Angiopoietin-like Protein Research Articles

A novel fully human anti-NT-ANGPTL3 antibody from phage display library exhibits potent ApoB, TG, and LDL-C lowering activities in hyperlipidemia mice.

Dyslipidemia is characterized by elevated plasma levels of low-density lipoprotein cholesterol (LDL-C), triglycerides (TG), and TG-rich lipoprotein (TGRLs) in circulation, and is closely associated with the incidence and development of cardiovascular disease. Angiopoietin-like protein 3 (ANGPTL3) deficiency has been identified as a cause of familial combined hypolipidemia in humans, which allows it to be an important therapeutic target for reducing plasma lipids. Here, we report the discovery and characterization of a novel fully human antibody F1519-D95aA against N-terminal ANGPTL3 (NT-ANGPTL3), which potently inhibits NT-ANGPTL3 with a KD as low as 9.21 nM. In hyperlipidemic mice, F1519-D95aA shows higher apolipoprotein B (ApoB) and TG-lowering, and similar LDL-C reducing activity as compared to positive control Evinacumab (56.50% vs 26.01% decrease in serum ApoB levels, 30.84% vs 25.28% decrease in serum TG levels, 23.32% vs 22.52% decrease in serum LDLC levels, relative to vehicle group). Molecular docking and binding energy calculations reveal that the F1519-D95aA-ANGPTL3 complex (10 hydrogen bonds, -65.51 kcal/mol) is more stable than the Evinacumab-ANGPTL3 complex (4 hydrogen bonds, -63.76 kcal/mol). Importantly, F1519-D95aA binds to ANGPTL3 with different residues in ANGPTL3 from Evinacumab, suggesting that F1519-D95aA may be useful for the treatment of patients resistant to Evinacumab. In conclusion, F1519-D95aA is a novel fully human anti-NT-ANGPTL3 antibody with potent plasma ApoB, TG, and LDL-C lowering activities, which can potentially serve as a therapeutic agent for hyperlipidemia and relevant cardiovascular diseases.

Correlation of serum VEGF-C, ANGPTL4, and activin A levels with frailty

BackgroundSecretory factors linked to lymphogenesis, such as vascular endothelial growth factor C (VEGF-C), angiopoietin like protein 4 (ANGPTL4), and activin A (ACV-A), have been recognized as potential markers of chronic inflammatory status and age-related diseases. Furthermore, these factors may also be linked to frailty. The primary objective of this study was to examine the serum VEGF-C, ANGPTL4, and ACV-A levels in young individuals, healthy older individuals, and older individuals with pre-frailty and frailty, and to determine their association with pro-inflammatory factor levels. MethodsWe conducted an observational study, enrolling a total of 210 older individuals and 20 young healthy volunteers. Participants were divided into four groups based on the Freid frailty phenotype: healthy young group, older patients without frailty group, pre-frail older group, and frail older group. Plasma and peripheral blood mononuclear cells (PBMCs) were collected from all four groups. ELISA was used to measure the serum levels of VEGF-C, ANGPTL4, ACV-A, and pro-inflammatory cytokines, while RT-qPCR was used to measure the transcription level of VEGF-C, ANGPTL4 and ACV-A in PBMCs. ResultsIn comparison to healthy young individuals and older participants without frailty, older participants with frailty exhibited lower renal function, higher serum levels and transcription levels of VEGF-C, ANGPTL4, ACV-A, and elevated levels of pro-inflammatory cytokines (CRP, IL-1β, and TNF-α). Multiple linear regression analysis revealed that serum levels of VEGF-C, ANGPTL4, and ACV-A were positively correlated with the frailty index, independent of age, eGFR, and comorbidities. Furthermore, the receiver operating characteristic (ROC) curve analysis demonstrated that serum levels of VEGF-C, ANGPTL4, and ACV-A have great accuracy in predicting frailty. ConclusionElevated serum levels of VEGF-C, ANGPTL4, and ACV-A are associated with frailty status.

Angiopoietin-Like Protein 2 Serves as an Independent Prognostic Biomarker and Correlates with Immune Infiltration in Osteosarcoma

Osteosarcoma mostly occurs in adolescents, with high disability and mortality rates and poor prognosis. Angiopoietin-like protein 2 (ANGPTL2) is a secreted glycoprotein protein, which plays important roles in cellular processes and various diseases. Microarray gene expression data GSE16088 and GSE36001 were downloaded from Gene Expression Omnibus (GEO, <ext-link ext-link-type="uri" xlink:href="http://www.ncbi.nlm.nih.gov/geo">http://www.ncbi.nlm.nih.gov/geo</ext-link>). The Complex Heatmap package was used to construct heatmaps, the gglot2 R language package to plot volcanoes and differential expression data, and the “VennDiagram” R language package to plot Wayne plots. Western booting and qRT-PCR was used to detect ANGPTL2 expression in osteosarcoma tissues. proteins. In addition, the GeneMANIA database (<ext-link ext-link-type="uri" xlink:href="http://www.genemania.org">http://www.genemania.org</ext-link>) was cited to predict the ANGPTL2 interaction network. We used the single-sample gene-set enrichment analysis (ss GSEA) algorithm to quantify the immune infiltration of osteosarcoma. In the GSE16088 database there were 5005 that met the selected threshold of |log2(FC)| > 1 and P <0.05, of which 2719 were highly expressed and 2286 were lowly expressed. WB and qRT-PCR results showed that ANGPTL2 was significantly up-regulated in osteosarcoma tissues. ssGSEA showed that high ANGPTL2 expression in osteosarcoma patients had a worse prognosis. ssGSEA showed that high ANGPTL2 expression was correlated with Mast cells and Th1 cells. Collectively, ANGPTL2 can be an independent prognostic biomarker and correlated with immune infiltration in osteosarcoma.

Advances in Dyslipidaemia Treatments: Focusing on ApoC3 and ANGPTL3 Inhibitors.

Apolipoprotein C3 (apoC3) and angiopoietin-like protein 3 (ANGPTL3) inhibit lipolysis by lipoprotein lipase and may influence the secretion and uptake of various lipoproteins. Genetic studies show that depletion of these proteins is associated with improved lipid profiles and reduced cardiovascular events so it was anticipated that drugs which mimic the effects of loss-of-function mutations would be useful lipid treatments. ANGPTL3 inhibitors were initially developed as a treatment for severe hypertriglyceridaemia including familial chylomicronaemia syndrome (FCS), which is usually not adequately controlled with currently available drugs. However, it was found ANGPTL3 inhibitors were also effective in reducing low-density lipoprotein cholesterol (LDL-C) and they were studied in patients with homozygous familial hypercholesterolaemia (FH). Evinacumab targets ANGPTL3 and reduced LDL-C by about 50% in patients with homozygous FH and it has been approved for that indication. The antisense oligonucleotide (ASO) vupanorsen targeting ANGPTL3 was less effective in reducing LDL-C in patients with moderate hypertriglyceridaemia and its development has been discontinued but the small interfering RNA (siRNA) ARO-ANG3 is being investigated in Phase 2 studies. ApoC3 can be inhibited by the ASO volanesorsen, which reduced triglycerides by >70% in patients with FCS and it was approved for FCS in Europe but not in the United States because of concerns about thrombocytopaenia. Olezarsen is an N-acetylgalactosamine-conjugated ASO targeting apoC3 which appears as effective as volanesorsen without the risk of thrombocytopaenia and is undergoing Phase 3 trials. ARO-APOC3 is an siRNA targeting apoC3 that is currently being investigated in Phase 3 studies.

Atrial Fibrillation and Adipokines: A Pathophysiological Perspective

Atrial fibrillation (AF) is a prevalent cardiac arrhythmia characterized by irregular and frequently rapid electrical activity in the atria. Adipokines are bioactive molecules that are secreted by adipose tissue, and exert diverse effects on health and disease. Obesity is a complex condition influenced by multiple interconnected factors, and the specific mechanisms linking obesity to AF may vary among individuals. Obesity contributes to the development of atrial arrhythmia. Moreover, obesity plays major roles in the pathophysiology of AF and its associated complications by inducing systemic changes, including altered hemodynamics, heightened sympathetic tone, and a persistent low-grade inflammatory state. Although the associations between overweight or obesity and elevated risk of AF have been established, the underlying mechanisms remain incompletely characterized. This article highlights the pathophysiological aspects of adipokines, such as Angiopoietin-like protein 2, Fibroblast growth factor 21, Lipocalin, Vaspin, Visfatin, and Nesfatin-1, in AF and concludes that adipokines play major roles in AF pathogenesis.

The effects of fermented vegetables on the gut microbiota for prevention of cardiovascular disease.

This study investigated the impact of regular consumption of fermented vegetables (FVs) on inflammation and the composition of the gut microbiota in adults at increased risk for cardiovascular disease. Eighty-seven adults ages 35-64 were randomized into an FV group, who consumed 100g FVs daily at least five times per week for eight weeks, or a usual diet (UD) group. Blood and stool samples were obtained before and after the intervention. Dependent samples t tests and adjusted linear models were used for within- and between-group comparisons. The mean age and body mass index of participants were 45years and 30kg/m2, and 80% were female. Bloating or gas was the most common side effect reported (19.3% FV group vs. 9.4% UD group). There were no changes in C-reactive protein, oxidized low-density lipoprotein-receptor 1, angiopoietin-like protein 4, trimethylamine oxide, and lipopolysaccharide-binding protein or bacterial alpha diversity between groups. Our findings indicate that consuming 100g of FVs for at least five days per week for eight weeks does not change inflammatory biomarkers or microbial alpha diversity as measured by the Shannon index. It is possible that higher doses of FVs are necessary to elicit a significant response by gut bacteria.

Exploring Biomarkers in Gestational Diabetes Mellitus: A Comprehensive Review

Gestational Diabetes Mellitus (GDM) is a common complication during pregnancy, typically diagnosed in the second or third trimester. Factors such as advanced maternal age, obesity and a sedentary lifestyle contribute to its prevalence. The pathophysiology involves insulin resistance, β-cell dysfunction, gluconeogenesis, adipose tissue dysfunction, gut microbiota dysbiosis and oxidative stress. GDM is associated with maternal and neonatal complications, both short-term and long-term. Managing GDM requires interventions such as medication, dietary adjustments and regular physical activity. However, early detection in low-risk populations remains challenging. The Oral Glucose Tolerance Test (OGTT) is the gold standard for diagnosis but is limited by its inconvenience and reliance on multiple blood samples. The present review focuses on novel biomarkers for early and accurate GDM diagnosis. It discusses emerging biomarkers such as vitamin D, vitamin B9, vitamin B12, preptin, angiopoietin-like protein 8, adiponectin, chemerin, omentin-1, leptin, Interleukin-6 (IL-6), homocysteine, C-peptide, irisin, adropin, nesfatin-1, Afamin, fetuin A, amylin, galectin, osteocalcin, resistin, visfatin and Fatty Acid-binding Protein 4 (FABP4). The review explores the pathophysiology of these biomarkers in GDM and presents preliminary study findings.

Circulating Angiopoietin-like Protein 6 Levels and Clinical Features in Patients with Type 2 Diabetes.

Aims The main purpose of this study was to evaluate the associations between circulating angiopoietin-like protein 6 (ANGPTL6) levels and various diabetes- and atherosclerosis-related variables in patients with type 2 diabetes. Methods Serum ANGPTL6 levels in patients with type 2 diabetes hospitalized for glycemic control and/or diabetic education were measured using a chemiluminescent immunoassay (CLIA). Results Most patients had elevated HbA1c levels; 85.7% and 71.4% of patients had HbA1c levels of (8% and (9%, respectively. ANGPTL6 levels were significantly higher in patients with type 2 diabetes than in non-diabetic controls. In patients with type 2 diabetes, ANGPTL6 was significantly and positively correlated with the duration of diabetes, systolic blood pressure (SBP), gamma-glutamyl transpeptidase (GGT), C-reactive protein (CRP), and the intimal medial complex thickness of the carotid artery (IMT), and inversely correlated with hemoglobin A1c (HbA1c). In the multiple regression analysis, ANGPTL6 had a significant positive association with triglyceride (TG) in one of the models in which it was included as a variable. Furthermore, ANGPTL6 also showed significant positive associations with CRP and IMT in models in which they were included as variables. Conclusion The current study suggests that circulating levels of ANGPTL6 may be negatively associated with poor glycemic control and positively associated with the degree of atherosclerosis, as reflected by IMT, in patients with type 2 diabetes, most of whom had elevated HbA1c levels.

Effects of exercise training on ANGPTL3/8 and ANGPTL4/8 and their associations with cardiometabolic traits

Angiopoietin-like protein (ANGPTL) complexes 3/8 and 4/8 are established inhibitors of LPL and novel therapeutic targets for dyslipidemia. However, the effects of regular exercise on ANGPTL3/8 and ANGPTL4/8 are unknown. We characterized ANGPTL3/8 and ANGPTL4/8 and their relationship with in vivo measurements of lipase activities and cardiometabolic traits before and after a 5-month endurance exercise training intervention in 642 adults from the HERITAGE (HEalth, RIsk factors, exercise Training And GEnetics) Family Study. At baseline, higher levels of both ANGPTL3/8 and ANGPTL4/8 were associated with a worse lipid, lipoprotein, and cardiometabolic profile, with only ANGPTL3/8 associated with postheparin LPL and HL activities. ANGPTL3/8 significantly decreased with exercise training, which corresponded with increases in LPL activity and decreases in HL activity, plasma triglycerides, apoB, visceral fat, and fasting insulin (all P < 5.1 × 10−4). Exercise-induced changes in ANGPTL4/8 were directly correlated to concomitant changes in total cholesterol, LDL-C, apoB, and HDL-triglycerides and inversely related to change in insulin sensitivity index (all P < 7.0 × 10−4). In conclusion, exercise-induced decreases in ANGPTL3/8 and ANGPTL4/8 were related to concomitant improvements in lipase activity, lipid profile, and cardiometabolic risk factors. These findings reveal the ANGPTL3-4-8 model as a potential molecular mechanism contributing to adaptations in lipid metabolism in response to exercise training.

ANGPTL4 binds to the leptin receptor to regulate ectopic bone formation.

Leptin protein was thought to be unique to leptin receptor (LepR), but the phenotypes of mice with mutation in LepR [db/db (diabetes)] and leptin [ob/ob (obese)] are not identical, and the cause remains unclear. Here, we show that db/db, but not ob/ob, mice had defect in tenotomy-induced heterotopic ossification (HO), implicating alternative ligand(s) for LepR might be involved. Ligand screening revealed that ANGPTL4 (angiopoietin-like protein 4), a stress and fasting-induced factor, was elicited from brown adipose tissue after tenotomy, bound to LepR on PRRX1+ mesenchymal cells at the HO site, thus promotes chondrogenesis and HO development. Disruption of LepR in PRRX1+ cells, or lineage ablation of LepR+ cells, or deletion of ANGPTL4 impeded chondrogenesis and HO in mice. Together, these findings identify ANGPTL4 as a ligand for LepR to regulate the formation of acquired HO.

The serum levels of angiopoietin-like protein 3 and 4 in type 2 diabetic patients with and without metabolic syndrome compared to the control group.

ANGPTLs (Angiopoietin-like proteins) 3 and 4 play an important role in the development of type 2 diabetes. These glycoproteins affect the modulation of glucose and lipid metabolism. They inhibit lipoprotein lipase (LPL) activity and provoke lipolysis. This study was aimed to investigate the protein levels of ANGPTL3 and 4 in the serum of type 2 diabetic patients with metabolic syndrome in comparison to the type 2 diabetic patients without metabolic syndrome and the control group. Three groups of individuals were included in this study; Group I: 47 patients with type 2 diabetes and metabolic syndrome; Group II: 25 patients with type 2 diabetes without metabolic syndrome; Group III: 40 non-diabetic healthy people without metabolic syndrome as a control group. After collection of 5 mL fasting blood samples, serum concentrations of fasting blood sugar (FBS), cholesterol (Chol), triglyceride (TG), HDL-C (High-density lipoprotein-Cholesterol) and LDL-C (Low-density lipoprotein-Cholesterol) were measured by the enzymatic method; blood pressure (BP), height and weight with stadiometers; and ANGPTL3 and 4 by the enzyme-linked immunosorbent assay (ELISA). The serum levels of ANGPTL3 was significantly different among our three groups (p = .000). In patients with type 2 diabetes and metabolic syndrome (Group I), ANGPTL3 and 4 levels were lower than the control group. The serum levels of the parameters evaluated in this study (except HDL-C) was lower in the group II in comparison with the group I, and this difference was significant for TG, Chol, BP and BMI between these two groups. Also, our results revealed that there was a negative correlation between FBS, TG, Chol, LDL-C and BMI with ANGPTL3 and 4. While, there was a significant positive correlation between ANGPTL4 and ANGPTL3. Altogether, our findings suggest that the decreased levels of ANGPTL3 and 4 may be a causative factor for type 2 diabetes.

Serum Angiopoietin-like Protein 3 Levels Are Associated with Endothelial Function in Patients with Maintenance Hemodialysis.

Angiopoietin-like protein 3 (ANGPTL3) plays an important role in lipid and lipoprotein trafficking and metabolism and is positively correlated with cardiovascular disease. Our objective was to evaluate the association between serum ANGPTL3 levels and endothelial function in patients on maintenance hemodialysis (MHD). We enrolled 116 patients on MHD and obtained their blood test results from their medical records. Using a noninvasive digital thermal monitor, we determined the vascular reactivity index (VRI) as a measure of endothelial function. Serum ANGPTL3 concentration was measured by a commercial-enzyme-linked immunosorbent assay. Vascular reactivity was classified as poor in 17 (14.7%) patients, intermediate (1.0 ≤ VRI < 2.0) in 50 (43.1%) patients, and high (VRI ≥ 2.0) in 49 (42.2%) patients. Serum levels of ANGPTL3 (p < 0.001) and alkaline phosphatase (ALP, p = 0.025) increased significantly as the VRI decreased. The log-transformed serum ALP (log-ALP, r = -0.187, p = 0.045) and log-ANGPTL3 (r = -0.319, p < 0.001) showed a negative correlation with the VRI on univariate linear regression analysis. A significant negative correlation was found between log-ANGPTL3 and VRI (p < 0.001) on multivariate stepwise linear regression analysis. The findings of our investigation showed that, in patients with MHD, the ANGPTL3 concentration had a negative correlation with the VRI.

Friend or foe? The elusive role of ANGPTL4 in inflammation

Angiopoietin-like 4 (ANGPTL4) belongs to the angiopoietin-like protein family and mediates the inhibition of lipoprotein lipase activity. Emerging evidence suggests that ANGPTL4 has pleiotropic functions with anti- and pro-inflammatory properties. Here, we have reviewed the research progress on ANGPTL4 and systematically discussed the dual role of ANGPTL4 in inflammation and inflammatory diseases. Understanding the potential mechanisms of ANGPTL4 in inflammation will aid in drug discovery and treatment development.

Angiopoietin-like protein 2 mediates vasculopathy-driven fibrogenesis in a mouse model of skin fibrosis

Angiopoietin-like protein 2 mediates vasculopathy-driven fibrogenesis in a mouse model of skin fibrosis

Hepatic fat changes with antisense oligonucleotide therapy targeting ANGPTL3

Angiopoietin-like protein 3 (ANGPTL3) is a novel therapeutic target for hyperlipidemia. Vupanorsen, an antisense oligonucleotide targeting ANGPTL3, reduced triglycerides up to 57% in a phase 2b trial, but caused dose-dependent increases in hepatic fat fraction (HFF). To determine the degree of HFF progression with escalating doses of vupanorsen, differential HFF increases in key patient subgroups, and the correlation between changes in HFF and liver enzymes. TRANSLATE-TIMI 70 was a randomized, placebo-controlled trial testing 7 dosing regimens of vupanorsen in 286 adults with hyperlipidemia. A total of 227 patients had HFF measured at baseline and 24 weeks and were included in this analysis. The median HFF at baseline was 8.5%. Vupanorsen led to dose-dependent relative increases in HFF of up to 76% at 24 weeks (p < 0.001), corresponding to an absolute increase of up to 7.0% at the highest dose (p < 0.001). Increases in HFF were numerically greater in patients who had elevated baseline HFF, body mass index, triglycerides, or diabetes. Vupanorsen also increased liver enzymes in a dose-dependent manner, and changes in HFF were moderately positively correlated with changes in aspartate transaminase (AST) (rho = 0.49, p < 0.001) and alanine transaminase (ALT) (rho = 0.50, p < 0.001). Vupanorsen, an inhibitor of ANGPTL3 protein synthesis, caused dose-dependent increases in HFF. Increases in HFF were only moderately correlated with elevations in AST and ALT, suggesting that liver enzymes are an imperfect indicator to detect increases in hepatic fat. These results highlight the need to monitor HFF in clinical trials of therapies targeting intracellular ANGPTL3 inhibition, especially those that are targeted to the liver.

Emerging insights into the roles of ANGPTL8 beyond glucose and lipid metabolism.

Angiopoietin-like protein 8 (ANGPTL8) is a secreted protein predominantly expressed in liver and adipose tissue. ANGPTL8 modulates the clearance of triglycerides (TGs) by suppressing the activity of lipoprotein lipase (LPL) within the plasma. Previous studies found that circulating ANGPTL8 levels were significantly increased in metabolic disorder-related diseases, such as type 2 diabetes mellitus (T2DM), obesity, metabolic syndrome and nonalcoholic fatty liver disease (NAFLD). Whether ANGPTL8 has a direct pathogenic role in these diseases remains to be determined. In this review, we summarize the emerging roles of ANGPTL8 in the regulation of inflammation, tumours, circulatory system-related diseases, and ectopic lipid deposition, which may provide new insights into the diverse functions of ANGPTL8 in various diseases beyond its well-established functions in glucose and lipid metabolism.

PPARβ/δ-ANGPTL4 axis mediates the promotion of mono-2-ethylhexyl phthalic acid on MYCN-amplified neuroblastoma development

Di-2-ethylhexyl phthalic acid (DEHP) is one of the most widely used plasticizers in the industry, which can improve the flexibility and durability of plastics. It is prone to migrate from various daily plastic products through wear and leaching into the surrounding environment and decompose into the more toxic metabolite mono-2-ethylhexyl phthalic acid (MEHP) after entering the human body. However, the impacts and mechanisms of MEHP on neuroblastoma are unclear. We exposed MYCN-amplified neuroblastoma SK-N-BE(2)C cells to an environmentally related concentration of MEHP and found that MEHP increased the proliferation and migration ability of tumor cells. The peroxisome proliferator-activated receptor (PPAR) β/δ pathway was identified as a pivotal signaling pathway in neuroblastoma, mediating the effects of MEHP through transcriptional sequencing analysis. Because MEHP can bind to the PPARβ/δ protein and initiate the expression of the downstream gene angiopoietin-like 4 (ANGPTL4), the PPARβ/δ-specific agonist GW501516 and antagonist GSK3787, the recombinant human ANGPTL4 protein, and the knockdown of gene expression confirmed the regulation of the PPARβ/δ-ANGPTL4 axis on the malignant phenotype of neuroblastoma. Based on the critical role of PPARβ/δ and ANGPTL4 in the metabolic process, a non-targeted metabolomics analysis revealed that MEHP altered multiple metabolic pathways, particularly lipid metabolites involving fatty acyls, glycerophospholipids, and sterol lipids, which may also be potential factors promoting tumor progression. We have demonstrated for the first time that MEHP can target binding to PPARβ/δ and affect the progression of neuroblastoma by activating the PPARβ/δ-ANGPTL4 axis. This mechanism confirms the health risks of plasticizers as tumor promoters and provides new data support for targeted prevention and treatment of neuroblastoma.

New Insights into Cardiovascular Diseases Treatment Based on Molecular Targets

Cardiovascular diseases (CVDs) which consist of ischemic heart disease, stroke, heart failure, peripheral arterial disease, and several other cardiac and vascular conditions are one of the most common causes of death worldwide and often co-occur with diabetes mellitus and lipid disorders which worsens the prognosis and becomes a therapeutic challenge. Due to the increasing number of patients with CVDs, we need to search for new risk factors and pathophysiological changes to create new strategies for preventing, diagnosing, and treating not only CVDs but also comorbidities like diabetes mellitus and lipid disorders. As increasing amount of patients suffering from CVDs, there are many therapies which focus on new molecular targets like proprotein convertase subtilisin/kexin type 9 (PCSK9), angiopoietin-like protein 3, ATP-citrate lyase, or new technologies such as siRNA in treatment of dyslipidemia or sodium-glucose co-transporter-2 and glucagon-like peptide-1 in treatment of diabetes mellitus. Both SGLT-2 inhibitors and GLP-1 receptor agonists are used in the treatment of diabetes, however, they proved to have a beneficial effect in CVDs as well. Moreover, a significant amount of evidence has shown that exosomes seem to be associated with myocardial ischaemia and that exosome levels correlate with the severity of myocardial injury. In our work, we would like to focus on the above mechanisms. The knowledge of them allows for the appearance of new strategies of treatment among patients with CVDs.

Gender-Dependent Associations between Serum Betatrophin Levels and Lipoprotein Subfractions in Diabetic and Nondiabetic Obese Patients.

Betatrophin, also known as angiopoietin-like protein 8 (ANGPTL8), mainly plays a role in lipid metabolism. To date, associations between betatrophin and lipoprotein subfractions are poorly investigated. For this study, 50 obese patients with type 2 diabetes (T2D) and 70 nondiabetic obese (NDO) subjects matched in gender, age, and body mass index (BMI) as well as 49 gender- and age-matched healthy, normal-weight controls were enrolled. Serum betatrophin levels were measured with ELISA, and lipoprotein subfractions were analyzed using Lipoprint gel electrophoresis. Betatrophin concentrations were found to be significantly higher in the T2D and NDO groups compared to the controls in all subjects and in females, but not in males. We found significant positive correlations between triglyceride, very low density lipoprotein (VLDL), large LDL (low density lipoprotein), small LDL, high density lipoprotein (HDL) -6-10 subfractions, and betatrophin, while negative correlations were detected between betatrophin and IDL, mean LDL size, and HDL-1-5. Proportion of small HDL was the best predictor of betatrophin in all subjects. Small LDL and large HDL subfractions were found to be the best predictors in females, while in males, VLDL was found to be the best predictor of betatrophin. Our results underline the significance of serum betatrophin measurement in the cardiovascular risk assessment of obese patients with and without T2D, but gender differences might be taken into consideration.

Abstract 17120: ARO-ANG3, an Investigational RNAi Therapeutic, Silences the Expression of ANGPTL3 and Decreases Atherogenic Lipoproteins in Patients With Mixed Dyslipidemia: ARCHES-2 Study Results

Background: Angiopoietin-like protein 3 (ANGPTL3) regulates lipoprotein metabolism by inhibiting lipoprotein and endothelial lipases. ANGPTL3 loss-of-function carriers have decreased circulating triglycerides (TGs), LDL-C, and HDL-C, and a lower risk of atherosclerotic cardiovascular disease (ASCVD). ARO-ANG3 is an investigational RNAi therapeutic designed to inhibit hepatic ANGPTL3 expression and reduce atherogenic lipoproteins. Aim: We report end-of-study results (data cutoff 09 December 2022) from ARCHES-2, a Phase 2b double-blind, placebo (pbo)-controlled study (NCT04832971) to evaluate the safety and efficacy of ARO-ANG3 in adults with mixed dyslipidemia (MD). Methods: Patients with fasting TGs 150-499 mg/dL and LDL-C ≥70 mg/dL or non-HDL-C ≥100 mg/dL were randomized to receive 50 mg, 100 mg or 200 mg ARO-ANG3 or pbo by subcutaneous injections on Day 1 and Week 12. Patients were on a stable diet and optimal lipid-lowering therapies. The primary endpoint was the percent change in TGs from baseline at Week 24. Liver fat was assessed at baseline and Week 24 in a subset of patients with hepatic steatosis. Mixed models repeated measures was used for statistical analyses. Results: At Week 24, ARO-ANG3 decreased ANGPTL3 (up to 77%), TGs (up to 56%), remnant cholesterol (up to 56%), and apolipoprotein B (apoB) (up to 20%). Other lipoproteins including LDL-C, non-HDL-C, lipoprotein(a) and HDL-C were also decreased. Liver fat decreased similarly in ARO-ANG3 and pbo groups. TEAEs were consistent with those expected in this patient population and with associated underlying comorbidities. Conclusions: ARCHES-2 data demonstrate ARO-ANG3 efficacy by significantly lowering ANGPTL3 and atherogenic triglyceride-rich lipoproteins (TRLs), LDL and total apoB in patients with MD. The favorable changes in serum lipids and lipoproteins and safety profile support the potential of ARO-ANG3 to treat residual ASCVD risk in patients with elevated TRLs not at LDL-C goal.