ANGPTL3 Levels Research Articles

Inflammatory and Lipid Biomarkers in Early Atherosclerosis: A Comprehensive Analysis

Introduction: Atherosclerosis is a leading cause of cardiovascular disease, characterized by lipid accumulation and chronic inflammation within arterial walls. Early detection in young adults is crucial for preventing adverse cardiovascular events. This study investigates the associations between inflammatory indices, lipid biomarkers, and the presence of atherosclerosis in patients aged 18 to 55 years. Methods: A cross-sectional study was conducted involving 89 participants divided into two groups: 62 patients with documented atherosclerosis (main group) and 27 healthy controls without significant atherosclerosis. Comprehensive data—including demographic information, medication use, imaging results, laboratory parameters, and calculated inflammatory indices (SIRI, SII, AISI, NLR, PLR, MLR)—were collected. Statistical analyses included correlation assessments, group comparisons using the Mann–Whitney U test, logistic regression modeling, feature importance analysis with Random Forest and Gradient Boosting classifiers, receiver operating characteristic (ROC) curves, and K-means clustering. Results: Significant differences were observed between the main and control groups. Patients with atherosclerosis exhibited elevated inflammatory indices (SIRI, NLR, MLR, SII) and lipid profile abnormalities (higher TC and LDL-C, lower HDL-C). Lp(a) and ANGPTL3 levels were significantly higher in the main group (p < 0.001 and p < 0.01, respectively). Logistic regression identified SIRI and ANGPTL3 as significant predictors of atherosclerosis, with the model demonstrating high accuracy (77%) and sensitivity (93%). Feature importance analysis confirmed the significance of SIRI and ANGPTL3, alongside traditional lipid biomarkers, in predicting disease presence. ROC analysis showed excellent model performance (AUC > 0.80). Clustering analysis revealed two distinct patient subgroups characterized by predominant inflammatory profiles or lipid metabolism disturbances. Conclusions: Systemic inflammation and lipid abnormalities play significant roles in early atherosclerosis among young adults. Elevated SIRI and ANGPTL3 levels are potent predictors of disease presence. The integration of inflammatory indices and lipid biomarkers into predictive models enhances risk stratification and supports personalized medicine approaches.

Impact of a post-lifestyle modification program in circulating angiopoietin-like proteins in Arab adolescents

This study investigated the differences and associations between serum levels of angiopoietin-like (ANGPTL)3, ANGPTL4, and ANGPTL8 in Saudi adolescents with varying levels of obesity and glycemia before and after undergoing a 12-month lifestyle change intervention. A total of 218 Saudi adolescents (45 normal, 77 overweight, and 96 obese) (mean age = 15.1 ± 1.5 years; mean BMI = 35.1 ± 6.6 kg/m2) were included. Anthropometrics were measured at baseline and follow-up. Overnight-fasting serum samples were also collected at baseline and after 12 months of intervention for routine analysis of fasting glucose, glycated hemoglobin (HbA1c) and lipid profile. Serum levels of insulin and ANGPTLs were assessed using commercial assays. At baseline, obese children had a higher ANGPTL8 level [0.7 ng/ml (0.4–1.3), p = 0.03]. In children with prediabetes (defined as those with HbA1c > 5.7), ANGPTL8 levels and HbA1c were significantly lower post-intervention [0.2 (0.1–0.8), p = 0.002; 5.5 ± 1.1), p < 0.001, respectively]. Follow-up lipid profile and insulin levels were significantly higher in all participants with prediabetes and obesity (p-values < 0.05). ANGPTL8 levels of those who achieved 5 % weight loss (N = 25) showed no difference after follow-up (p = 0.59). In conclusion, following a 12-month lifestyle modification program, decreased levels of circulating ANGPTL8 were observed in adolescents with obesity and prediabetes. Consequently, the degree of insulin resistance may be improved by reducing reduced ANGPTL8 levels.

Triglyceride-rich lipoprotein, remnant cholesterol, and apolipoproteins CII, CIII, and E in patients with schizophrenia

Patients with schizophrenia show a disproportionally increased risk of cardiovascular disease. Hypertriglyceridemia is prevalent in this population; however, how this relates to levels of remnant cholesterol, triglyceride (TG)-rich lipoprotein (TRL) particle size and composition, TG turnover, and apolipoprotein (apo) and angiopoietin-like protein (ANGPTL) concentrations is unknown. Fasting levels of cholesterol (total [TC], LDL-C, HDL-C, non-HDL-C and remnant cholesterol) and TG were determined in 110 patients diagnosed with schizophrenia, and 46 healthy controls. TRL particle size, concentration and composition, and β-hydroxybutyrate (TG turnover marker) were assessed by NMR. Levels of apoCII, apoCIII, apoE, ANGPTL3, ANGPTL4, and ANGPTL8 were measured by ELISA, and apoCII, apoCIII and apoE were further evaluated in HDL and non-HDL fractions. Patients with schizophrenia had significantly elevated TG, TG:apoB ratio, non-HDL-C, remnant cholesterol, non-HDL-apoCII and non-HDL-apoCIII, and HDL-apoE (all P < 0.05), lower HDL-C and apoA-I (all P < 0.001), and comparable apoB, TC, TC:apoB ratio, LDL-C, β-hydroxybutyrate, ANGPTL3, ANGPTL4 and ANGPTL8 to healthy controls. Patients had a 12.0- and 2.5-fold increase in the concentration of large and medium TRL particles respectively, but similar cholesterol:TG ratio within each particle. Plasma TG, remnant cholesterol, and large and medium TRL particle concentrations correlated strongly with apoCII, apoCIII, and apoE in the non-HDL fraction, and with apoCIII and apoE in the HDL fraction in patients with schizophrenia. Differences in TG, HDL-C, TRL particle concentrations, apoCIII, and apoE persisted after adjustment for conventional risk factors. These results are consistent with impaired TRL lipolysis and clearance in patients with schizophrenia which may be responsive to targeting apoCIII.

Dyslipidemia and ANGPTL8 evaluation in young females with Type 1 diabetes mellitus.

ANGPTL8, commonly referred to as betatrophin, has demonstrated promise as a dependable marker for the onset of complications associated with diabetes mellitus, such as dyslipidemia. The objective of this study is to evaluate the lipid profile and ANGPTL8 levels in people diagnosed with Type 1 Diabetes Mellitus (T1DM). A retrospective case-control study was performed on a group of 100 adolescent females, aged 13-17 years. This group consisted of individuals diagnosed with T1DM from the Diabetes and Endocrine Department at Medina's King Fahad Hospital in Saudi Arabia. Additionally, 100 healthy adolescent females of the same age range were included as controls. The hospital conducted laboratory studies to evaluate glucose, HbA1c, insulin, and lipid profiles. The ANGPTL8 levels were quantified using Enzyme-Linked Immunosorbent Assay (ELISA). Patients with T1DM had ANGPTL8 levels that were twice as high as those observed in individuals without any health conditions. The two groups had contrasting levels of fasting blood glucose (FBG), glycated hemoglobin (HbA1c), C-peptides, triacylglycerol (TG), and cholesterol, along with elevated Atherogenic Index of Plasma readings. Diabetes mellitus patients had considerably elevated values compared to the control group. There was a significant correlation between ANGPTL8 concentrations and lipid abnormalities, with P-values less than 0.05. 56% of the 100 patients exhibited dyslipidemia. The research found a correlation between dyslipidemia and elevated levels of ANGPTL8 in diabetic patients. The concentration of ANGPTL8 had a positive correlation with glucose, HbA1c, TG, and C-peptides while displaying a negative correlation with high-density lipoprotein cholesterol (HDL-C). ANGPTL8 levels were found to be elevated in Saudi young women who were diagnosed with TIDM. ANGPTL8 may potentially contribute to dyslipidemia in individuals with T1DM, hence increasing the susceptibility to cardiovascular disease (CVD). Therefore, ANGPTL8 has the potential to impact lipid metabolism, namely Triglycerides, as a biological route. The results highlight the need to analyze lipid profiles and do ANGPTL8 testing in young females diagnosed with T1DM at an early stage to prevent complications.

Zodasiran, an RNAi Therapeutic Targeting ANGPTL3, for Mixed Hyperlipidemia

BackgroundAngiopoietin-like 3 (ANGPTL3) inhibits lipoprotein and endothelial lipases and hepatic uptake of triglyceride-rich lipoprotein remnants. ANGPTL3 loss-of-function carriers have lower levels of triglycerides, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, and non-HDL cholesterol and a lower risk of atherosclerotic cardiovascular disease than noncarriers. Zodasiran is an RNA interference (RNAi) therapy targeting expression of ANGPTL3 in the liver.MethodsWe conducted a double-blind, placebo-controlled, dose-ranging phase 2b trial to evaluate the safety and efficacy of zodasiran in adults with mixed hyperlipidemia (fasting triglyceride level of 150 to 499 mg per deciliter and either an LDL cholesterol level of ≥70 mg per deciliter or a non-HDL cholesterol level of ≥100 mg per deciliter). Eligible patients were randomly assigned in a 3:1 ratio to receive subcutaneous injections of zodasiran (50, 100, or 200 mg) or placebo on day 1 and week 12 and were followed through week 36. The primary end point was the percent change in the triglyceride level from baseline to week 24.ResultsA total of 204 patients underwent randomization. At week 24, substantial mean dose-dependent decreases from baseline in ANGPTL3 levels were observed with zodasiran (difference in change vs. placebo, −54 percentage points with 50 mg, −70 percentage points with 100 mg, and −74 percentage points with 200 mg), and significant dose-dependent decreases in triglyceride levels were observed (difference in change vs. placebo, −51 percentage points, −57 percentage points, and −63 percentage points, respectively) (P<0.001 for all comparisons). Other differences in change from baseline as compared with placebo included the following: for non-HDL cholesterol level, −29 percentage points with 50 mg, −29 percentage points with 100 mg, and −36 percentage points with 200 mg; for apolipoprotein B level, −19 percentage points, −15 percentage points, and −22 percentage points, respectively; and for LDL cholesterol level, −16 percentage points, −14 percentage points, and −20 percentage points, respectively. We observed a transient elevation in glycated hemoglobin levels in patients with preexisting diabetes who received the highest dose of zodasiran.ConclusionsIn patients with mixed hyperlipidemia, zodasiran was associated with significant decreases in triglyceride levels at 24 weeks. (Funded by Arrowhead Pharmaceuticals; ARCHES-2 ClinicalTrials.gov number, NCT04832971.)

Drug-target Mendelian randomization analysis supports lowering plasma ANGPTL3, ANGPTL4, and APOC3 levels as strategies for reducing cardiovascular disease risk.

APOC3, ANGPTL3, and ANGPTL4 are circulating proteins that are actively pursued as pharmacological targets to treat dyslipidaemia and reduce the risk of atherosclerotic cardiovascular disease. Here, we used human genetic data to compare the predicted therapeutic and adverse effects of APOC3, ANGPTL3, and ANGPTL4 inactivation. We conducted drug-target Mendelian randomization analyses using variants in proximity to the genes associated with circulating protein levels to compare APOC3, ANGPTL3, and ANGPTL4 as drug targets. We obtained exposure and outcome data from large-scale genome-wide association studies and used generalized least squares to correct for linkage disequilibrium-related correlation. We evaluated five primary cardiometabolic endpoints and screened for potential side effects across 694 disease-related endpoints, 43 clinical laboratory tests, and 11 internal organ MRI measurements. Genetically lowering circulating ANGPTL4 levels reduced the odds of coronary artery disease (CAD) [odds ratio, 0.57 per s.d. protein (95% CI 0.47-0.70)] and Type 2 diabetes (T2D) [odds ratio, 0.73 per s.d. protein (95% CI 0.57-0.94)]. Genetically lowering circulating APOC3 levels also reduced the odds of CAD [odds ratio, 0.90 per s.d. protein (95% CI 0.82-0.99)]. Genetically lowered ANGPTL3 levels via common variants were not associated with CAD. However, meta-analysis of protein-truncating variants revealed that ANGPTL3 inactivation protected against CAD (odds ratio, 0.71 per allele [95%CI, 0.58-0.85]). Analysis of lowered ANGPTL3, ANGPTL4, and APOC3 levels did not identify important safety concerns. Human genetic evidence suggests that therapies aimed at reducing circulating levels of ANGPTL3, ANGPTL4, and APOC3 reduce the risk of CAD. ANGPTL4 lowering may also reduce the risk of T2D.

Angiopoietin-2 and Angiopoietin-like Proteins with a Prospective Role in Predicting Diabetic Nephropathy.

Angiopoietins are crucial growth factors for maintaining a healthy, functional endothelium. Patients with type 2 diabetes (T2D) exhibit significant levels of angiogenic markers, particularly Angiopoietin-2, which compromises endothelial integrity and is connected to symptoms of endothelial injury and failure. This report examines the levels of circulating angiopoietins in people with T2D and diabetic nephropathy (DN) and explores its link with ANGPTL proteins. We quantified circulating ANGPTL3, ANGPTL4, ANGPTL8, Ang1, and Ang2 in the fasting plasma of 117 Kuwaiti participants, of which 50 had T2D and 67 participants had DN. The Ang2 levels increased with DN (4.34 ± 0.32 ng/mL) compared with T2D (3.42 ± 0.29 ng/mL). This increase correlated with clinical parameters including the albumin-to-creatinine ratio (ACR) (r = 0.244, p = 0.047), eGFR (r = -0.282, p = 0.021), and SBP (r = -0.28, p = 0.024). Furthermore, Ang2 correlated positively to both ANGPTL4 (r = 0.541, p < 0.001) and ANGPTL8 (r = 0.41, p = 0.001). Multiple regression analysis presented elevated ANGPTL8 and ACRs as predictors for Ang2's increase in people with DN. In people with T2D, ANGPTL4 positively predicted an Ang2 increase. The area under the curve (AUC) in receiver operating characteristic (ROC) analysis of the combination of Ang2 and ANGPTL8 was 0.77 with 80.7% specificity. In conclusion, significantly elevated Ang2 in people with DN correlated with clinical markers such as the ACR, eGFR, and SBP, ANGPTL4, and ANGPTL8 levels. Collectively, this study highlights a close association between Ang2 and ANGPTL8 in a population with DN, suggesting them as DN risk predictors.

Association Between rs2278426 Polymorphism of the ANGPTL8 Gene and Polycystic Ovary Syndrome.

To study the relationship between the single nucleotide polymorphism (SNP) rs2278426 in the angiopoietin-like protein 8 gene (ANGPTL8) and polycystic ovary syndrome (PCOS). A total of 122 patients with PCOS and 108 controls were recruited for comparison of glucose, lipid, insulin, sex hormone, and ANGPTL8 levels. Polymerase chain reaction (PCR) and gene sequencing were performed for comparison of the frequency of the CC, CT, and TT rs2278426 genotypes and the rs2278426 allele distributions between the PCOS and control groups and between the obese and non-obese subgroups of the PCOS and control groups. The frequency of the T allele was significantly higher in the PCOS group than that in the controls (P = 0.037). In the dominant genetic model, the proportion of the CT+TT genotype in the PCOS group was significantly higher than that in the controls (P = 0.047). Subgroup analysis demonstrated that the T allele proportion was significantly higher in obese PCOS group than obese control group (P = 0.027). PCOS with the CT+TT genotype had significantly higher body mass index (BMI; P = 0.001), triglyceride (TG; P = 0.005), homeostasis model assessment of insulin resistance (HOMA-IR; P = 0.035), testosterone (P = 0.041), and ANGPTL8 (P = 0.037) levels and significantly lower high-density lipoprotein (HDL) levels (P = 0.025) than PCOS with the CC genotype. Obese PCOS group with the CT+TT genotype had significantly higher TG (P = 0.015), luteinizing hormone (LH; P = 0.030), fasting insulin (FINS; P = 0.039), HOMA-IR (P = 0.018), and ANGPTL8 (P = 0.049) levels than obese PCOS group with the CC genotype. Polymorphisms of rs2278426 may induce glycolipid metabolic disorders by affecting ANGPTL8 levels and functions in Han Chinese females with obesity from the Shandong region, increasing the risk of PCOS in this population.

Abstract 5169: Circulating levels of ANGPTL3, PCSK9, apoCIII and lipoprotein (a) in high-grade serous ovarian cancer

Abstract Background: Ovarian cancers require abundant amounts of lipids for their growth. Recent years have highlighted the role of ANGPTL3, PCSK9, ApoCIII and Lp(a) as key players in lipid metabolism. But circulating levels of these factors in ovarian cancers have not been thoroughly investigated to date. Objective: We assessed the profiles of plasma ANGPTL3, PCSK9, ApoCIII and Lp(a) in ovarian high-grade serous carcinoma (HGSC). Methods: Plasma samples collected from women diagnosed with an HGSC (n=31) or a benign ovarian lesion (BOL, n=40) were analyzed for plasma lipid profile (ApoB, total cholesterol, HDL, triglycerides, Lp(a) levels) on a clinical modular platform (Roche). ApoCIII, ANGPTL3 and PCSK9 levels were measured with commercially-available ELISA kits. Differences between HGSC and BOL were assessed by two-group comparisons. Pairwise correlation strength between variables was evaluated with Spearman’s rank order tests. Logistic regression modelling was used to further examine the associations between selected variables and HGSC diagnoses. Results: ANGPTL3 levels increased in HGSC (84.1 ng/ml, SD=29.2ng/ml, n=31) compared to BOL (66.9ng/ml, SD=30.7 ng/ml, n=40; HGSC vs BOL p=0.02). Receiver operating characteristic (ROC) curve suggested that plasma ANGPTL3 levels were moderately associated with HGSC (AUC=67.7%, p=0.005 1) and did not increase predictive performance of ovarian tumor biomarkers CA125 and HE4 in multivariable model. Associations between ANGPTL3 levels and cholesterol (HDL, non-HDL, LDL and total) could be observed in the control group but not in the HGSC group. The same dissociation was observed for the inverse correlation between HDL and triglycerides in HGSC. Furthermore, moderate associations were observed between PCSK9 &amp; CA19-9 in the entire cohort (rho=0.34, n=53, p=0.013) and Lp(a) &amp; CA125 in HGSC cases (rho=0.51, p= 0.017). Conclusion: In this cohort of 71 women, we report increased levels of ANGPTL3 in HGSC with an effect size (Cohen’s D) of 0.57. Confirmation of this result in larger cohort studies (minimal n&amp;gt;50 in each group) would warrant further investigation into the roles of circulating ANGPTL3. Its inhibition may allow to tackle deregulated lipid metabolic pathways contributing to ovarian cancer progression. Citation Format: Emilie Wong Chong, France-Hélène Joncas, Pierre Douville, Dimcho Bachvarov, Frédéric Calon, Nabil Seidah, Caroline Diorio, Anne Gangloff. Circulating levels of ANGPTL3, PCSK9, apoCIII and lipoprotein (a) in high-grade serous ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5169.

ANGPTL3 is a novel HDL component that regulates HDL function

BackgroundAngiopoietin-like protein 3 (ANGPTL3) is secreted by hepatocytes and inhibits lipoprotein lipase and endothelial lipase activity. Previous studies reported the correlation between plasma ANGPTL3 levels and high-density lipoprotein (HDL). Recently ANGPTL3 was found to preferentially bind to HDL in healthy human circulation. Here, we examined whether ANGPTL3, as a component of HDL, modulates HDL function and affects HDL other components in human and mice with non-diabetes or type 2 diabetes mellitus.MethodsHDL was isolated from the plasma of female non-diabetic subjects and type-2 diabetic mellitus (T2DM) patients. Immunoprecipitation, western blot, and ELISA assays were used to examine ANGPTL3 levels in HDL. Db/m and db/db mice, AAV virus mediated ANGPTL3 overexpression and knockdown models and ANGPTL3 knockout mice were used. The cholesterol efflux capacity induced by HDL was analyzed in macrophages preloaded with fluorescent cholesterol. The anti-inflammation capacity of HDL was assessed using flow cytometry to measure VCAM-1 and ICAM-1 expression levels in TNF-α-stimulated endothelial cells pretreated with HDL.ResultsANGPTL3 was found to bind to HDL and be a component of HDL in both non-diabetic subjects and T2DM patients. Flag-ANGPTL3 was found in the HDL of transgenic mice overexpressing Flag-ANGPTL3. ANGPLT3 of HDL was positively associated with cholesterol efflux in female non-diabetic controls (r = 0.4102, p = 0.0117) but not in female T2DM patients (r = − 0.1725, p = 0.3224). Lower ANGPTL3 levels of HDL were found in diabetic (db/db) mice compared to control (db/m) mice and were associated with reduced cholesterol efflux and inhibition of VCAM-1 and ICAM-1 expression in endothelial cells (p < 0.05 for all). Following AAV-mediated ANGPTL3 cDNA transfer in db/db mice, ANGPTL3 levels were found to be increased in HDL, and corresponded to increased cholesterol efflux and decreased ICAM-1 expression. In contrast, knockdown of ANGPTL3 levels in HDL by AAV-mediated shRNA transfer led to a reduction in HDL function (p < 0.05 for both). Plasma total cholesterol, total triglycerides, HDL-c, protein components of HDL and the cholesterol efflux function of HDL were lower in ANGPTL3−/− mice than ANGPTL3+/+ mice, suggesting that ANGPTL3 in HDL may regulate HDL function by disrupting the balance of protein components in HDL.ConclusionANGPTL3 was identified as a component of HDL in humans and mice. ANGPTL3 of HDL regulated cholesterol efflux and the anti-inflammatory functions of HDL in T2DM mice. Both the protein components of HDL and cholesterol efflux capacity of HDL were decreased in ANGPTL3−/− mice. Our findings suggest that ANGPTL3 in HDL may regulate HDL function by disrupting the balance of protein components in HDL. Our study contributes to a more comprehensive understanding of the role of ANGPTL3 in lipid metabolism.

Characterization of sexual dimorphism in ANGPTL4 levels and function

ANGPTL4 is an attractive pharmacological target for lowering plasma triglycerides and cardiovascular risk. Since most preclinical studies on ANGPTL4 were performed in male mice, little is known about sexual dimorphism in ANGPTL4 regulation and function. Here, we aimed to study potential sexual dimorphism in ANGPTL4 mRNA and protein levels and ANGPTL4 function. Additionally, we performed exploratory studies on the function of ANGPTL4 in the liver during fasting using Angptl4-transgenic and Angptl4−/− mice. Compared to female mice, male mice showed higher hepatic and adipose ANGPTL4 mRNA and protein levels, as well as a more pronounced effect of genetic ANGPTL4 modulation on plasma lipids. By contrast, very limited sexual dimorphism in ANGPTL4 levels was observed in human liver and adipose tissue. In human and mouse adipose tissue, ANGPTL8 mRNA and/or protein levels were significantly higher in females than males. Adipose LPL protein levels were higher in female than male Angptl4−/− mice, which was abolished by ANGPTL4 (over) expression. At the human genetic level, the ANGPTL4 E40K loss-of-function variant was associated with similar plasma triglyceride reductions in women and men. Finally, ANGPTL4 ablation in fasted mice was associated with changes in hepatic gene expression consistent with PPARα activation. In conclusion, the levels of ANGPTL4 and the magnitude of the effect of ANGPTL4 on plasma lipids exhibit sexual dimorphism. Nonetheless, inactivation of ANGPTL4 should confer a similar metabolic benefit in women and men. Expression levels of ANGPTL8 in human and mouse adipose tissue are highly sexually dimorphic, showing higher levels in females than males.

Positive correlation of ANGPTL8 expression in human visceral adipose tissue with body mass index

BackgroundAngiopoietin-like protein 8 (ANGPTL8) is an important regulator of lipid metabolism. We aimed to investigate the difference of ANGPTL8 expression in different depots of adipose tissues between individuals with and without obesity, and its correlation with various metabolic parameters. MethodsSubcutaneous (SAT) and visceral adipose tissue (VAT) samples were collected from patients who underwent bariatric or intra-abdominal surgery. Expression levels of ANGPTL8, monoglyceride lipase (MGL), monocyte chemoattractant protein-1 (MCP-1), leptin and adiponectin (APM1) were determined using real-time quantitative polymerase chain reaction. The correlation of ANGPTL8 expression with various metabolic parameters and other gene expression levels was analyzed using Person's correlation analysis. Logistic regression was used to establish a prediction model of obesity. ResultsTotally 330 subjects (obese: 281, non-obese: 49) were recruited. ANGPTL8 expression in VAT was significantly higher in the obesity group than in the non-obesity group (P = 0.0096). ANGPTL8 expression in VAT was positively correlated with body mass index (BMI) (r = 0.1169, P < 0.05) and was independently associated with obesity (O.R., 1.246; 95 % C.I. 1.013–21.533, P = 0.038). We also found the gene expression of ANGPTL8 in SAT and VAT was negatively correlated with APM1 expression in respective SAT and VAT. ConclusionANGPTL8 expression levels in VAT were higher in subjects with obesity, and positively correlated with BMI. This suggests a role of ANGPTL8 in the pathophysiology of obesity and may pave the way for novel treatment target of obesity.

Adolescent obesity and ANGPTL8: correlations with high sensitivity C-reactive protein, leptin, and chemerin.

Angiopoietin-like proteins (ANGPTLs) mediate many metabolic functions. We had recently reported increased plasma levels of ANGPTL8 in obese adults of Arab ethnicity. However, data on ANGPTL8 levels in adolescent obesity is lacking. Arab population is characterized by a rapid transition, due to sudden wealth seen in the post-oil era, in lifestyle, food habits and extent of physical activity. We adopted a cross-sectional study on Arab adolescents from Kuwait to examine the role of ANGPTL8 in adolescent obesity. The study cohort included 452 adolescents, aged 11-14 years, recruited from Middle Schools across Kuwait. BMI-for-age growth charts were used to categorize adolescents as normal-weight, overweight, and obese. ELISA and bead-based multiplexing assays were used to measure plasma levels of ANGPTL8 and other inflammation and obesity-related biomarkers. Data analysis showed significant differences in the plasma levels of ANGPTL8 among the three subgroups, with a significant increase in overweight and obese children compared to normal-weight children. This observation persisted even when the analysis was stratified by sex. Multinomial logistic regression analysis illustrated that adolescents with higher levels of ANGPTL8 were 7 times more likely to become obese and twice as likely to be overweight. ANGPTL8 levels were correlated with those of hsCRP, leptin and chemerin. ANGPTL8 level had a reasonable prognostic power for obesity with an AUC of 0.703 (95%-CI=0.648-0.759). These observations relating to increased ANGPTL8 levels corresponding to increased BMI-for-age z-scores indicate that ANGPTL8, along with hsCRP, leptin and chemerin, could play a role in the early stages of obesity development in children. ANGPTL8 is a potential early marker for adolescent obesity and is associated with well-known obesity and inflammatory markers.

ANGPTL3 Deficiency and Risk of Hepatic Steatosis.

ANGPTL3 (angiopoietin-like 3) is a therapeutic target for reducing plasma levels of triglycerides and low-density lipoprotein cholesterol. A recent trial with vupanorsen, an antisense oligonucleotide targeting hepatic production of ANGPTL3, reported a dose-dependent increase in hepatic fat. It is unclear whether this adverse effect is due to an on-target effect of inhibiting hepatic ANGPTL3. We recruited participants with ANGPTL3 deficiency related to ANGPTL3 loss-of-function (LoF) mutations, along with wild-type (WT) participants from 2 previously characterized cohorts located in Campodimele, Italy, and St. Louis, MO. Magnetic resonance spectroscopy and magnetic resonance proton density fat fraction were performed to measure hepatic fat fraction and the distribution of extrahepatic fat. To estimate the causal relationship between ANGPTL3 and hepatic fat, we generated a genetic instrument of plasma ANGPTL3 levels as a surrogate for hepatic protein synthesis and performed Mendelian randomization analyses with hepatic fat in the UK Biobank study. We recruited participants with complete (n=6) or partial (n=32) ANGPTL3 deficiency related to ANGPTL3 LoF mutations, as well as WT participants (n=92) without LoF mutations. Participants with ANGPTL3 deficiency exhibited significantly lower total cholesterol (complete deficiency, 78.5 mg/dL; partial deficiency, 172 mg/dL; WT, 188 mg/dL; P<0.05 for both deficiency groups compared with WT), along with plasma triglycerides (complete deficiency, 26 mg/dL; partial deficiency, 79 mg/dL; WT, 88 mg/dL; P<0.05 for both deficiency groups compared with WT) without any significant difference in hepatic fat (complete deficiency, 9.8%; partial deficiency, 10.1%; WT, 9.9%; P>0.05 for both deficiency groups compared with WT) or severity of hepatic steatosis as assessed by magnetic resonance imaging. In addition, ANGPTL3 deficiency did not alter the distribution of extrahepatic fat. Results from Mendelian randomization analyses in 36 703 participants from the UK Biobank demonstrated that genetically determined ANGPTL3 plasma protein levels were causally associated with low-density lipoprotein cholesterol (P=1.7×10-17) and triglycerides (P=3.2×10-18) but not with hepatic fat (P=0.22). ANGPTL3 deficiency related to LoF mutations in ANGPTL3, as well as genetically determined reduction of plasma ANGPTL3 levels, is not associated with hepatic steatosis. Therapeutic approaches to inhibit ANGPTL3 production in hepatocytes are not necessarily expected to result in the increased risk for hepatic steatosis that was observed with vupanorsen.

Increased Levels of Circulating IGFBP4 and ANGPTL8 with a Prospective Role in Diabetic Nephropathy.

Diabetic nephropathy (DN) is a complicated condition related to type 2 diabetes mellitus (T2D). ANGPTL8 is a hepatic protein highlighted as a risk factor for DN in patients with T2D; additionally, recent evidence from DN studies supports the involvement of growth hormone/IGF/IGF-binding protein axis constituents. The potential link between ANGPTL8 and IGFBPs in DN has not been explored before. Here, we assessed changes in the circulating ANGPTL8 levels in patients with DN and its association with IGFBP-1, -3, and -4. Our data revealed a significant rise in circulating ANGPTL8 in people with DN, 4443.35 ± 396 ng/mL compared to 2059.73 ± 216 ng/mL in people with T2D (p < 0.001). Similarly, levels of IGFBP-3 and -4 were significantly higher in people with DN compared to the T2D group. Interestingly, the rise in ANGPTL8 levels correlated positively with IGFBP-4 levels in T2DM patients with DN (p < 0.001) and this significant correlation disappeared in T2DM patients without DN. It also correlated positively with serum creatinine and negatively with the estimated glomerular filtration rate (eGFR, All < 0.05). The area under the curve (AUC) on receiver operating characteristic (ROC) analysis of the combination of ANGPTL8 and IGFBP4 was 0.76 (0.69-0.84), p < 0.001, and the specificity was 85.9%. In conclusion, our results showed a significant increase in ANGPTL8 in patients with DN that correlated exclusively with IGFBP-4, implicating a potential role of both proteins in the pathophysiology of DN. Our findings highlight the significance of these biomarkers, suggesting them as promising diagnostic molecules for the detection of diabetic nephropathy.

Evaluation of Adiponectin and ANGPTL8 in Women With Metabolic Syndrome in the Madinah Region of Saudi Arabia.

"Metabolic syndrome" (MetS) is a set of abnormalities that may be risk factors for cardiovascular disease (CVD) and diabetes. The current study sought to (1) determine MetS prevalence and (2) examine Adiponectin and ANGPTL8 levels in connection to MetS components and CVDs and diabetes risk in females with MetS. A total of 350, 20-35-year-old Saudi females were studied. Waist circumference (WC), body mass index (BMI), glucose, HbA1c, insulin, lipid profiles, and blood pressure (BP) were examined for MetS. ANGPTL8 and Adiponectin were also measured. The patients were classified into two groups, namely MetSand non-MetS, according to the criteria established by the National Cholesterol Education Program Adult Treatment Panel III (NCEP-ATPIII).We examined biomarker and anthropometric results between these groups. One hundred forty-four of 350 female participants (41.2%) had MetS, with a mean age of 30.5 years. Fasting blood glucose (FBG), high-density lipoprotein cholesterol (HDL-C), triglycerides (TG), ANGPTL8, adiponectin, and insulin resistance (IR) were statistically significant differences observed between the two groups. BP, BMI, WC, and Atherogenic Index of Plasma (AIP) all changed significantly (P ≤0.05).Correlation studies linked MetS components to higher ANGPTL-8 and reduced adiponectin. The levels of ANGPTL8 were shown to be influenced by the increase in FBG, TG, BP, IR, and AIP (P < 0.05). Factors such as FBG, BMI, WC, and IR have been found to have an inverse relationship with adiponectin levels. 41.2% out of 350 Saudi females at Taibah University in the Madinah region had MetS, medium CVD risk, and slightly elevated BMI, TG, WC, and BP.To lower their risk of CVD and diabetes later in life, overweight young women should be evaluated for MetS. FBG and TG were substantially associated with ANGPTL8 while reducing adiponectin was associated with elevated TG and BP. Our findings may lead to ANGPTL8 and adiponectin's possible predictive function for CVD in early MetS in females.

ANGPTL2+cancer-associated fibroblasts and SPP1+macrophages are metastasis accelerators of colorectal cancer.

Liver metastasis (LM) is a leading cause of cancer-related deaths in CRC patients, whereas the associated mechanisms have not yet been fully elucidated. Therefore, it is urgently needed to deeply explore novel metastasis accelerators and therapeutic targets of LM-CRC. The bulk RNA sequencing data and clinicopathological information of CRC patients were enrolled from the TCGA and GEO databases. The single-cell RNA sequencing (scRNA-seq) datasets of CRC were collected from and analyzed in the Tumor Immune Single-cell Hub (TISCH) database. The infiltration levels of cancer-associated fibroblasts (CAFs) and macrophages in CRC tissues were estimated by multiple immune deconvolution algorithms. The prognostic values of genes were identified by the Kaplan-Meier curve with a log-rank test. GSEA analysis was carried out to annotate the significantly enriched gene sets. The biological functions of cells were experimentally verified. In the present study, hundreds of differentially expressed genes (DEGs) were selected in LM-CRC compared to primary CRC, and these DEGs were significantly associated with the regulation of endopeptidase activity, blood coagulation, and metabolic processes. Then, SPP1, CAV1, ANGPTL2, and COLEC11 were identified as the characteristic DEGs of LM-CRC, and higher expression levels of SPP1 and ANGPTL2 were significantly associated with worse clinical outcomes of CRC patients. In addition, ANGPTL2 and SPP1 mainly distributed in the tumor microenvironment (TME) of CRC tissues. Subsequent scRNA-seq analysis demonstrated that ANGPTL2 and SPP1 were markedly enriched in the CAFs and macrophages of CRC tissues, respectively. Moreover, we identified the significantly enriched gene sets in LM-CRC, especially those in the SPP1+macrophages and ANGPTL2+CAFs, such as the HALLMARK_EPITHELIAL_MESENCHYMAL_TRANSITION and the HALLMARK_COMPLEMENT. Finally, our in vitro experiments proved that ANGPTL2+CAFs and SPP1+macrophages promote the metastasis of CRC cells. Our study selected four characteristic genes of LM-CRC and identified ANGPTL2+CAFs and SPP1+macrophages subtypes as metastasis accelerators of CRC which provided a potential therapeutic target for LM-CRC.

Role of glycosylphosphatidylinositol-anchored high-density lipoprotein binding protein 1 in hypertriglyceridemia and diabetes.

In diabetes, the impairment of insulin secretion and insulin resistance contribute to hypertriglyceridemia, as the enzymatic activity of lipoprotein lipase (LPL) depends on insulin action. The transport of LPL to endothelial cells and its enzymatic activity are maintained by the formation of lipolytic complex depending on the multiple positive (glycosylphosphatidylinositol-anchored high-density lipoprotein binding protein 1 [GPIHBP1], apolipoprotein C-II [APOC2], APOA5, heparan sulfate proteoglycan [HSPG], lipase maturation factor 1 [LFM1] and sel-1 suppressor of lin-12-like [SEL1L]) and negative regulators (APOC1, APOC3, angiopoietin-like proteins [ANGPTL]3, ANGPTL4 and ANGPTL8). Among the regulators, GPIHBP1 is a crucial molecule for the translocation of LPL from parenchymal cells to the luminal surface of capillary endothelial cells, and maintenance of lipolytic activity; that is, hydrolyzation of triglyceride into free fatty acids and monoglyceride, and conversion from chylomicron to chylomicron remnant in the exogenous pathway and from very low-density lipoprotein to low-density lipoprotein in the endogenous pathway. The null mutation of GPIHBP1 causes severe hypertriglyceridemia and pancreatitis, and GPIGBP1 autoantibody syndrome also causes severe hypertriglyceridemia and recurrent episodes of acute pancreatitis. In patients with type 2 diabetes, the elevated serum triglyceride levels negatively correlate with circulating LPL levels, and positively with circulating APOC1, APOC3, ANGPTL3, ANGPTL4 and ANGPTL8 levels. In contrast, circulating GPIHBP1 levels are not altered in type 2 diabetes patients with higher serum triglyceride levels, whereas they are elevated in type 2 diabetes patients with diabetic retinopathy and nephropathy. The circulating regulators of lipolytic complex might be new biomarkers for lipid and glucose metabolism, and diabetic vascular complications.

Levels of ANGPTL3 and characterization of other circulating cholesterol-related factors in high-grade serous ovarian cancers.

e17583 Background: Cancer cells require important amounts of cholesterol to sustain their growth. High-grade serous ovarian carcinomas (HGSOC), as an aggressive form of ovarian cancer, are no exception. Mechanisms allowing HGSOC to secure their lipid supplies are not yet fully elucidated. Recent years have highlighted ANGPTL3, PCSK9 and Apo CIII as key players in lipid metabolism. To date, impact of HGSOC on these key lipid-regulating factors is scantly documented. Herein, we compared ANGPTL3, PCSK9, Apo CIII and Lp(a) levels in women with HGSOC versus benign ovarian lesion (BOL) to better understand lipid metabolism in HGSOC. Methods: Plasma samples from 31 women with a HGSOC and 40 women with a BOL were assayed for ANGPTL3, PCSK9, and Apo CIII levels by ELISA. The lipid panel, Apo B and Lp(a) levels were measured on a Roche Modular analytical platform. Results: Higher levels of ANGPTL3 was observed in HGSOC (84 ng/ml, SD ±29 ng/ml, n = 31) vs. BOL (67 ng/ml, SD ±31 ng/ml, n = 40); HGSOC vs BOL p = 0.019. Receiver operating characteristic (ROC) curve analyses for ANGPTL3 combined with age indicated an area under curve of 67.7% (p = 0.005). Partial correlations indicated associations between the lipid panel and ANGPTL3, but only for BOL. Conclusions: In this cohort of 71 women, ANGPTL3 levels were higher in patients with HGSOC. This finding requires further validation in a larger cohort of HGSOC patients.

Circulating levels of PCSK9, ANGPTL3, and other lipid-related factors in men with high-grade prostate cancer.

e17001 Background: Cancer cells rely on abundant lipid supplies for growth and metastasis. Previous studies have shown that lipid-lowering drugs provide a protective effect against cancer progression, including prostate cancer. However, the role of hyperlipidemic factors has not yet been extensively studied. Here, we aimed to measure circulating levels of hyperlipidemic factors, such as PCSK9 and ANGPTL3, in a small cohort of men diagnosed with high-grade prostate cancer compared to men without cancer. Methods: Plasma samples and data were obtained from 70 consenting men treated at CHU de Québec-Université Laval. Thirty-five patients with high-grade prostate cancer (cases) were age and BMI-matched to 35 patients without cancer (controls). The circulating levels of various lipids, Apo B and Lp(a) were obtained with a Roche Modular analytical platform, whereas levels of PCSK9, ANGPTL3 and leptin were measured by ELISA. We performed group comparisons and correlations using R version 4.2.1. Results: As expected, Prostate-specific antigen (PSA) levels were significantly higher in the cancer group. The lipid profile as well as Lp(a) and leptin levels did not differ between groups. ANGPTL3 level tended to be lower in patients with prostate cancer without reaching statistical significance (mean 32.2 vs 36.3 ng/mL, p = 0.051). ANGPTL3 level also inversely correlated with leptin among the cases (rho = -0.44, p = 0.008). PCSK9 level was similar in both groups, but inversely correlated with PSA in the cancer group (rho = -0.39, p = 0.022). PSA level correlated with triglycerides, total cholesterol, Apo B, non-HDL-cholesterol and LDL in the control group (p &lt; 0.05). Conclusions: None of the hyperlipidemic factors measured here was significantly different between high-grade prostate cancer patients and controls. However, the trend for lower ANGPTL3 levels in cancer, as well as the inverse correlations between PCSK9 and PSA and between ANGPTL3 and leptin levels in cancer patients, warrant further investigation in larger cohorts.