Apolipoprotein C-III Research Articles

Apolipoprotein CIII correlates with lipoproteins in the fed state and is not regulated by leptin administration in states of hypoleptinemia induced by acute or chronic energy deficiency: Results from two randomised controlled trials.

Medications targeting the leptin and Apolipoprotein CIII (APOC3) pathways are currently under development for the treatment of hypertriglyceridaemia. Given that both pathways are implicated in triglyceride regulation, it is unknown whether they function independently or interact under physiological conditions and under acute or long-term energy deficiency. APOC3 levels and their association with circulating lipids and lipoproteins were evaluated in the context of two randomised controlled studies. In Study-1, 15 healthy individuals were examined under three distinct conditions, each lasting 72 h: isocaloric feeding, fasting with placebo administration and fasting with leptin administered at replacement doses. In Study-2, 20 females with hypoleptinemia due to relative energy deficiency in sport (REDs) for a minimum of 6 months were treated with either leptin or a placebo for 36 weeks. In Study-1, APOC3 levels remained stable across all arms and were unaffected by leptin administration. In the fed state, APOC3 levels presented positive correlations with various VLDL, IDL, LDL and HDL sizes, and free fatty acids (FFA), most of which were not replicated in fasting. During complete energy deprivation, APOC3 was correlated with HDL molecules, glutamine and FFA, whereas its levels were positively associated only with FFA under leptin treatment. In Study-2, APOC3 levels were lower in the leptin group, but this was not a leptin-dependent effect. A positive correlation between APOC3 levels and HDL was observed in the leptin group. These results contribute towards our better understanding of the intricate nature of lipid regulation under energy deficiency, suggesting that medications targeting the leptin and APOC3 pathways act through different metabolic pathways and thus may have independent effects from each other in regulating triglycerides.

Relationship between serum levels of ANGPTL8, Apo C2, and human placental lactogen (hPL) in patients with gestational diabetes mellitus: Interaction of LPL regulators with hPL, a possible contributing factor to insulin resistance.

Gestational diabetes mellitus (GDM) is defined as glucose intolerance during pregnancy. We aimed to investigate the potential effects of betatrophin and ApoC2 in GDM, focusing on their roles in LPL (lipoprotein lipase) regulation and their relationship with hPL to elucidate the possible impact of hPL on lipid metabolism and its potential contribution to the development of GDM. Thirty pregnant women with normal glucose tolerance and 29 with gestational diabetes mellitus (diagnosed by 75g OGTT between 24 and 28 weeks) were included in the study. Serum betatrophin, hPL, and ApoC2 were measured by Elisa and HOMA-IR was calculated. In the GDM group, hPL levels correlated with betatrophin and ApoC2 (r=0.552, p<0.05; r=0.588, p<0.05 respectively) while betatrophin correlated with the ApoC2 (r=0.584, p<0.05). A linear relationship between hPL and betatropin and also between hPL and ApoC2 values in the control group (r=0.454, p<0.05; r=0.779, p<0.01 respectively) were observed. ApoC2 levels in the GDM group (n=20) with HOMA-IR cut-off >2.5 were significantly higher than the control group (n=10) (p<0.05). There was also a positive relationship between betatrophin and ApoC2 (r=0.591) (p<0.05). GDM patients may have impaired LPL enzyme regulation in addition to insulin resistance, with hPL potentially contributing to this disruption. Impaired lipoprotein lipase activity and its dysregulation secondary to genetic disorders may play a role in the etiopathogenesis of GDM. Further investigation into the correlation between betatrophin, ApoC2, and other LPL modulators in patients with various forms of diabetes could be beneficial for understanding this interaction more comprehensively.

Curcumin inhibits the progression of hyperlipidemia via OGT mediated O-GlcNAcylation modulation of APOC3.

The etiology of hyperlipidemia is complex, and our understanding of its underlying mechanisms is limited. Effective therapeutic strategies for hyperlipidemia remain elusive. This study aimed to confirm the effect of curcumin on hyperlipidemia treatment and elucidate the precise mechanism. A high-fat diet-induced hyperlipidemia model using C57BL/6J mice and HaCaT cells was established. Co-immunoprecipitation and immunofluorescence were performed to detect protein interactions, and immunoprecipitation coupled with Western blotting was used to assess protein succinylation. 40μM of curcumin administration promoted cell viability, increased the levels of glutathione peroxidase, glutathione, catalase, and superoxide dismutase, while reducing reactive oxygen species activity and the levels of triglycerides and malondialdehyde. Additionally, curcumin attenuated the development of hyperlipidemia in vivo. Mechanistically, 100mg/kg of curcumin promoted O-GlcNAcylation and increased the expression of O-linked N-acetylglucosamine transferase in HaCaT cells. Furthermore, apolipoprotein C3 was identified as a substrate of O-linked N-acetylglucosamine transferase, and O-GlcNAcylation of apolipoprotein C3 enhanced its stability. Rescue experiments further verified that curcumin exerts its effects by regulating apolipoprotein C3 expression. In conclusion, these findings provide novel insights into the treatment of hyperlipidemia.

Factors of Long-Term Prognosis for Cardiovascular Complications in Patients After Acute Myocardial Infarction, Based on the Plasma Proteome.

To study the plasma proteome of patients with type 1 acute myocardial infarction (AMI) to identify potential markers for long-term prognosis of the risk for developing cardiovascular complications. The study included 64 patients with type 1 AMI with and without ST segment elevation who underwent primary percutaneous coronary intervention upon admission. The following information on cardiovascular events was collected for 36 months after admission: death from cardiovascular pathology, recurrent AMI, stroke, repeat myocardial revascularization and/or endarterectomy. Peripheral blood sampling followed by a plasma proteome analysis using chromatography-mass spectrometry was performed in all patients before hospitalization. During 36 months after hospitalization, cardiovascular complications were detected in 23 (36%) patients. These patients were included in the group with an unfavorable prognosis, while the remaining patients made up the group with a positive prognosis. A mass spectrometric analysis of the plasma proteome and comparison of the groups identified seven differentially represented proteins. Also, a multivariate regression analysis, ROC curves, and Kaplan-Meier models showed that four proteins (apolipoprotein C1, complement factor H, di-N-acetylchitobiase, and ficolin-2) were predictors of the risk for developing cardiovascular complications in the long term. An integrated parameter was developed that took into account the plasma concentrations of all four above proteins. This parameter was used to construct a model for assessing the risks of unfavorable long-term prognosis in AMI patients with a sensitivity of 87% and a specificity of 78%. The study results demonstrated that plasma concentrations of apolipoprotein C1, complement factor H, di-N-acetylchitobiase, and ficolin-2 are reliable prognostic markers for assessing the risks of cardiovascular events in patients with AMI in the long term.

Association of APOE alleles and polygenic profiles comprising APOE-TOMM40-APOC1 variants with Alzheimer's disease neuroimaging markers.

TOMM40 and APOC1 variants can modulate the APOE-ε4-related Alzheimer's disease (AD) risk by up to fourfold. We aim to investigate whether the genetic modulation of ε4-related AD risk is reflected in brain morphology. We tested whether 27 magnetic resonance imaging-derived neuroimaging markers of neurodegeneration (volume and thickness in temporo-limbic regions) are associated with APOE-TOMM40-APOC1 polygenic profiles using the National Alzheimer's Coordinating Center Uniform Data Set linked to the AD Genetic Consortium data. All brain regions studied using structural phenotypes were smaller in individuals with AD. The ε4 allele was associated with smaller limbic (entorhinal, hippocampus, parahippocampus) brain volume and cortical thickness in AD cases than controls. There were significant differences in the associations for the higher-risk and lower-risk ε4-bearing APOE-TOMM40-APOC1 profiles with temporo-limbic region markers. The APOE-AD heterogeneity may be partly attributed to the modulating role of the TOMM40 and APOC1 genes in the APOE cluster. The ε4 allele is associated with smaller values of neuroimaging markers in AD cases. Larger values of neuroimaging markers may protect against AD in the ε4 carriers. TOMM40 and APOC1 variants differentiate AD risk in the ε4 carriers. The same variants can differentiate the links between ε4 and neuroimaging markers.

Genetic correlation between genes targeted by lipid-lowering drugs and venous thromboembolism: A drug-target Mendelian randomization study.

Dyslipidemia has been established as a potential risk factor for venous thromboembolism (VTE) in several observational studies. Statins and novel lipid-modifying agents are being explored for their potential in VTE prevention, encompassing deep vein thrombosis (DVT), and pulmonary embolism (PE). Nonetheless, conclusive evidence supporting the effectiveness remains uncertain. Without definitive proof, the current recommendation of lipid-lowering drugs (LLDs) for preventing VTE, either primarily or secondarily, is not support. An investigation into the impact of 8 classes of LLDs on VTE was conducted using a drug-target Mendelian randomization approach. The drug categories examined included 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR), apolipoprotein B, proprotein convertase subtilisin/kexin type 9, Niemann-Pick C1-like 1, lipoprotein lipase (LPL), angiopoietin-like 3, apolipoprotein C3 (APOC3), and peroxisome proliferator-activated receptor alpha. Leveraging genetic variants situated proximate to or within drug-target genes linked with low-density lipoprotein and triglycerides, we acted as proxies for LLDs. The UK Biobank study was the source of data on VTE, PE, and DVT of lower extremities (LEDVT). We employed the inverse-variance weighted method for the core analysis in Mendelian randomization, complemented by sensitivity analysis to investigate horizontal pleiotropy and heterogeneity. Employing genetic proxies to inhibit HMGCR revealed a notable correlation with reduced LEDVT risk (odds ratio [OR]: 0.995, 95% CI: 0.992-0.998, P = .002), VTE (OR: 0.994, 95% CI: 0.988-1.000, P = .033), but a no significant association with PE (OR: 1.000, 95% CI: 0.994-1.002, P = .246). The suppression of APOB was linked with an elevated risk of experiencing LEDVT (OR: 1.002, 95% CI: 1.001-1.004, P = .006), VTE (OR: 1.005, 95% CI: 1.002-1.007, P < .001), and PE (OR: 1.002, 95% CI: 1.000-1.004, P = .031). Similarly, the activation of LPL was associated with increased risks for VTE (OR: 1.003, 95% CI: 1.001-1.005, P = .003) and PE (OR: 1.003, 95% CI: 1.002-1.005, P < .001). Additionally, the inhibition of APOC3 was linked to a higher DVT risk (OR: 1.002, 95% CI: 1.000-1.004, P = .038). Research has shown that HMGCR, out of 8 lipid-lowering drug-targets evaluated, exhibited a significant correlation with VTE and LEDVT, highlighting its potential as an effective target for the treatment or prevention of these conditions. In contrast, APOB, LPL, and APOC3 each contribute to an increased risk of VTE, PE, and LEDVT in various degrees, pharmacovigilance for VTE, PE, and LEDVT risk among users of APOB inhibitors, LPL activation, and APOC3 inhibitors may be warranted.

Vaccination as a Promising Approach in Cardiovascular Risk Mitigation: Are We Ready to Embrace a Vaccine Strategy?

Cardiovascular disease (CVD) remains a leading global health concern, with atherosclerosis being its principal cause. Standard CVD treatments primarily focus on mitigating cardiovascular (CV) risk factors through lifestyle changes and cholesterol-lowering therapies. As atherosclerosis is marked by chronic arterial inflammation, the innate and adaptive immune systems play vital roles in its progression, either exacerbating or alleviating disease development. This intricate interplay positions the immune system as a compelling therapeutic target. Consequently, immunomodulatory strategies have gained increasing attention, though none have yet reached widespread clinical adoption. Safety concerns, particularly the suppression of host immune defenses, remain a significant barrier to the clinical application of anti-inflammatory therapies. Recent decades have revealed the significant role of adaptive immune responses to plaque-associated autoantigens in atherogenesis, opening new perspectives for targeted immunological interventions. Preclinical models indicate that vaccines targeting specific atherosclerosis-related autoantigens can slow disease progression while preserving systemic immune function. In this context, numerous experimental studies have advanced the understanding of vaccine development by exploring diverse targeting pathways. Key strategies include passive immunization using naturally occurring immunoglobulin G (IgG) antibodies and active immunization targeting low-density lipoprotein cholesterol (LDL-C) and apolipoproteins, such as apolipoprotein B100 (ApoB100) and apolipoprotein CIII (ApoCIII). Other approaches involve vaccine formulations aimed at proteins that regulate lipoprotein metabolism, including proprotein convertase subtilisin/kexin type 9 (PCSK9), cholesteryl ester transfer protein (CETP), and angiopoietin-like protein 3 (ANGPTL3). Furthermore, the literature highlights the potential for developing non-lipid-related vaccines, with key targets including heat shock proteins (HSPs), interleukins (ILs), angiotensin III (Ang III), and a disintegrin and metalloproteinase with thrombospondin motifs 7 (ADAMTS-7). However, translating these promising findings into safe and effective clinical therapies presents substantial challenges. This review provides a critical evaluation of current anti-atherosclerotic vaccination strategies, examines their proposed mechanisms of action, and discusses key challenges that need to be overcome to enable clinical translation.

Decreased neuronal excitability in hypertriglyceridemia hamsters with acute seizures.

Neonatal seizures are the most common clinical manifestation of neurological dysfunction in newborns, with an incidence ranging from 1 to 5‰. However, the therapeutic efficacy of current pharmacological treatments remains suboptimal. This study aims to utilize genetically modified hamsters with hypertriglyceridaemia (HTG) to investigate the effects of elevated triglycerides on neuronal excitability and to elucidate the underlying mechanisms. The ultimate goal is to identify novel therapeutic targets for the treatment of neonatal seizures. Acute seizure models were established both in vivo and ex vivo using wild-type and Apolipoprotein C2 knockout (Apoc2 -/-) hamsters. The frequency of tonic-clonic seizures was recorded. Excitatory postsynaptic potentials (EPSPs) and evoked action potentials (eAPs) of pyramidal neurons in the frontal cortex were measured. Fatty acid metabolomic analysis was conducted on microdialysate from the frontal cortex tissue post-seizure, and mRNA expression changes were also assessed. Apoc2 -/- hamsters exhibited a reduced frequency of tonic-clonic seizures and diminished EPSP and eAP in comparison to wild-type hamsters. Following seizure induction, free palmitic acid levels in the frontal cortex dialysate significantly decreased, while the expression of palmitoyl acyltransferase 14 (ZDHHC14) in the frontal cortex tissue was higher in Apoc2 -/- hamsters than in wild-type hamsters. Additionally, the amplitude of transient outward potassium currents (IA) in cortical neurons of Apoc2 -/- hamsters was observed to be elevated compared to wild-type hamsters. Hypertriglyceridemic Apoc2 -/- hamsters exhibited reduced seizure frequency and decreased cortical neuron excitability. The upregulation of ZDHHC14, leading to increased IA, may be a crucial mechanism underlying the observed seizure protection.

Novel agents for treating severe hypertriglyceridemia.

The PALISADE trial extended the data available for inhibition of apolipoprotein (apo) C3 inhibition for treating severe hypertriglyceridemia.1 75 patients with persistent chylomicronemia were allocated to 2 doses of plozasiran or placebo. Triglycerides were reduced by a net 53%-58%, and a borderline significant 17% reduction was seen in pancreatitis events. These results offer potential treatments for familial or multifactorial chylomicronemia syndromes.

ApoC-III proteoforms are associated with better lipid, inflammatory, and glucose profiles independent of total apoC-III

BackgroundApolipoprotein (apo) C-III is involved in several processes that increase triglyceride levels, inflammation, and insulin resistance. Four of its proteoforms have been the focus of several studies and have shown differential associations with cardiovascular risk biomarkers, mostly lipids. However, there are other proteoforms of apoC-III that have not yet been investigated in detail. The aim of this study was to evaluate the associations of seven apoC-III proteoforms with a comprehensive set of biomarkers, including lipid metabolism, inflammation, and glucose homeostasis.MethodsSeven apoC-III proteoforms (apoC-III0a, apoC-III0b, apoC-III1, apoC-III1d, apoC-III2, apoC-III2d, and apoC-III0f) were measured using a mass spectrometry immunoassay in 875 participants from the cross-sectional study of the Di@bet.es cohort. The complete lipoprotein profile was obtained via the Liposcale test, and the proton nuclear magnetic resonance (1H-NMR)-assessed glycoprotein signals were also obtained as biomarkers of inflammation.ResultsThree proteoform ratios (apoC-III2d, apoC-III2, and apoC-III0f normalized to apoC-III1) showed protective associations with most of the cardiovascular risk biomarkers in comparison with total apoC-III in linear regression models and were negatively associated with triglycerides (β=-0.173, p < 0.001; β=-0.297, p < 0.001; β=-0.223, p = 0.002), very low-density (VLDL) particle concentration (β=-0.133, p < 0.001; β=-0.265, p < 0.001; β=-0.203, p < 0.001), GlycA (β=-0.148, p < 0.001; β=-0.263, p < 0.001; β=-0.211, p < 0.001) and homeostatic model assessment of insulin resistance (HOMA-IR) (β=-0.096, p = 0.003; β=-0.199, p < 0.001; β=-0.114, p = 0.002). These associations were partly independent of total apoC-III concentrations. Participants with high levels of these proteoforms had a lower prevalence of cardiometabolic disorders, such as type 2 diabetes (p = 0.022), obesity (p = 0.001), and metabolic syndrome (p = 0.013).ConclusionsWhile apoC-III is positively associated with biomarkers of cardiometabolic risk, the proportions of three apoC-III proteoforms show opposite associations, independent of total apoC-III concentrations. Measuring not only apoC-III but also the proportions of apoC-III proteoforms can provide valuable information since individuals with similar levels of total apoC-III could display opposite lipid profiles depending on the proportion of apoC-III proteoforms.Graphical abstract

Metabolic Dysfunction-Associated Steatotic Liver Disease, Hypertriglyceridemia and Cardiovascular Risk.

Metabolic dysfunction-associated steatotic liver disease (MASLD) encompasses a spectrum of liver conditions ranging from simple steatosis to the more severe metabolic dysfunction-associated steatohepatitis (MASH). MASLD is strongly linked to insulin resistance disorders, with a high prevalence among patients with type 2 diabetes. Long-term complications include liver cirrhosis, liver cancer, and cardiovascular disease. This article elucidates the complex interplay between hypertriglyceridemia, obesity, insulin resistance, and MASLD and provides an exploration of various etiologies, including genetic predispositions and secondary factors such as diabetes, medication use, and alcohol consumption. While MASLD treatment remains an unmet need, multiple pharmacological therapies are targeting hypertriglyceridemia and MASLD, including statins, peroxisome proliferator-activated receptors (PPARs) agonists, biguanides, incretins, and emerging therapies including angiopoietin-like (ANGPTL) 3 and apolipoprotein (APO) C-III inhibitors, fibroblast growth factor (FGF) 21 analogues, and thyroid hormone receptor agonists. By examining these interconnected facets, this review offers insights into potential therapeutic strategies for MASLD and associated comorbidities.

Apoc1 Knockdown Alleviates High Glucose-induced Oxidative Stress and Apoptosis of Renal Tubular Cells by Binding to Clusterin.

Diabetic nephropathy (DN) is a serious diabetic complication. Renal tubular damage is an important aspect of DN. Increased apolipoprotein C1 (Apoc1) has been confirmed in serum of patients with DN. The exact mechanism of Apoc1 in DN is unclear as yet. We aimed to elaborate the molecular mechanism underlying high glucose (HG)-induced renal tubular epithelial damage. In this content, a DN mouse model was established to assess renal damage. Apoc1 and Clusterin expression in renal tissue was detected using immunoblotting and immunofluorescence staining. In vitro, human kidney proximal tubular epithelial cells (HK-2 cells) were exposed to HG to simulate the DN model. After Apoc1 and/or Clusterin knockdown, HK-2 cell viability under HG conditions was detected using CCK-8 assay. DCFH-DA staining was used to examine the production of intracellular reactive oxygen species (ROS). MDA and SOD levels were tested by kits. Moreover, cell apoptosis was measured using TUNEL staining. Immunoblotting was employed to evaluate the expression of proteins. Additionally, the binding between Apoc1 and Clusterin was analyzed using co-immunoprecipitation experiments. Our data revealed that Apoc1 expression was upregulated while Clusterin expression was downregulated in renal tissue of DN mice and HG-treated HK-2 cells. Apoc1 knockdown alleviated oxidative stress and apoptosis in HG-treated HK-2 cells. Importantly, Apoc1 could bind to Clusterin and regulate Clusterin expression in HK-2 cells. Finally, Clusterin silencing blocked the influences of Apoc1 knockdown on the oxidative stress and apoptosis in HK-2 cells under HG conditions. Collectively, Apoc1 knockdown exerts potential anti-DN effects by binding to Clusterin to alleviate HG-induced renal tubular damage, suggesting that Apoc1/Clusterin can be used as a valuable therapeutic target for DN.

Multifaceted Role of Apolipoprotein C3 in Cardiovascular Disease Risk and Metabolic Disorder in Diabetes.

Apolipoprotein C3 (APOC3) plays a critical role in regulating triglyceride levels and serves as a key predictor of cardiovascular disease (CVD) risk, particularly in patients with diabetes. While APOC3 is known to inhibit lipoprotein lipase, recent findings reveal its broader influence across lipoprotein metabolism, where it modulates the structure and function of various lipoproteins. Therefore, this review examines the complex metabolic cycle of APOC3, emphasizing the impact of APOC3-containing lipoproteins on human metabolism, particularly in patients with diabetes. Notably, APOC3 affects triglyceride-rich lipoproteins and causes structural changes in high-, very low-, intermediate-, and low-density lipoproteins, thereby increasing CVD risk. Evidence suggests that elevated APOC3 levels-above the proposed safe range of 10-15 mg/dL-correlate with clinically significant CVD outcomes. Recognizing APOC3 as a promising biomarker for CVD, this review underscores the urgent need for high-throughput, clinically feasible methods to further investigate its role in lipoprotein physiology in both animal models and human studies. Additionally, we analyze the relationship between APOC3-related genes and lipoproteins, reinforcing the value of large-population studies to understand the impact of APOC3 on metabolic diseases. Ultimately, this review supports the development of therapeutic strategies targeting APOC3 reduction as a preventive approach for diabetes-related CVD.

A Combined Fertility and Developmental Toxicity Study with an Antisense Oligonucleotide Targeting Murine Apolipoprotein C-III mRNA in Mice.

Here, we present the reproductive toxicology profile of ISIS 838707, a GalNAc-conjugated antisense oligonucleotide (ASO) targeting mouse Apolipoprotein C-III (ApoC-III) mRNA. ISIS 838707 was subcutaneously administered during the premating, mating, and gestation periods to male and female mice at 0, 5, 10, and 20 mg/kg/week. Key focus areas included fertility, reproductive cell functions, estrus cycle, tubal transport, implantation, embryo development stages, and teratogenic potential. We also investigated the toxicokinetics and target mRNA knockdown effects. The treatment was well-tolerated at all dose levels, with no overt toxicity. Treatment led to decreased total cholesterol and/or triglyceride levels at doses ≥5 mg/kg/week, concordant with effective knockdown of ApoC-III mRNA (>85% reduction at all dose levels). Toxicokinetic analysis revealed predominant distribution to the liver of parental animals and minimally to the placenta, with no detectable transfer to fetal liver. Despite these pharmacological effects, there were no discernible adverse impacts on developmental and reproductive functions. These findings suggest that ISIS 838707, while effective in modulating ApoC-III mRNA and lipid profiles, does not adversely impact on reproductive and developmental functions in mice. The study contributes insights into the safety profile of ASOs and reduction of ApoC-III expression, particularly in the context of reproductive and developmental health.

Heavy metal exposure and its effects on APOC3, CFAI, and ZA2G

Despite increasing heavy metal pollution, traditional epidemiology often fails to link exposure to health outcomes. This study used multi-omics to investigate associations between heavy metal exposure and health. Blood and urine samples from 294 participants in heavy metal-exposed and control areas were analyzed, revealing key biomarkers. Meta P analysis revealed consistent trends in apolipoprotein C3 (APOC3) expression, and mediation analysis showed significant effects of APOC3 and zinc-alpha-2-glycoprotein (ZA2G) on metabolites: the mediating effect of APOC3 from blood cadmium to serotonin was 0.023 (P < 0.001) and that to 3-phosphoglyceric acid (3PG) was 0.0125 (P = 0.002). Mendelian randomization confirmed the positive impact of APOC3 and Complement Factor I (CFAI) and the negative effect of ZA2G on metabolites, with apolipoprotein H (APOH) methylation significantly altering APOC3 (β = −0.22, P = 0.017), CFAI (β = 0.176, P = 0.035), and ZA2G (β = 0.139, P = 0.048) protein levels. Liver function variables, including albumin, total protein, calcium, and lactate dehydrogenase, correlated with 3PG and serotonin levels in the exposed areas. Sex-specific analysis showed that men exhibited stronger compensatory mechanisms via CFAI and myo-inositol, while women’s greater vulnerability to heavy metal exposure highlighted the need for targeted interventions. These findings suggest APOH methylation affects APOC3, CFAI, and ZA2G levels, elevating 3PG, inosine monophosphate, and serotonin levels and harming liver function via lipolysis, supporting the use of these markers in health monitoring, therapies, and policies to limit heavy metal risks.

Study on serum proteomic characteristics of workers with rare earth samarium oxide pneumoconiosis

Objective: To screen differential proteins in the serum of workers with rare earth samarium oxide pneumoconiosis, in order to provide new ideas for finding its early diagnostic biomarkers. Methods: In April 2019, three male workers diagnosed with samarium oxide pneumoconiosis at a rare earth factory in Baotou City, Inner Mongolia Autonomous Region were selected as the observation group, and three male workers who were not exposed to dust were selected as the control group. The serum was sequenced using the Label-free proteomic method to screen for differentially expressed proteins, followed by cluster of orthologous groups of proteins (COG) annotation, gene ontology (GO) enrichment analysis, and Kyoto encyclopedia of genes and genomes (KEGG) pathway analysis. The interaction gene library retrieval tool database and Cytoscape 3.9.1 software were used to draw protein-protein interaction networks. CytoHubba plugin was used to screen for differentially expressed proteins with high scores, and real-time fluorescence quantitative polymerase chain reaction (RT/q-PCR) was used to validate the proteomic sequencing results. Results: A total of 45 up-regulated differentially expressed proteins and 5 down-regulated differentially expressed proteins were screened out in the serum of workers with rare earth samarium oxide pneumoconiosis. In the COG functional classification, post-translational modifications, protein turnover, and chaperones were the most numerous. GO enrichment included 25 entries for biological processes such as complement activation (classical pathways), 15 entries for cellular components such as extracellular recombinants, and 10 entries for molecular functions such as protein binding. The pathways identified by KEGG enrichment analysis mainly included infectious diseases, immune system, signal transduction, and immune related diseases. The top 10 scoring proteins were haptoglobin, complement C1r subcomponent, complement C1s subcomponent, apolipoprotein C-Ⅲ, apolipoprotein A-Ⅱ, prothrombin, afamin, complement component C8 gamma chain, complement component C6, complement component C7. The RT/q-PCR validation results showed that the mRNA expression levels of haptoglobin, prothrombin and complement C1s subcomponent in the observation group were significantly higher than those in the control group, and the differences were statistically significant (P<0.05) . Conclusion: Ten differentially expressed proteins in the serum of workers with rare earth samarium oxide pneumoconiosis are screened, which provides a good idea for the screening of biomarkers for early diagnosis of samarium oxide pneumoconiosis.

Serum Apolipoprotein C3: A Link Between Diabetic Nephropathy and Subclinical Atherosclerosis in Children with Diabetes Mellitus

Serum Apolipoprotein C3: A Link Between Diabetic Nephropathy and Subclinical Atherosclerosis in Children with Diabetes Mellitus

The Emerging Potential of Apolipoprotein C-III Inhibition for ASCVD Prevention: A State-of-the-Art Review.

Multiple agents are being developed that inhibit apolipoprotein (apo) C-III. This state-of-the-art review examines their potential for atherosclerotic cardiovascular disease (ASCVD) risk reduction. Apo C-III, an apolipoprotein on the surface of triglyceride-rich lipoproteins (TRLs), impairs clearance of TRLs through both lipoprotein lipase dependent and independent pathways, thereby resulting in increased concentrations of triglycerides. Apo C-III has also been shown to have pro-atherogenic effects when bound to high-density lipoprotein (HDL) particles. Classical and genetic epidemiology studies provide support for the concept that apo C-III is associated with an increased risk of ASCVD events. Drug efficacy of agents that silence APOC3 mRNA has been studied in populations with varying hypertriglyceridemia severity, including those with familial chylomicronemia syndrome, multifactorial chylomicronemia syndrome/severe hypertriglyceridemia, and mixed hyperlipidemia. Randomized controlled trials have reported significant reductions in TG and non-HDL cholesterol levels among these patients treated with APOC3 inhibitors. Upcoming clinical outcomes trials seek to establish a role for APOC3 inhibitors to reduce risk of ASCVD.

Abstract 4120854: Case Report: Elevated HDL in Familial Hyper-Alpha-Lipoproteinemia: Atheroprotective or Atherogenic?

Introduction: Familial hyper-alpha-lipoproteinemia (HALP) is a heterogenous genetic lipid disorder that is found in only 8% of the population and manifests as elevated HDL levels above the 90 th percentile. HALP is due to mutations in various genes including cholesteryl ester transfer protein (CETP), hepatic lipase, or apolipoprotein C-III (APOC3). While epidemiological studies have noted an inverse relationship between high HDL and the development of coronary artery disease, recent data have shown a lack of causal atheroprotective effects. We present a case of a patient with significantly elevated HDL and peripheral vascular disease. Case Description: Patient is a 64-year-old female with past medical history of peripheral artery disease with occlusion of the left femoral artery and popliteal arteries status post angioplasty, hypertension, type 2 diabetes, alcohol use, and CKD Stage 4 who presented to the advanced lipid clinic for management of elevated lipoproteins. Patient’s laboratory data was significant for total cholesterol (TC) of 375 mg/dL, a high-density lipoprotein (HDL) of &gt;200 mg/dL, triglycerides (TG) of 66 mg/dL, and a low-density lipoprotein (LDL) of 175 mg/dL. Further testing revealed elevated apolipoprotein A-I of 231 mg/dL. Patient was subsequently initiated on a high intensity statin with improvement in her lipid panel with a TC of 247 mg/dL, HDL of 133 mg/dL, TG of 50 mg/dL, and LDL of 106 mg/dL, with plan for further uptitration of lipid therapy to target LDL &lt;70 mg/dL. Discussion: CETP exchanges cholesteryl esters from HDL for TG, making HDL smaller and more TG-rich. Studies have shown that in vitro addition of CETP and hepatic lipase, which hydrolyzes phospholipids and TG, into CETP-deficient patients led to the development of very small HDL particles that were able to remove cholesterol from lipid laden macrophages. Conversely, larger HDL molecules seen in CETP-deficient patients did not have such anti-atherogenic properties. In addition to recognizing HALP in the setting of elevated HDL, it is also important to exclude secondary causes of elevated HDL, such as primary biliary cirrhosis and high-dose niacin. Genetic testing should also be considered.

Abstract 4146303: A Single-Dose of a Novel CasX-Editor Lowers APOC3 Levels In Vivo

Background: Apolipoprotein C-III (APOC3) is a key regulator of lipid metabolism that inhibits the catabolism and clearance of triglyceride (TG)-rich lipoproteins in the blood. Loss-of-function APOC3 variants are associated with significantly lower TG levels and a reduced risk of heart disease, underscoring the potential of APOC3 inactivation as a therapeutic strategy for patients with familial chylomicronemia syndrome (FCS) and severe hypertriglyceridemia (SHTG). Here, we developed STX-1400 lead molecules as a novel investigational gene editing treatment using a highly engineered CRISPR-CasX mRNA and a guide RNA (gRNA) encapsulated into lipid nanoparticles (LNPs) to edit the APOC3 gene and knock out its hepatic expression. Methods: STX-1400 lead molecules were evaluated for editing potency and resulting functional effects on APOC3 reduction in vitro in primary human hepatocytes (PHHs) and primary cynomolgus hepatocytes (PCHs). In vivo studies were conducted in PXB mice, a humanized liver mouse model. Liver biopsies and serum samples were collected at two weeks post-dose. Human APOC3 mRNA and APOC3 protein levels were measured in liver biopsies and serum samples, respectively. Lipid profile evaluation, which included measuring TGs and total cholesterol (TC) levels, was also performed. Results: Treatment of PHHs with LNPs containing STX-1400 lead molecules showed a dose-dependent increase in editing activity; up to 90% editing at the APOC3 locus was associated with &gt;70% reduction in secreted APOC3 protein levels. Potency was also observed in PCHs, with up to 70% editing. A single dose of LNPs encapsulating STX-1400 lead molecules delivered into PXB humanized mice resulted in &gt;60% editing at the APOC3 locus in the liver, which was associated with &gt;90% reduction of serum hAPOC3 protein levels, accompanied by reduction in TG and TC levels. Conclusions: These data demonstrate that the STX-1400 lead molecules efficiently knock down hepatic expression of APOC3 in preclinical models. This work suggests that the CRISPR-CasX-based editor approach could be developed as a single dose therapy for the treatment of hypertriglyceridemia.