non-HDL-C was reduced and HDL-C increased with treatment in both groups (Table 1). AEs were similar between groups, suggesting a comparable safety profile. Conclusions: In patients with severe HTG, ARO-APOC3 was safe, and consistently decreased APOC3, TG, and non-HDL-C, and increased HDL-C, regardless of underlying genetic cause of HTG, and may represent a promising RNAi therapeutic for the treatment of severe HTG.

Abstract 13528: Interventional Hepatic ApoC-III Knockdown Improves Atherosclerotic Plaque Stability and Remodeling via Lowering Remnant Lipoproteins

Introduction: Apolipoprotein C-III (apoC-III) is a key regulator in triglyceride (TG) metabolism and correlates positively with hypertriglyceridemia and incidences of CVD. Recent studies also identified apoC-III as an inducer of sterile inflammation by activating the inflammasome, another CVD risk factor. It remains unclear if therapeutic apoC-III lowering can reduce CVD risk, nor is it clear if this is dependent on lipid-lowering or anti-inflammatory properties or both. Hypothesis: We set out to test the concept that interventional apoC-III lowering reduces atherosclerosis development only when TG-lowering is achieved. Methods: We determined the impact of interventional apoC-III lowering on atherogenesis using an apoC-III antisense oligonucleotides (ASOs) in hypertriglyceridemic mouse models where the intervention results in TG-lowering ( Apoe -/- Ndst1 f/f Alb-Cre + , Ldlr -/- Ndst1 f/f Alb-Cre + ) or not ( Ldlr -/- Lrp1 f/f Alb-Cre + ). Results: ApoC-III ASO treatment did not alter atherosclerotic lesion volume in the murine models mice simultaneously fed a Western diet. However, when TG-lowering was obtained, apoC-III ASO treatment significantly attenuated advanced and unstable plaque development. In contrast, no improvement in lesion composition and hyperlipidemia was observed in apoC-III ASO-treated Ldlr -/- Lrp1 f/f Alb-Cre + mice lacking hepatic receptors responsible for apoC-III inhibition of TRL clearance. To mimic an interventional setting, we tested the impact of therapeutic apoC-III lowering in combination with a switch to a lipid-poor chow diet intervention after 12-week Western diet feeding. We observed that apoC-III ASO treatment significantly reduced atherosclerotic lesion size progression when an additive TG-lowering was achieved. No differences in lesion development were observed in similarly treated Ldlr -/- Lrp1 f/f Alb-Cre + mice wherein no additive TG-lowering was achieved by apoC-III ASO intervention. Conclusions: Our data highlight that the impact of apoC-III on atherogenesis depends on its lipid-modifying properties and suggest that interventional apoC-III lowering in hypertriglyceridemia patients can prevent plaque rupture and reduce CVD-associated mortality.

Abstract 11850: Targeted Next-Generation Sequencing of 36 Lipid-Related Genes in Patients With Clinically Diagnosed Familial Hypercholesterolemia

Background: Familial hypercholesterolemia (FH) is characterized by elevated serum low-density lipoprotein cholesterol (LDL-C) levels and premature coronary artery disease. This condition is considered to be caused by mutations of conventional FH genes such as LDL receptor (LDLR), apolipoprotein B (APOB), and proprotein convertase subtilisin/kexin type 9 (PCSK9). However, it is not fully elucidated whether other lipid-related gene variants may be overlapped in addition to these FH genes. Methods and Results: One hundred twenty-five heterozygous FH (HeFH) patients in Osaka University Hospital and Rinku General Medical Center, who met the clinical FH criteria of Japan Atherosclerosis Society were enrolled. Genomic DNA for each patient was extracted from peripheral blood cells. Targeted exon sequencing was performed to investigate 36 lipid-related genes including conventional FH genes. Among variants with a minor allele frequency of &lt;5% in 1000 Genomes Project of East-Asian population, we have defined pathogenic variants if they fulfilled i) protein truncating variants, ii) damaging missense variants, and iii) ClinVar-registered pathogenic or likely pathogenic variants. Among 125 HeFH patients, we have identified LDLR pathogenic variants in 89 patients (71.2%), PCSK9 variants in 6 patients (4.8%), and APOB variants in 1 patient (0.8%). Among these 96 patients, 37 patients (38.5%) additionally have pathogenic variants of other lipid-related genes, which include apolipoprotein E2 (APOE2) in 3 patients, apolipoprotein E4 (APOE4) in 19 patients, variants of ATP-binding cassette subfamily G member 5 (ABCG5) in 3 patients, apolipoprotein C3 (APOC3) in 1 patient, and CD36 in 11 patients. As for remaining 29 patients without conventional FH gene variants, 17 patients (58.6%) have pathogenic variants of other lipid-related genes, which include APOE4 in 13 patients, apolipoprotein E5 (APOE5) in 1 patient, variants of ABCG5 in 1 patient, and CD36 in 2 patients. Conclusion: Approximately 40% clinically diagnosed HeFH patients have pathogenic variants of other lipid-related genes in addition to those of conventional FH genes. These overlapping variants may affect the atherogenicity of patients and selection of medication.

Abstract 13534: Plasma Apolipoprotein C3 is Negatively Associated With High Lipoprotein(a) Plasma Levels in Healthy Volunteers

Introduction: ApoliproteinC3 (apoC3) is a small (~8.8kDa) protein, made in the liver. It is an inhibitor of lipoprotein lipase as well as the uptake of triglyceride (TG) rich lipoproteins and remnants by the liver. Overexpression contributes to atherosclerosis by increasing plasma concentration of TG-rich lipoproteins. A recent study reported the presence of apoC3 on lipoprotein(a) [Lp(a)] particles in subjects with mild to moderate aortic stenosis. Lp(a) is an apoB100 containing lipoprotein with apo(a) covalently bound and is a causal factor of ASCVD. Our goal was to investigate relationships between apoC3 and Lp(a) in a healthy population. Methods: We analyzed data from 39 healthy subjects who completed studies of lipoprotein metabolism at the Columbia University Irving Medical Center. Subjects were 18 - 75 years old, and 44% were female. Twenty were Black, 9 Hispanic, 8 White, and 2 mixed race. Lipids (total Cholesterol (C), TG, HDLC, LDLC) were measured by an automatic analyzer. Plasma apoC3, apoB100 and Lp(a) levels were measured via validated ELISA assays. Lp(a) particles were isolated from plasma by immunoprecipitation (IP) with a monoclonal antibody and Western blots were performed. Results: We did not find an association between plasma Lp(a) and apoC3 levels. In a sub-group analysis of participants (N=15), with Lp(a) levels &gt;100nmol/L, we found a significant negative association between apoC3 and Lp(a) plasma concentrations (R = -0.58, p=0.018). Based on the Western blots and ELISA analysis, we see an interaction between Lp(a) (apo(a) and apoB100 intact) and apoC3. There seem to be some differences in the Lp(a) and apoC3 interaction based on Lp(a) plasma concentration. Conclusion and Future Direction: In healthy subjects, there is no association of apoC3 with Lp(a) plasma levels. In a subset of subjects (high Lp(a)), we observed an association with apoC3 plasma levels. Our small data set suggests possible distinct roles for apoC3 in healthy individuals with high Lp(a) level. ApoC3 may be associated with specific circulating isoform sizes of Lp(a). Future studies will focus on analysis of larger cohorts and examining lipid composition in the isolated particles.

Recruiting a transcription factor in the liver to prevent atherosclerosis.

Hypertriglyceridemia is associated with obesity, diabetes, and atherosclerosis. While lipoprotein lipase (LPL) hydrolyzes triglyceride (TG) cargo into remnant lipoproteins with atherogenic properties, how remnant lipoprotein clearance relates to atherosclerosis in people with diabetes remains unclear. In this issue of the JCI, Shimizu-Albergine et al. examined the effects of the basic leucine zipper transcription factor CREBH, which induces genes that activate LPL in mouse models of type I diabetes. Overexpression of a CREBH fragment reduced apolipoprotein C3 (APOC3) levels, which reduced plasma TGs. Notably, the TGs were lowered by a mechanism that was independent of LPL, and atherosclerosis was alleviated by enhanced lipoprotein remnant clearance as opposed to increased lipolysis of TG-rich lipoprotein precursors. A proinflammatory mechanism likely underlies the atherogenicity of remnant lipoproteins. These findings suggest that modifying CREBH expression in the liver may ameliorate atherosclerosis and, perhaps, other diabetes complications.

Clinical value of serum biomarkers, squamous cell carcinoma antigen and apolipoprotein C-II in follow-up of patients with locally advanced cervical squamous cell carcinoma treated with radiation: A multicenter prospective cohort study.

There are currently no reliable, established serum biomarkers to predict the prognosis of radiotherapy for advanced cervical cancer. We aimed to identify serum biomarkers for survival after radiotherapy for cervical cancer. In this multicenter prospective cohort study, the usefulness of pre- and posttreatment serum protein levels of potential biomarkers, including squamous cell carcinoma antigen (SCC-Ag), apolipoprotein C-II (ApoC-II), matrix metalloproteinase (MMP)1, and MMP2, were evaluated together with clinical factors in 145 cervical cancer patients in order to determine their suitability to predict survival. Progression-free survival (PFS) was the primary endpoint, and overall survival (OS), pelvic PFS (PPFS), and distant metastasis-free survival (DMFS) were the secondary endpoints. Blood samples were collected before and 1 month after radiotherapy to measure serum biomarker levels. ApoC-II was measured using a monoclonal antibody-based enzyme-linked immunosorbent assay, which was developed for this purpose. Kaplan-Meier method, log-rank test, and univariate and multivariate Cox proportional hazards models were used for statistical analyses. In multivariate analysis, larger tumor size was independently associated with shorter PFS, OS, PPFS, and DMFS, while longer overall treatment time was independently associated with shorter PPFS. Higher pretreatment SCC-Ag (P < 0.001) was associated with shorter DMFS. Higher posttreatment SCC-Ag (P = 0.017) was also associated with shorter DMFS. Pretreatment ApoC-II was associated with PPFS in univariate analysis (P = 0.048), but not in multivariate analysis. Patients with pretreatment ApoC-II levels ≤ 25.8 μg/ml had shorter PPFS than those with pretreatment ApoC-II levels > 25.8 μg/ml (P = 0.023, log-rank test). Pre- and posttreatment serum SCC-Ag and pretreatment serum ApoC-II levels may be important biomarkers to predict survival outcomes of patients with cervical cancer after radiotherapy. Pre- and posttreatment SCC-Ag and pretreatment ApoC-II might be useful in clinical settings for screening patients to improve treatment strategies in cervical cancer.

Dyslipidemia in diabetic kidney disease classified by proteinuria and renal dysfunction: A cross-sectional study from a regional diabetes cohort.

ABSTRACTAims/IntroductionDiabetic kidney disease (DKD) exacerbates dyslipidemia and increases the incidence of atherosclerotic cardiovascular disease. DKD is a concept that includes typical diabetic nephropathy and an atypical phenotype without proteinuria. We investigated dyslipidemia in different DKD phenotypes that have not been fully studied.Materials and MethodsFasting plasma was obtained from 1,073 diabetes patients enrolled in the regional diabetes cohort (ViNA cohort). Non‐proteinuric and proteinuric DKD were defined as an estimated glomerular filtration rate <60 mL/min/1.73 m2 in the absence or presence of urinary albumin‐to‐creatinine ratio >300 mg/g. Novel lipid risk factors, low‐density lipoprotein (LDL) triglyceride (TG) and small dense LDL cholesterol were measured using our established homologous assay.ResultsThe proportion of atherosclerotic cardiovascular disease patients was higher in non‐proteinuric DKD and even higher in proteinuric DKD than in non‐DKD. Increased estimated glomerular filtration rate grade and albuminuric stage were independently correlated with higher TG, TG‐rich lipoprotein cholesterol and apolipoprotein CIII. Therefore, proteinuric DKD had the highest of these levels. Small dense LDL cholesterol and LDL‐TG were higher in the proteinuria without renal dysfunction group in the lipid‐lowering drug‐free subset. Lipoprotein(a) was higher in DKD regardless of proteinuria.ConclusionsProteinuria was associated with an atherogenic subspecies of LDL, whereas renal dysfunction was associated with increased lipoprotein(a). Proteinuria and renal dysfunction independently exacerbated TG‐rich lipoprotein‐related dyslipidemia. This is in good agreement with the results of large‐scale clinical studies in which proteinuria and renal dysfunction synergistically increased the risk of atherosclerotic cardiovascular disease in populations with diabetes.

Lipoprotein size is a main determinant for the rate of hydrolysis by exogenous LPL in human plasma

LPL is a key player in plasma triglyceride metabolism. Consequently, LPL is regulated by several proteins during synthesis, folding, secretion, and transport to its site of action at the luminal side of capillaries, as well as during the catalytic reaction. Some proteins are well known, whereas others have been identified but are still not fully understood. We set out to study the effects of the natural variations in the plasma levels of all known LPL regulators on the activity of purified LPL added to samples of fasted plasma taken from 117 individuals. The enzymatic activity was measured at 25°C using isothermal titration calorimetry. This method allows quantification of the ability of an added fixed amount of exogenous LPL to hydrolyze triglyceride-rich lipoproteins in plasma samples by measuring the heat produced. Our results indicate that, under the conditions used, the normal variation in the endogenous levels of apolipoprotein C1, C2, and C3 or the levels of angiopoietin-like proteins 3, 4, and 8 in the fasted plasma samples had no significant effect on the recorded activity of the added LPL. Instead, the key determinant for the LPL activity was a lipid signature strongly correlated to the average size of the VLDL particles. The signature involved not only several lipoprotein and plasma lipid parameters but also apolipoprotein A5 levels. While the measurements cannot fully represent the action of LPL when attached to the capillary wall, our study provides knowledge on the interindividual variation of LPL lipolysis rates in human plasma.