Reduced miR-181d level in obesity and its role in lipid metabolism via regulation of ANGPTL3. Abu-Farha Mohamed,Cherian Preethi,Al-Khairi Irina,Nizam Rasheeba,Alkandari Abdullah,Arefanian Hossein,Tuomilehto Jaakko,Al-Mulla Fahd,Abubaker Jehad Scientific reports Obesity impacts the endocrine and metabolic functions of the adipose tissue. There is increasing interest in the role of epigenetic factors in obesity and its impact on diabetes and dyslipidemia. One such substance, miR-181, reduces plasma triglyceride levels in mice by targeting isocitrate dehydrogenase 1. In the other hand, the adipocyte differentiation and lipid regulating hormone angiopoietin-like 3 (ANGPTL3) is a known regulator of circulating apolipoproteins through its inhibition of the lipoprotein lipase activity. We aimed to study the miR-181d expression in the blood and adipose tissue in a cohort of obese and non-obese people, assessing its possible role in obesity. We also aimed to confirm whether miR-181d can bind and regulate ANGPTL3. miR-181d expression levels were investigated in 144 participants, 82 who were non-obese (body mass index [BMI] < 30) and 62 who were obese (BMI > 30). miR-181d levels in plasma and adipose tissue were measured by RT-PCR. Hepatocyte cell cultures were assessed by overexpression and 3'-UTR-luciferase assays for miR-181d binding to its target protein and its effect on the protein. The plasma levels of ANGPTL3 were also measured by ELISA. The miR-181d levels were significantly lower in obese than in non-obese individuals. In vitro analysis confirmed miR-181 binding to and repression of the ANGPTL3 transcript. Obesity leads to alterations in miR-181d expression. Its downregulation in obese humans was inversely correlated with ANGPTL3, a protein involved in adipocyte differentiation and lipid metabolism. miR-181d can be used as an inhibitor of ANGPTL3 to reduce the TG plasma level. 10.1038/s41598-019-48371-2
    Angiopoietin-like protein 3 governs LDL-cholesterol levels through endothelial lipase-dependent VLDL clearance. Adam Rene C,Mintah Ivory J,Alexa-Braun Corey A,Shihanian Lisa M,Lee Joseph S,Banerjee Poulabi,Hamon Sara C,Kim Hye In,Cohen Jonathan C,Hobbs Helen H,Van Hout Cristopher,Gromada Jesper,Murphy Andrew J,Yancopoulos George D,Sleeman Mark W,Gusarova Viktoria Journal of lipid research Angiopoietin-like protein (ANGPTL)3 regulates plasma lipids by inhibiting LPL and endothelial lipase (EL). ANGPTL3 inactivation lowers LDL-C independently of the classical LDLR-mediated pathway and represents a promising therapeutic approach for individuals with homozygous familial hypercholesterolemia due to mutations. Yet, how ANGPTL3 regulates LDL-C levels is unknown. Here, we demonstrate in hyperlipidemic humans and mice that ANGPTL3 controls VLDL catabolism upstream of LDL. Using kinetic, lipidomic, and biophysical studies, we show that ANGPTL3 inhibition reduces VLDL-lipid content and size, generating remnant particles that are efficiently removed from the circulation. This suggests that ANGPTL3 inhibition lowers LDL-C by limiting LDL particle production. Mechanistically, we discovered that EL is a key mediator of ANGPTL3's novel pathway. Our experiments revealed that, although dispensable in the presence of LDLR, EL-mediated processing of VLDL becomes critical for LDLR-independent particle clearance. In the absence of EL and LDLR, ANGPTL3 inhibition perturbed VLDL catabolism, promoted accumulation of atypical remnants, and failed to reduce LDL-C. Taken together, we uncover ANGPTL3 at the helm of a novel EL-dependent pathway that lowers LDL-C in the absence of LDLR. 10.1194/jlr.RA120000888
    Angiopoietin-like 7, a novel pro-angiogenetic factor over-expressed in cancer. Parri Matteo,Pietrovito Laura,Grandi Alberto,Campagnoli Susanna,De Camilli Elisa,Bianchini Francesca,Marchiò Serena,Bussolino Federico,Jin Boquan,Sarmientos Paolo,Grandi Guido,Viale Giuseppe,Pileri Piero,Chiarugi Paola,Grifantini Renata Angiogenesis Angiopoietin-like (ANGPTL) proteins are secreted proteins showing structural similarity to members of the angiopoietin family. Some ANGPTL proteins possess pleiotropic activities, being involved in cancer lipid, glucose energy metabolisms, and angiogenesis. ANGPTL7 is the less characterized member of the family whose functional role is only marginally known. In this study, we provide experimental evidences that ANGPTL7 is over-expressed in different human cancers. To understand the role played by ANGPTL7 in tumor biology, we asked whether ANGPTL7 is endogenously expressed by malignant cells or in response to environmental stimuli. We found that ANGPTL7 is marginally expressed under standard growth condition while it is specifically up-regulated by hypoxia. Interestingly, the protein is secreted and partially associated with the exosomal fraction, suggesting that it could be found in the systemic circulation of oncologic patients and act in an endocrine way. Moreover, we found that ANGPTL7 exerts a pro-angiogenetic effect on human differentiated endothelial cells by stimulating their proliferation, motility, invasiveness, and capability to form capillary-like networks while it does not stimulate progenitor endothelial cells. Finally, we showed that ANGPTL7 promotes vascularization in vivo in the mouse Matrigel sponge assay, thereby accrediting this molecule as a pro-angiogenic factor. 10.1007/s10456-014-9435-4
    Angiopoietin-like 2 has auxo-action in atherosclerosis by promoting atherosclerotic calcification. Jiao Lei,Zhuang Yan,Jiang Ming,Zhou Jiao-Hao,Wu Min,Chen Ze-Jun,Fang Jing-Hai,Deng Ying-Sheng International journal of clinical and experimental pathology OBJECTIVE:To study the effects of angiopoietin-like 2 (Angptl2) on atherosclerotic calcification in aortic artery of ApoE mice. METHODS:Twelve 6-week-old male mice were randomly divided into control group (n=6) and interventional group (n=6), the control group were fed with high fat diet and the interventional group were fed with high fat diet and at the eighth week interventional group mice were infused (intravenously) with purified recombinant Angptl-2 once a week for one month. All mice were sacrificed when the mice were 16 weeks old, blood was collected and plasma triglyceride (TG), total cholesterol (TC), low density lipoprotein cholesterol (LDLC) were measured, aortic sections were stained with hematoxylin and eosin (HE) or Von Kossa and were observed under microscope. Calcium content and alkaline phosphatase activity of aorta were measured to measure the degree of vascular calcification. The expressions of Runx2 protein and mRNA levels in aortic sections of mice were detected by immunohistochemistry, Western Blot and qRT-PCR respectively. RESULTS:The plasma TG, TC and LDLC level in interventional group was significantly higher than that in control group and the expression of Runx2 in aortic had the similar results. HE staining demonstrated significant thickening of the intima, with typical atherosclerotic plaque formation in interventional group mice, and Von Kossa staining showed spotty black clumps of aortic calcification under the fibrous cap plaque, while control group had atherosclerotic plaques without significant calcium deposits formation; The quantitative analysis showed that aortic vascular wall calcium and alkaline phosphatase activity were significantly higher in the intervention group than that of the control group (). CONCLUSIONS:Angptl-2 could increase ApoE mice plasma lipid level, it also facilitate the expression of Runx2, calcium content and ALP activity in aortic and then accelerate atherosclerotic calcification. Our experiments demonstrated that Angptl2 could accelerate atherosclerotic calcification. It reminded us that by controlling or decreasing the Anglt-2 level in plasma could help inhibit atherosclerotic calcification and then provides a new target to prevent coronary heart disease.
    ANGPTL8 requires ANGPTL3 to inhibit lipoprotein lipase and plasma triglyceride clearance. Haller Jorge F,Mintah Ivory J,Shihanian Lisa M,Stevis Panayiotis,Buckler David,Alexa-Braun Corey A,Kleiner Sandra,Banfi Serena,Cohen Jonathan C,Hobbs Helen H,Yancopoulos George D,Murphy Andrew J,Gusarova Viktoria,Gromada Jesper Journal of lipid research Angiopoietin-like (ANGPTL)3 and ANGPTL8 are secreted proteins and inhibitors of LPL-mediated plasma triglyceride (TG) clearance. It is unclear how these two ANGPTL proteins interact to regulate LPL activity. ANGPTL3 inhibits LPL activity and increases serum TG independent of ANGPTL8. These effects are reversed with an ANGPTL3 blocking antibody. Here, we show that ANGPTL8, although it possesses a functional inhibitory motif, is inactive by itself and requires ANGPTL3 expression to inhibit LPL and increase plasma TG. Using a mutated form of ANGPTL3 that lacks LPL inhibitory activity, we demonstrate that ANGPTL3 activity is not required for its ability to activate ANGPTL8. Moreover, coexpression of ANGPTL3 and ANGPTL8 leads to a far more efficacious increase in TG in mice than ANGPTL3 alone, suggesting the major inhibitory activity of this complex derives from ANGPTL8. An antibody to the C terminus of ANGPTL8 reversed LPL inhibition by ANGPTL8 in the presence of ANGPTL3. The antibody did not disrupt the ANGPTL8:ANGPTL3 complex, but came in close proximity to the LPL inhibitory motif in the N terminus of ANGPTL8. Collectively, these data show that ANGPTL8 has a functional LPL inhibitory motif, but only inhibits LPL and increases plasma TG levels in mice in the presence of ANGPTL3. 10.1194/jlr.M075689
    Structure and Function of Angiopoietin-like Protein 3 (ANGPTL3) in Atherosclerosis. Lu Xinjie Current medicinal chemistry BACKGROUND:Angiopoietin-Like Proteins (ANGPTLs) are structurally related to the angiopoietins. A total of eight ANGPTLs (from ANGPTL1 to ANGPTL8) have been identified so far. Most ANGPTLs possess multibiological functions on lipid metabolism, atherosclerosis, and cancer. Among them, ANGPTL3 has been shown to regulate the levels of Very Low-Density Lipoprotein (VLDL) made by the liver and play a crucial role in human lipoprotein metabolism. METHOD:A systematic appraisal of ANGPTLs was conducted, focusing on the main features of ANGPTL3 that has a significant role in atherosclerosis. RESULTS:Angiopoietins including ANGPTL3 are vascular growth factors that are highly specific for endothelial cells, perform a variety of other regulatory activities to influence inflammation, and have been shown to possess both pro-atherosclerotic and atheroprotective effects. CONCLUSION:ANGPTL3 has been demonstrated as a promising target in the pharmacological management of atherosclerosis. However, many questions remain about its biological functions. 10.2174/0929867326666190621120523
    Lipoprotein Lipase and Its Regulators: An Unfolding Story. Wu Shuangcheng Alivia,Kersten Sander,Qi Ling Trends in endocrinology and metabolism: TEM Lipoprotein lipase (LPL) is one of the most important factors in systemic lipid partitioning and metabolism. It mediates intravascular hydrolysis of triglycerides packed in lipoproteins such as chylomicrons and very-low-density lipoprotein (VLDL). Since its initial discovery in the 1940s, its biology and pathophysiological significance have been well characterized. Nonetheless, several studies in the past decade, with recent delineation of LPL crystal structure and the discovery of several new regulators such as angiopoietin-like proteins (ANGPTLs), glycosylphosphatidylinositol-anchored high-density lipoprotein-binding protein 1 (GPIHBP1), lipase maturation factor 1 (LMF1) and Sel-1 suppressor of Lin-12-like 1 (SEL1L), have completely transformed our understanding of LPL biology. 10.1016/j.tem.2020.11.005
    ANGPTL3 Inhibitors - Their Role in Cardiovascular Disease Through Regulation of Lipid Metabolism. Geladari Eleni,Tsamadia Panagiota,Vallianou Natalia G Circulation journal : official journal of the Japanese Circulation Society Elevated plasma lipid levels are linked to atherosclerosis, a hallmark for coronary artery disease (CAD), documented by animal studies as well as angiographic and clinical studies. The ability to treat hyperlipidemia through lifestyle changes and lipid-lowering agents has been related to the slow progression of atherosclerosis and decreased incidence of major coronary events. Angiopoietin-like proteins (ANGPTLs) are a family of secreted glycoproteins expressed in the liver that share common domain characteristics with angiopoietins, the main regulators of angiogenesis. Although ANGPTLs cannot bind the angiopoietin receptors expressed on endothelial cells, 2 ANGPTL family members (ANGPTL3 and ANGPTL4) have clinical importance because of their unambiguous effects on lipoprotein metabolism in mice and humans. The regulation of plasma lipid levels by ANGPTL3 is controlled via affecting lipoprotein lipase and endothelial lipase-mediated hydrolysis of triglycerides (TGs) and phospholipids. ANGPTL 3, along with the other 2 members, 4 and 8, is a key to balancing the distribution of circulating TGs between white adipose tissue (WAT) and oxidative tissues. Thus, ongoing trials with newly discovered medications in the form of monoclonal antibodies or antisense oligonucleotides with novel targets are under analysis and may represent a fresh frontier in the treatment of hyperlipidemia and CAD. 10.1253/circj.CJ-18-0442
    Effect of ANGPTL7 on Proliferation and Differentiation of MC3T3-E1 Cells. Lu XiaoQing,Lu JunHui,Zhang Lin,Xu YouJia Medical science monitor : international medical journal of experimental and clinical research BACKGROUND Angiopoietin-like proteins (ANGPTL) are a family of secretory glycoproteins that are involved in many pathophysiological processes. ANGPTL7 is a newly-discovered member of the ANGPTL family and plays a role in corneal morphogenesis, angiogenesis, glaucoma, and cancer. To date, whether ANGPTL7 is involved in osteoporosis is unknown. Therefore, to discover the effects of ANGPTL7 on osteoporosis, we explored the expression of ANGPTL7 in preosteoblasts and assessed the mechanism underlying its effects on proliferation and differentiation abilities of preosteoblasts. MATERIAL AND METHODS Mouse MC3T3-E1 cells were cultured in osteogenic medium for osteogenic differentiation. The expression levels of ANGPTL7 were detected by RT-qPCR and Western blot assays. Moreover, the overexpressed plasmid of ANGPTL7 pMSCV-ANGPTL7 was transfected into MC3T3-E1 cells. CCK-8 was used to evaluate cell proliferation. ALP activity detection and alizarin red staining were performed to measure the effect of ANGPTL7 on osteogenic differentiation. The expression levels bone morphogenetic proteins (BMPs) and osteogenic markers ALP, runt-related transcription factor 2 (Runx2), osteocalcin (OCN), and collagen I (Col I) were analyzed by Western blot. RESULTS When MC3T3-E1 cells were exposed to osteogenic medium, there was a significant increase in ANGPTL7, and overexpression of ANGPTL7 markedly promoted cell proliferation, ALP activity, and mineralization. Moreover, ANGPTL7 upregulated the levels of BMPs, especially BMP2/7, and the osteogenic markers ALP, Runx2, OCN, and Col I. CONCLUSIONS The results suggest that by regulating the expression of BMPs, ANGPTL7 directly promotes proliferation, differentiation, and mineralization of osteoblasts. 10.12659/MSM.918333
    Angiopoietin-like proteins as therapeutic targets for cardiovascular disease: focus on lipid disorders. Morelli Marco Bruno,Chavez Christopher,Santulli Gaetano Expert opinion on therapeutic targets : Angiopoietin-like (ANGPTL) proteins belong to a family of eight secreted factors that are structurally related to proteins that modulate angiogenesi, commonly known as angiopoietins. Specifically, ANGPTL3, ANGPTL4, and ANGPTL8 (the 'ANGPT L3-4-8 triad'), have surfaced as principal regulators of plasma lipid metabolism by functioning as potent inhibitors of lipoprotein lipase. The targeting of these proteins may open up future therapeutic avenues for metabolic and cardiovascular disease.: This article systematically summarizes the compelling literature describing the mechanistic roles of ANGPTL3, 4, and 8 in lipid metabolism, emphasizing their importance in determining the risk of cardiovascular disease. We shed light on population-based studies linking loss-of-function variations in ANGPTL3, 4, and 8 with decreased risk of metabolic conditions and cardiovascular disorders. We also discuss how the strategies aiming at targeting the ANGPT L3-4-8 triad could offer therapeutic benefit in the clinical scenario.: Monoclonal antibodies and antisense oligonucleotides that target ANGPTL3, 4, and 8 are potentially an efficient therapeutic strategy for hypertriglyceridemia and cardiovascular risk reduction, especially in patients with limited treatment options. These innovative therapeutical approaches are at an embryonic stage in development and hence further investigations are necessary for eventual use in humans. 10.1080/14728222.2020.1707806
    Thrombospondins Differentially Regulate Proteins Involved in Arterial Remodeling. Kassem M M,Helkin A,Maier K G,Gahtan V Physiological research Thrombospondins (TSPs) are matricellular glycoproteins expressed in response to vascular injury. TSP-1 and TSP-2 are promotors of arterial remodeling while TSP-5 is believed to be protective. The current study assessed the differential effect of TSPs on protein expression in vascular smooth muscle cells (VSMCs). We hypothesized that TSP-1, TSP-2 and TSP-5 would regulate VSMC proteins involved in arterial remodeling. Human VSMCs were exposed to TSP-1, -2, -5 or serum free media (24 hours). Cell lysates were used to assess the targets TSP-1, TSP-2, TSP-5 and CD44), while the culture media was used to detect TGF-ß1, PDGF-BB, ANGPTL-4 and IL-8. Statistical analysis was performed by t-test and p< 0.05 was considered significant. All TSPs increased their own expression and TSP-5 increased TSP-2. TSP-1 and TSP-2 increased production of ANGPTL-4 and PDGF-BB, while TSP-5 only increased ANGPTL-4. TSP-1 increased exclusively TGF-ß1 and CD44 production. TSP-2 increased TSP-1 expression. All TSPs decreased IL-8. The findings suggest that TSP-1 and TSP-2 may promote vascular remodeling, in part, by increasing ANGPTL-4, PDGF-BB and their own expression. TSP-5 did not upregulate the inflammatory mediators TSP-1, PDGF-BB or TGF-ß1, but upregulated its own expression, which could be a protective mechanism against the response to vascular injury. 10.33549/physiolres.934148
    Angiopoietin-Like Proteins in Angiogenesis, Inflammation and Cancer. Carbone Carmine,Piro Geny,Merz Valeria,Simionato Francesca,Santoro Raffaela,Zecchetto Camilla,Tortora Giampaolo,Melisi Davide International journal of molecular sciences Altered expression of secreted factors by tumor cells or cells of the tumor microenvironment is a key event in cancer development and progression. In the last decade, emerging evidences supported the autocrine and paracrine activity of the members of the Angiopoietin-like (ANGPTL) protein family in angiogenesis, inflammation and in the regulation of different steps of carcinogenesis and metastasis development. Thus, ANGPTL proteins become attractive either as prognostic or predictive biomarkers, or as novel target for cancer treatment. Here, we outline the current knowledge about the functions of the ANGPTL proteins in angiogenesis, cancer progression and metastasis. Moreover, we discuss the most recent evidences sustaining their role as prognostic or predictive biomarkers for cancer therapy. Although the role of ANGPTL proteins in cancer has not been fully elucidated, increasing evidence suggest their key effects in the proliferative and invasive properties of cancer cells. Moreover, given the common overexpression of ANGPTL proteins in several aggressive solid tumors, and their role in tumor cells and cells of the tumor microenvironment, the field of research about ANGPTL proteins network may highlight new potential targets for the development of future therapeutic strategies. 10.3390/ijms19020431
    Correlation between angiopoietin-like proteins in inflammatory mediators in peripheral blood and severity of coronary arterial lesion in patients with acute myocardial infarction. Cao Yuejuan,Li Rongqing,Zhang Fengping,Guo Zhaozeng,Tuo Shaoyong,Li Yuming Experimental and therapeutic medicine The effects of angiopoietin-like protein 2 (Angptl 2) and interleukin-6 (IL-6) in inflammatory mediators on the severity of coronary arterial lesion in patients with acute myocardial infarction were investigated. One hundred and twenty-six patients with acute myocardial infarction admitted to Tianjin Union Medical Center (the myocardial infarction group) and 133 healthy individuals (the control group) were selected for retrospective analysis from January 2013 to December 2015. The levels of Angptl 2 and IL-6 in serum of patients were detected by enzyme linked immunosorbent assay (ELISA), and the correlation analysis between the levels and the degree of coronary stenosis in patients with myocardial infarction was conducted. The expression level of Angptl 2 and IL-6 in the myocardial infarction group was significantly higher than that in the control group P<0.001. In the myocardial infarction group, the expression levels of Angptl 2 and IL-6 were the highest in the patients with severe stenosis, followed by the moderate stenosis, and the lowest in the patients with mild stenosis (P<0.050). Pearson's correlation analysis showed that Angptl 2 and IL-6 were positively correlated with the diameter of coronary stenosis (r=0.696, 0.750, P<0.001). In conclusion, both Angptl 2 and IL-6 are highly expressed in the peripheral blood of patients with acute myocardial infarction and involved in the occurrence and development of the disease. Moreover, Angptl2 and IL-6 are positively correlated with the severity of coronary arterial lesion in patients with acute myocardial infarction, and they are expected to become a target for the diagnosis and treatment of coronary atherosclerosis (CA) in the future. 10.3892/etm.2019.7386
    The potential role of angiopoietin-like protein-8 in type 2 diabetes mellitus: a possibility for predictive diagnosis and targeted preventive measures? Issa Yasmine Amr,Abd ElHafeez Samar Samy,Amin Noha Gaber The EPMA journal Background:Previous studies showed altered angiopoietin-like protein-8 (ANGPTL-8) circulating levels in type 2 diabetes mellitus (DM). Whether or not the alteration in ANGPTL-8 level can be a predictive maker for increased DM risk remains unclear. Aim:Investigating possible role of ANGPTL-8 as a risk predictor of type2 DM, in addition to a set of factors likely to affect ANGPTL-8 level. Methods:One hundred recently diagnosed persons with type 2 DM and 100 sex- and age-matched healthy controls were enrolled. Exclusion criteria included type 1 DM, acute infections, history of chronic kidney disease, malignancy, and blood loss or transfusion. Serum levels of ANGPTL-8, blood pressure, weight, height, glycosylated hemoglobin (HbA1c), fasting blood glucose, cystatin C, lipid profile, liver, and kidney function tests were assessed. The independent relationship between DM and ANGPTL-8 was tested in the unadjusted and multiple-adjusted regression models. Results:Serum ANGPTL-8 levels showed significant elevation among persons with vs. without DM ( = 0.006), positive correlation with HbA1c ( < 0.001), and negative correlation with estimated GFR (eGFR) ( = 0.003) but no significant correlation to fasting glucose level. In the unadjusted model, patients in the third tertile of ANGPTL-8 had 4 times risk of DM (OR 4.03; 95% CI = 1.37-11.84). Data adjustment for cardiovascular diseases, smoking, body mass index, systolic blood pressure, alanine transaminase (ALT), and low-density lipoprotein (LDL) increased the direct relationship between ANGPTL-8 and DM (OR 6.26; 95% CI = 1.21-32.50). However, the risk significantly decreased after adjustment of Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) eGFR creatinine-cystatin (OR 2.17; 95% CI = 0.10-49.84). Conclusion:This study highlights a possible predictive role of ANGPTL-8 in diabetic complications, particularly nephropathy. Larger prognostic studies are needed to validate the cause-effect relationship between ANGPTL-8 and deteriorated kidney functions. 10.1007/s13167-019-00180-3
    Association of circulating ANGPTL 3, 4, and 8 levels with medical status in a population undergoing routine medical checkups: A cross-sectional study. Morinaga Jun,Zhao Jiabin,Endo Motoyoshi,Kadomatsu Tsuyoshi,Miyata Keishi,Sugizaki Taichi,Okadome Yusuke,Tian Zhe,Horiguchi Haruki,Miyashita Kazuya,Maruyama Nobuhiro,Mukoyama Masashi,Oike Yuichi PloS one PURPOSE:Angiopoietin-like proteins (ANGPTLs) 3, 4, and 8 reportedly contribute to progression of metabolic disease, a risk factor for cardiovascular disease (CVD). The purpose of this study was to investigate whether circulating ANGPTL levels are associated with CVD risk after adjustment for potential confounding factors. METHODS:We conducted a single center, cross-sectional study of 988 Japanese subjects undergoing routine health checks. Serum ANGPTL3, 4, and 8 levels were measured using an enzyme-linked immunosorbent assay. Using multiple regression analysis we evaluated potential association of circulating ANGPTL3, 4, and 8 levels with general medical status including age, sex, smoking, drinking, obesity, hypertension, impaired glycometabolism, dyslipidemia, hyperuricemia, hepatic impairment, chronic kidney disease, anemia, cardiac abnormality, and inflammation. RESULTS:Circulating ANGPTL3 levels were relatively high in health-related categories of hepatic impairment and inflammation. Circulating ANGPTL4 levels were also significantly high in impaired glycometabolism or hepatic impairment but decreased in inflammation. Finally, increased ANGPTL8 levels were observed in obesity, impaired glycometabolism and dyslipidemia. Particularly, increased levels of circulating ANGPTL8 were positively correlated with circulating triglycerides and LDL-cholesterol levels and inversely correlated with circulating HDL-cholesterol levels. CONCLUSIONS:Circulating ANGPTL3, 4, and 8 levels reflect some risk factors for CVD development. 10.1371/journal.pone.0193731
    ANGPTL-4 correlates with vascular endothelial growth factor in patients with proliferative diabetic retinopathy. Lu Qianyi,Zou Wenjun,Chen Bin,Zou Chen,Zhao Minjie,Zheng Zhi Graefe's archive for clinical and experimental ophthalmology = Albrecht von Graefes Archiv fur klinische und experimentelle Ophthalmologie PURPOSE:To investigate the relationship between angiopoietin-like protein 4 (ANGPTL-4) and vascular endothelial growth factor (VEGF) in the serum and vitreous of eyes in patients with proliferative diabetic retinopathy (PDR). METHODS:Thirty-five eyes of 35 patients with PDR, 20 eyes of 20 patients with non-proliferative diabetic retinopathy, 20 eyes of 20 patients with diabetes but no diabetic retinopathy, and 14 eyes of 14 nondiabetic patients with an idiopathic macular hole (IMH) were recruited from Shanghai First People's Hospital. The ANGPTL-4 and VEGF concentrations were determined using enzyme-linked immunosorbent assays. Group means were compared using one-way analysis of variance with GraphPad Prism 4.0 and SPSS ver. 17.0. The research followed the tenets of the Declaration of Helsinki. RESULTS:The ANGPTL-4 and VEGF levels were significantly higher in the vitreous and serum of patients with PDR compared with patients with IMH. There were significant correlations between the ANGPTL-4 and VEGF levels in the vitreous and serum of patients with PDR. The vitreous and serum ANGPTL-4 levels were also significantly correlated in patients with PDR. The ANGPTL-4 in both the vitreous and serum correlated with the serum triglyceride and high-density lipoprotein cholesterol levels. CONCLUSIONS:The ANGPTL-4 levels were markedly elevated and the ANGPTL-4 expression was directly correlated with the VEGF expression in the vitreous and serum of patients with PDR. The vitreous and serum ANGPTL-4 levels were also significantly correlated with serum lipids in patients with PDR. Our results suggest that the ANGPTL-4 may be used as a new therapeutic target for the treatment of PDR. 10.1007/s00417-015-3187-8
    ANGPTL-4 induces diabetic retinal inflammation by activating Profilin-1. Lu Qianyi,Lu Peirong,Chen Wei,Lu Li,Zheng Zhi Experimental eye research Diabetic retinopathy (DR), the most common cause of irreversible blindness in working-age adults, results in central vision loss that is caused by microvascular damage to the inner lining of the back of the eye, the retina. The aim of this work was to assess the temporal relationships between angiopoietin-like protein-4 (ANGPTL-4), a novel adipocytokine factor, and diabetic retinal inflammation and microvascular dysfunction. The downstream pathway(s) and upstream mediator(s) of ANGPTL-4 were then determined under high glucose (HG) conditions. Diabetic rats and control animals were randomly assigned to receive hypoxia inducible factor-1 alpha (HIF-1α) blockade (doxorubicin or shRNA) or vehicle for 8 weeks. Human retinal microvascular endothelial cells (HRMECs) were incubated with normal or high glucose, with or without blockade or recombinant proteins, for ANGPTL-4, HIF-1α, and vascular endothelial growth factor (VEGF). The levels of ANGPTL-4, profilin-1, HIF-1α, VEGF, interleukin 1 beta (IL-1β), IL-6, and intercellular adherent molecule 1 (ICAM-1) in the rat retinas and HRMEC extracts were examined by Western blotting and real-time RT-PCR. The levels of ANGPTL-4, profilin-1, HIF-1α, and VEGF protein and mRNA were significantly higher in the diabetic rats and HG-exposed HRMECs. ANGPTL-4 was a potent modulator of increased inflammation, permeability, and angiogenesis via activation of the profilin-1 signaling pathway. Our results showed that ANGPTL-4 upregulation was induced by HG, which was dependent on HIF-1α activation that was also triggered by HG, both in vivo and in vitro. Our results suggest that targeting ANGPTL-4, alone or in combination with profilin-1, may be an effective therapeutic strategy and diagnostic screening biomarker for proliferative diabetic retinopathy and other vitreous-retinal inflammatory diseases. 10.1016/j.exer.2017.10.009
    Do ANGPTL-4 and galectin-3 reflect the severity of coronary artery disease? Goenka Luxitaa,George Melvin,Singh Vishakha,Jena Amrita,Seshadri Deepika,Karunakaran Vasanth,Elumalai Dhandapani Vellala,Rani Jamuna,Kaliappan Ilango Therapeutic advances in cardiovascular disease BACKGROUND:Coronary artery disease (CAD) is one of the leading causes of mortality and morbidity worldwide. We thereby sought to investigate whether the biomarkers, angiopoietin-like 4 (ANGPTL-4) and galectin-3, reflect the severity of CAD. METHODS:Patients were screened based on inclusion/exclusion criteria and written informed consent was obtained from the patients. Serum ANGPTL-4 and galectin-3 was quantified using enzyme-linked immunosorbent assay (ELISA) and correlated with the Global Registry of Acute Coronary Events (GRACE) and GENSINI score using Spearman's rank correlation coefficient and multivariate analysis. RESULTS:A total of 226 patients consisting of ST-segment elevation myocardial infarction (STEMI), non-STEMI/unstable angina (USA), chronic stable angina (CSA) and normal controls (NCs) participated in the study. ANGPTL-4 and galectin-3 were significantly higher in CAD than the NC group. ANGPTL-4 showed significant negative correlation with GRACE score in acute coronary syndrome (ACS) ( r = -0.211, p = 0.03) patients. ANGPTL-4 showed significant positive correlation with serum creatinine ( r = 0.304, p = 0.056) and body mass index (BMI) ( r = 0.424, p = 0.009) in CSA patients. A modest positive correlation was observed between the serum galectin-3 levels and GRACE score ( r = 0.187, p = 0.055) in ACS patients. However, on multivariate analysis the positive correlation relationship between ANGPTL-4 and galectin-3 with the severity of CAD was not sustained. CONCLUSION:In conclusion, ANGPTL-4 and galectin-3 do not appear to have a promising role for assessing the severity of CAD. Nevertheless these biomarkers do warrant further exploration in improving the management of CAD. 10.1177/1753944717723311
    Silencing of ANGPTL 3 (angiopoietin-like protein 3) in human hepatocytes results in decreased expression of gluconeogenic genes and reduced triacylglycerol-rich VLDL secretion upon insulin stimulation. Tikka Anna,Soronen Jarkko,Laurila Pirkka-Pekka,Metso Jari,Ehnholm Christian,Jauhiainen Matti Bioscience reports Homozygosity of loss-of-function mutations in ANGPTL3 (angiopoietin-like protein 3)-gene results in FHBL2 (familial combined hypolipidaemia, OMIM #605019) characterized by the reduction of all major plasma lipoprotein classes, which includes VLDL (very-low-density lipoprotein), LDL (low-density lipoprotein), HDL (high-density lipoprotein) and low circulating NEFAs (non-esterified fatty acids), glucose and insulin levels. Thus complete lack of ANGPTL3 in humans not only affects lipid metabolism, but also affects whole-body insulin and glucose balance. We used wild-type and ANGPTL3-silenced IHHs (human immortalized hepatocytes) to investigate the effect of ANGPTL3 silencing on hepatocyte-specific VLDL secretion and glucose uptake. We demonstrate that both insulin and PPARγ (peroxisome-proliferator-activated receptor γ) agonist rosiglitazone down-regulate the secretion of ANGPTL3 and TAG (triacylglycerol)-enriched VLDL1-type particles in a dose-dependent manner. Silencing of ANGPTL3 improved glucose uptake in hepatocytes by 20-50% and influenced down-regulation of gluconeogenic genes, suggesting that silencing of ANGPTL3 improves insulin sensitivity. We further show that ANGPTL3-silenced cells display a more pronounced shift from the secretion of TAG-enriched VLDL1-type particles to secretion of lipid poor VLDL2-type particles during insulin stimulation. These data suggest liver-specific mechanisms involved in the reported insulin-sensitive phenotype of ANGPTL3-deficient humans, featuring lower plasma insulin and glucose levels. 10.1042/BSR20140115
    Angptl 4 deficiency improves lipid metabolism, suppresses foam cell formation and protects against atherosclerosis. Adachi Hironori,Fujiwara Yukio,Kondo Tatsuya,Nishikawa Takeshi,Ogawa Rei,Matsumura Takeshi,Ishii Norio,Nagai Ryoji,Miyata Keishi,Tabata Mitsuhisa,Motoshima Hiroyuki,Furukawa Noboru,Tsuruzoe Kaku,Kawashima Junji,Takeya Motohiro,Yamashita Shizuya,Koh Gou Young,Nagy Andras,Suda Toshio,Oike Yuichi,Araki Eiichi Biochemical and biophysical research communications Angiopoietin-like protein family 4 (Angptl 4) has been shown to regulate lipoprotein metabolism through the inhibition of lipoprotein lipase (LPL). We generated ApoE(-/-)Angptl 4(-/-) mice to study the effect of Angptl 4 deficiency on lipid metabolism and atherosclerosis. Fasting and postolive oil-loaded triglyceride (TG) levels were largely decreased in ApoE(-/-)Angptl 4(-/-) mice compared with and ApoE(-/-)Angptl 4(+/+) mice. There was a significant (75+/-12%) reduction in atherosclerotic lesion size in ApoE(-/-)Angptl 4(-/-) mice compared with ApoE(-/-) Angptl 4(+/+) mice. Peritoneal macrophages, isolated from Angptl 4(-/-) mice to investigate the foam cell formation, showed a significant decrease in newly synthesized cholesteryl ester (CE) accumulation induced by acetyl low-density lipoprotein (acLDL) compared with those from Angptl 4(+/+) mice. Thus, genetic knockout of Angptl 4 protects ApoE(-/-) mice against development and progression of atherosclerosis and strongly suppresses the ability of the macrophages to become foam cells in vitro. 10.1016/j.bbrc.2008.12.018
    The Roles of ANGPTL Families in Cancer Progression. Endo Motoyoshi Journal of UOEH Angiopoietins play important roles in angiogenesis and the maintenance of hematopoietic stem cells. Angiopoietin-like proteins (ANGPTLs) are identified as proteins structurally similar to angiopoietins, and the ANGPTL family now consists of eight members. ANGPTLs are secretary proteins, and some ANGPTLs are not only angiogenic factors but also proteins with multiple functions such as glucose metabolism, lipid metabolism, redox regulation and chronic inflammation. Chronic inflammation is one of the key factors in carcinogenesis and cancer growth, proliferation, invasion and metastasis. ANGPTL 2, 3, 4, 6 and 7 are pro-inflammatory factors and regulate cancer progression, while ANGPTL1 inhibits tumor angiogenesis and metastasis. In this review, we describe the roles of ANGPTLs in cancer progression and discuss the possibility of disturbing the progression of cancer by regulating ANGPTLs expression. 10.7888/juoeh.41.317