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    ANGPTL4 is produced by entero-endocrine cells in the human intestinal tract
    Alex, S. ; Lichtenstein, L.L. ; Dijk, W. ; Mensink, R.P. ; Tan, N.S. ; Kersten, A.H. - \ 2014
    Histochemistry and Cell Biology 141 (2014)4. - ISSN 0948-6143 - p. 383 - 391.
    angiopoietin-like protein-4 - activated receptor-gamma - diet-induced obesity - lipoprotein-lipase - chromogranin-a - fatty-acids - enteroendocrine cells - gut microbiota - target gene - plasma
    Gut hormones produced by entero-endocrine cells (EEC) located throughout the gastrointestinal tract play a major role in the regulation of glucose and energy homeostasis. Angiopoietin-like 4 (ANGPTL4, also referred to as fasting induced adipose factor) is a secreted factor involved in regulation of lipid homeostasis and has been proposed as circulating mediator between the gut microbiota and fat storage in adipose tissue, although discordant data exist. Currently, little is known about the site and regulation of ANGPTL4 production in the intestine. Here, we show using immunohistochemistry and immunofluorescence that cells positive for ANGPTL4 are scattered along the epithelial layer in the human small and large intestine. ANGPTL4-positive cells exhibit typical features of EEC characterized by large ANGPTL4-positive secretory granules directed towards the basolateral side. In support, extensive overlap was observed between ANGPTL4-positive cells and cells positive for the entero-endocrine marker chromogranin A. Higher resolution images revealed that ANGPTL4 and chromogranin A are partially present in distinct intracellular vesicles. Using entero-endocrine HuTu-80 cells, ANGPTL4 secretion was shown to be induced by short chain fatty acids and reduced by bile acids. Finally, levels of ANGPTL4 in human plasma were significantly decreased following meal consumption. In conclusion, ANGPTL4 is produced by EEC in human intestine and expression may be regulated by short chain fatty acids and bile acids.
    Omega-3 long-chain fatty acids strongly induce angiopoietin-like 4 in humans
    Brands, M. ; Sauerwein, H.P. ; Ackermans, M.T. ; Kersten, A.H. ; Serlie, M.J. - \ 2013
    Journal of Lipid Research 54 (2013)3. - ISSN 0022-2275 - p. 615 - 621.
    triglyceride-metabolism - lipoprotein-lipase - target gene - plasma - angptl4 - protein - increase - insulin - glucose - hyperlipidemia
    Angiopoietin-like 4 (ANGPTL4) is a regulator of LPL activity. In this study we examined whether different fatty acids have a differential effect on plasma ANGPTL4 levels during hyperinsulinemia in healthy lean males. In 10 healthy lean males, 3 hyperinsulinemic euglycemic clamps were performed during concomitant 6 h intravenous infusion of soybean oil (Intralipid (R); rich in PUFA), olive oil (Clinoleic (R); rich in MUFA) and control saline. In 10 other healthy lean males, 2 hyperinsulinemic clamps were performed during infusion of a mixed lipid emulsion containing a mixture of fish oil (FO), medium-chain triglycerides (MCTs), and long-chain triglycerides (LCTs) (FO/MCT/LCT; SMOFlipid (R)) or saline. FFA levels of approximately 0.5 mmol/l were reached during each lipid infusion. Plasma ANGPTL4 decreased during hyperinsulinemia by 32% (18-52%) from baseline. This insulin-mediated decrease in ANGPTL4 concentrations was partially reduced during concomitant infusion of olive oil and completely blunted during concomitant infusion of soybean oil and FO/MCT/LCT. The reduction in insulin sensitivity was similar between all lipid infusions. In accordance, incubation of rat hepatoma cells with the polyunsaturated fatty acid C22:6 increased ANGPTL4 expression by 70-fold, compared with 27-fold by the polyunsaturated fatty acid C18:2, and 15-fold by the monounsaturated fatty acid C18:1. These results suggest that ANGPTL4 is strongly regulated by fatty acids in humans, and is also dependent on the type of fatty acid.-Brands, M., H. P. Sauerwein, M. T. Ackermans, S. Kersten, and M. J. Serlie. Omega-3 long-chain fatty acids strongly induce angiopoietin-like 4 in humans. J. Lipid Res. 2013. 54: 615-621.
    Short chain fatty acids stimulate Angiopoietin-like 4 synthesis in human colon adenocarcinoma cells by activating PPARy
    Alex, S. ; Lange, K. ; Amolo, T. ; Grinstead, J.S. ; Haakonsson, A.K. ; Szalowska, E. ; Koppen, A. ; Mudde, C.M. ; Haenen, D. ; Al-Lahham, S. ; Roelofsen, H. ; Houtman, R. ; Burg, B. van der; Mandrup, S. ; Bonvin, A.M.J.J. ; Kalkhoven, E. ; Muller, M.R. ; Hooiveld, G.J.E.J. ; Kersten, A.H. - \ 2013
    Molecular and Cellular Biology 33 (2013)7. - ISSN 0270-7306 - p. 1303 - 1316.
    inflammatory-bowel-disease - ppar-gamma - transcriptional activity - lipoprotein-lipase - skeletal-muscle - gut microbiota - target gene - expression - protein-4 - butyrate
    Angiopoietin-like protein 4 (ANGPTL4/FIAF) has been proposed as a circulating mediator between the gut microbiota and fat storage. Here, we show that transcription and secretion of ANGPTL4 in human T84 and HT29 colon adenocarcinoma cells is highly induced by physiological concentrations of short-chain fatty acids (SCFA). SCFA induce ANGPTL4 by activating the nuclear receptor peroxisome proliferator activated receptor ¿ (PPAR¿), as demonstrated using PPAR¿ antagonist, PPAR¿ knockdown, and transactivation assays, which show activation of PPAR¿ but not PPARa and PPARd by SCFA. At concentrations required for PPAR¿ activation and ANGPTL4 induction in colon adenocarcinoma cells, SCFA do not stimulate PPAR¿ in mouse 3T3-L1 and human SGBS adipocytes, suggesting that SCFA act as selective PPAR¿ modulators (SPPARM), which is supported by coactivator peptide recruitment assay and structural modeling. Consistent with the notion that fermentation leads to PPAR activation in vivo, feeding mice a diet rich in inulin induced PPAR target genes and pathways in the colon. We conclude that (i) SCFA potently stimulate ANGPTL4 synthesis in human colon adenocarcinoma cells and (ii) SCFA transactivate and bind to PPAR¿. Our data point to activation of PPARs as a novel mechanism of gene regulation by SCFA in the colon, in addition to other mechanisms of action of SCFA.
    Angiopoietin-like 4: a decade of research
    Zhu, P. ; Goh, Y.Y. ; Chin, H.F.A. ; Kersten, A.H. ; Tan, N.S. - \ 2012
    Bioscience Reports 32 (2012)3. - ISSN 0144-8463 - p. 211 - 219.
    induced adipose factor - fatty-acids - tgf-beta - anoikis resistance - lipoprotein-lipase - human adipocytes - target gene - protein - angptl4 - expression
    The past decade has seen a rapid development and increasing recognition of ANGPTL4 (angiopoietin-like 4) as a remarkably multifaceted protein that is involved in many metabolic and non-metabolic conditions. ANGPTL4 has been recognised as a central player in various aspects of energy homoeostasis, at least in part, via the inhibitory interaction between the coiled-coil domain of ANGPTL4 and LPL (lipoprotein lipase). The fibrinogen-like domain of ANGPTL4 interacts and activates specific integrins to facilitate wound healing, modulates vascular permeability, and regulates ROS (reactive oxygen species) level to promote tumorigenesis. The present review summarizes these landmark findings about ANGPTL4 and highlights several important implications for future clinical practice. Importantly, these implications have also raised many questions that are in urgent need of further investigations, particularly the transcription regulation of ANGPTL4 expression, and the post-translation cleavage and modifications of ANGPTL4. The research findings over the past decade have laid the foundation for a better mechanistic understanding of the new scientific discoveries on the diverse roles of ANGPTL4.
    Angiopoietin-like protein 4 is differentially regulated by glococorticoids and insulin in vitro and in vivo in healthy humans
    Raalte, D.H. ; Brands, M. ; Serlie, M.J. ; Mudde, C.M. ; Stienstra, R. ; Sauerwein, H.P. ; Kersten, A.H. ; Diamant, M. - \ 2012
    Experimental and Clinical Endocrinologie and Diabetes 120 (2012)10. - ISSN 0947-7349 - p. 598 - 603.
    lipoprotein-lipase - fatty-acids - adipose-tissue - target gene - plasma - angptl4 - glucose - hyperlipidemia - mice
    Objective: Angiopoietin-like protein 4 (Angptl4) is a circulating inhibitor of plasma triglyceride clearance via inhibition of lipoprotein lipase. The aim of the present study was to examine the regulation of Angptl4 by glucocorticoids and insulin in vivo in humans, since these factors regulate Angptl4 expression in vitro. Research design and methods: In a randomized, placebo-controlled, double-blind, dose-response intervention study, 32 healthy males (age: 22 +/- 3 years; BMI 22.4 +/- 1.7 kg m(-2)) were allocated to prednisolone 30 mg once daily (n = 12), prednisolone 7.5 mg once daily (n = 12), or placebo (n = 8) for 2 weeks. Angptl4 levels and lipid metabolism were measured before and at 2 weeks of treatment, in the fasted state and during a 2-step hyperinsulinemic clamp. Additionally, human hepatoma cells were treated with dexamethasone and/or insulin. Results: Compared to placebo, prednisolone treatment tended to lower fasting Angptl4 levels (P = 0.073), raised fasting insulin levels (P = 0.0004) and decreased fasting nonesterified fatty acid concentrations (NEFA) (P = 0.017). Insulin infusion reduced Angptl4 levels by 6 % (plasma insulin similar to 200 pmol/l, P = 0.006) and 22 % (plasma insulin similar to 600 pmol/l, P <0.0001), which was attenuated by prednisolone treatment (P = 0.03). Prednisolone 7.5 mg and 30 mg dose-dependently decreased insulin-mediated suppression of lipolysis (by 11 +/- 5 % and 34 +/- 6 % respectively). Prednisolone 30 mg enhanced fasting triglyceride levels (P = 0.028). Plasma Angptl4 was not related to prednisolone-induced changes in lipid metabolism. In human hepatoma cells, dexamethasone increased Angptl4 mRNA expression and protein secretion, whereas insulin had the opposite effect. Conclusions: Insulin lowers plasma Angptl4 levels in humans by lowering NEFA and by inhibiting Angptl4 expression and release. Glucocorticoids counteract insulin-mediated suppression of Angptl4.
    Podocyte-secreted angiopoietin-like-4 mediates proteinuria in glucocorticoid-sensitive nephrotic syndrome
    Clement, L.C. ; Avila-Casado, C. ; Mace, C. ; Soria, E. ; Bakker, W.W. ; Kersten, A.H. ; Chugh, S.S. - \ 2011
    Nature Medicine 17 (2011)1. - ISSN 1078-8956 - p. 117 - 122.
    gene-expression - target gene - oligomerization - apoptosis
    The main manifestations of nephrotic syndrome include proteinuria, hypoalbuminemia, edema, hyperlipidemia and lipiduria. Common causes of nephrotic syndrome are diabetic nephropathy, minimal change disease (MCD), focal and segmental glomerulosclerosis (FSGS) and membranous nephropathy. Among the primary glomerular diseases, MCD is usually sensitive to glucocorticoid treatment, whereas the other diseases show variable responses(1). Despite the identification of key structural proteins in the glomerular capillary loop which may contribute to defects in ultrafiltration, many of the disease mechanisms of nephrotic syndrome remain unresolved. In this study, we show that the glomerular expression of angiopoietin-like-4 (Angptl4), a secreted glycoprotein, is glucocorticoid sensitive and is highly upregulated in the serum and in podocytes in experimental models of MCD and in the human disease. Podocyte-specific transgenic overexpression of Angptl4 (NPHS2-Angptl4) in rats induced nephrotic-range, and selective, proteinuria (over 500-fold increase in albuminuria), loss of glomerular basement membrane (GBM) charge and foot process effacement, whereas transgenic expression specifically in the adipose tissue (aP2-Angptl4) resulted in increased circulating Angptl4, but no proteinuria. Angptl4-/-mice that were injected with lipopolysaccharide (LPS) or nephritogenic antisera developed markedly less proteinuria than did control mice. Angptl4 secreted from podocytes in some forms of nephrotic syndrome lacks normal sialylation. When we fed the sialic acid precursor N-acetyl-D-mannosamine (ManNAc) to NPHS2-Angptl4 transgenic rats it increased the sialylation of Angptl4 and decreased albuminuria by more than 40%. These results suggest that podocyte-secreted Angptl4 has a key role in nephrotic syndrome.
    Angptl4 Protects against Severe Proinflammatory Effects of Saturated Fat by Inhibiting Fatty Acid Uptake into Mesenteric Lymph Node Macrophages
    Lichtenstein, L.L. ; Mattijssen, F.B.J. ; Wit, N.J.W. de; Georgiadi, A. ; Hooiveld, G.J.E.J. ; Meer, R. van der; He, Y. ; Qi, L. ; Köster, A. ; Tamsma, J.T. ; Tan, N.S. ; Müller, M.R. ; Kersten, A.H. - \ 2010
    Cell Metabolism 12 (2010)6. - ISSN 1550-4131 - p. 580 - 592.
    endoplasmic-reticulum stress - mouse peritoneal-macrophages - angiopoietin-like protein-4 - low-density lipoproteins - induced adipose factor - insulin-resistance - target gene - lipase - obesity - activation
    Dietary saturated fat is linked to numerous chronic diseases, including cardiovascular disease. Here we study the role of the lipoprotein lipase inhibitor Angptl4 in the response to dietary saturated fat. Strikingly, in mice lacking Angptl4, saturated fat induces a severe and lethal phenotype characterized by fibrinopurulent peritonitis, ascites, intestinal fibrosis, and cachexia. These abnormalities are preceded by a massive acute phase response induced by saturated but not unsaturated fat or medium-chain fat, originating in mesenteric lymph nodes (MLNs). MLNs undergo dramatic expansion and contain numerous lipid-laden macrophages. In peritoneal macrophages incubated with chyle, Angptl4 dramatically reduced foam cell formation, inflammatory gene expression, and chyle-induced activation of ER stress. Induction of macrophage Angptl4 by fatty acids is part of a mechanism that serves to reduce postprandial lipid uptake from chyle into MLN-resident macrophages by inhibiting triglyceride hydrolysis, thereby preventing macrophage activation and foam cell formation and protecting against progressive, uncontrolled saturated fat-induced inflammation
    Modulation of plasma TG lipolysis by Angiopoietin-like proteins and GPIHBP1
    Lichtenstein, L.L. ; Kersten, A.H. - \ 2010
    Biochimica et Biophysica Acta. Molecular and Cell Biology of Lipids 1801 (2010)4. - ISSN 1388-1981 - p. 415 - 420.
    induced adipose factor - lipoprotein-lipase activity - endothelial-cell adhesion - activated receptor-alpha - ppar-gamma activators - coiled-coil domain - in-vivo - lipid concentrations - genetic-variation - target gene
    There is evidence that elevated plasma triglycerides (TG) serve as an independent risk factor for coronary heart disease. Plasma TG levels are determined by the balance between the rate of production of chylomicrons and VLDL in intestine and liver, respectively, and their rate of clearance in peripheral tissues. Lipolytic processing of TG-rich lipoproteins is mediated by the enzyme lipoprotein lipase (LPL), which is tethered to the capillary endothelium via heparin sulphate proteoglycans. In recent years the Angiopoietin-like proteins ANGPTL3 and ANGPTL4 have emerged as novel modulators of LPL activity. Studies in transgenic animals supported by in vitro experiments have demonstrated that ANGPTL3 and ANGPTL4 impair plasma TG clearance by inhibiting LPL activity. In humans, genetic variation within the ANGPTL3 and ANGPTL4 genes contributes to variation in plasma TG and HDL levels, thereby validating the importance of ANGPTLs in the regulation of lipoprotein metabolism in humans. Combined with the discovery of GPIHBP1 as a likely LPL anchor, these findings have led to a readjustment of the mechanism of LPL function. This review provides an overview of our current understanding of the role and regulation of ANGPTL3, ANGPTL4 and GPIHBP1, and places the newly acquired knowledge in the context of the established function and mechanism of LPL-mediated lipolysis
    Caloric Restriction and Exercise Increase Plasma ANGPTL4 Levels in Humans via Elevated Free Fatty Acids
    Kersten, A.H. ; Lichtenstein, L.L. ; Steenbergen, E. ; Mudde, C.M. ; Hendriks, H.F.J. ; Hesselink, M.K. ; Schrauwen, P. ; Müller, M.R. - \ 2009
    Arteriosclerosis Thrombosis and Vascular Biology 29 (2009). - ISSN 1079-5642 - p. 969 - 974.
    angiopoietin-like protein-4 - lipoprotein-lipase - adipose-tissue - target gene - inhibition - expression - metabolism - hyperlipidemia - overexpression - triglycerides
    Objective - Plasma lipoprotein levels are determined by the balance between lipoprotein production and clearance. Recently, angiopoietin-like protein 4 (ANGPTL4) was uncovered as a novel endocrine factor that potently raises plasma triglyceride levels by inhibiting triglyceride clearance. However, very little is known about ANGPTL4 in human. Here we set out to identify physiological determinants of plasma ANGPTL4 levels in humans, focusing on the effect of energy restriction and plasma FFAs. Methods and Results¿We developed an ELISA for quantitative measurement of ANGPTL4 in human plasma. Using this assay we found major variations in baseline plasma ANGPTL4 levels between individuals. Within an individual, plasma ANGPTL4 levels remain stable throughout the day but increase significantly in response to long-term fasting, chronic caloric restriction, and endurance exercise. Intralipid injection as well as treatment with a -adrenergic agonist, both of which lead to elevated plasma FFA levels, increased plasma ANGPTL4 levels compared to control treatment. Fatty acids markedly induced ANGPTL4 gene expression in rat hepatoma FAO cells, human primary myocytes, and mouse intestinal MSIE cells. Conclusion - In conclusion, our results show that plasma ANGPTL4 levels are increased by fasting, caloric restriction, and exercise, which is likely mediated by elevated plasma FFAs
    Angptl4 Upregulates Cholesterol Synthesis in Liver via Inhibition of LPL- and HL- Dependent Hepatic Cholesterol Uptake
    Lichtenstein, L.L. ; Berbee, J.F.P. ; Dijk, S.J. ; Willems van Dijk, K. ; Bensadoun, A. ; Kema, I.P. ; Voshol, P.J. ; Müller, M.R. ; Rensen, P.C.N. ; Kersten, A.H. - \ 2007
    Arteriosclerosis Thrombosis and Vascular Biology 27 (2007). - ISSN 1079-5642 - p. 2420 - 2427.
    angiopoietin-like protein-4 - triglyceride-rich lipoproteins - insulin-resistance - lipid-metabolism - target gene - lipase - mice - receptor - plasma - hyperlipidemia
    Background¿ Dysregulation of plasma lipoprotein levels may increase the risk for atherosclerosis. Recently, angiopoietin-like protein 4, also known as fasting-induced adipose factor Fiaf, was uncovered as a novel modulator of plasma lipoprotein metabolism. Here we take advantage of the fasting-dependent phenotype of Angptl4-transgenic (Angptl4-Tg) mice to better characterize the metabolic function of Angptl4. Methods and Results¿ In 24-hour fasted mice, Angptl4 overexpression increased plasma triglycerides (TG) by 24-fold, which was attributable to elevated VLDL-, IDL/LDL- and HDL-TG content. Angptl4 overexpression decreased post-heparin LPL activity by stimulating conversion of endothelial-bound LPL dimers to circulating LPL monomers. In fasted but not fed state, Angptl4 overexpression severely impaired LPL-dependent plasma TG and cholesteryl ester clearance and subsequent uptake of fatty acids and cholesterol into tissues. Consequently, hepatic cholesterol content was significantly decreased, leading to universal upregulation of cholesterol and fatty acid synthesis pathways and increased rate of cholesterol synthesis. Conclusions¿ The hypertriglyceridemic effect of Angptl4 is attributable to inhibition of LPL-dependent VLDL lipolysis by converting LPL dimers to monomers, and Angptl4 upregulates cholesterol synthesis in liver secondary to inhibition of LPL- and HL-dependent hepatic cholesterol uptake. The present study exploits the fasting-dependent phenotype of Angptl4-transgenic mice to characterize the function of Angptl4. We conclude that: (1) Angptl4 causes hypertriglyceridemia by inhibiting LPL-dependent VLDL lipolysis by converting LPL dimers to monomers, and (2) Angptl4 upregulates hepatic cholesterol synthesis secondary to inhibition of LPL- and HL-dependent hepatic cholesterol uptake.
    The Fasting-induced Adipose Factor/Angiopoietin-like Protein 4 Is Physically Associated with Lipoproteins and Governs Plasma Lipid Levels and Adiposity
    Mandard, S.J. ; Zandbergen, F.J. ; Straten, E. van; Wahli, W. ; Kuipers, F. ; Müller, M.R. ; Kersten, A.H. - \ 2006
    Journal of Biological Chemistry 281 (2006)2. - ISSN 0021-9258 - p. 934 - 944.
    angiopoietin-like protein-4 - high-density-lipoprotein - acylation stimulating protein - severe hypertriglyceridemia - triglyceride clearance - endothelial lipase - insulin-resistance - transgenic mice - target gene - expression
    Proteins secreted from adipose tissue are increasingly recognized to play an important role in the regulation of glucose metabolism. However, much less is known about their effect on lipid metabolism. The fasting-induced adipose factor (FIAF/angiopoietin-like protein 4/peroxisome proliferator-activated receptor angiopoietin-related protein) was previously identified as a target of hypolipidemic fibrate drugs and insulin-sensitizing thiazolidinediones. Using transgenic mice that mildly overexpress FIAF in peripheral tissues we show that FIAF is an extremely powerful regulator of lipid metabolism and adiposity. FIAF overexpression caused a 50% reduction in adipose tissue weight, partly by stimulating fatty acid oxidation and uncoupling in fat. In addition, FIAF overexpression increased plasma levels of triglycerides, free fatty acids, glycerol, total cholesterol, and high density lipoprotein (HDL)-cholesterol. Functional tests indicated that FIAF overexpression severely impaired plasma triglyceride clearance but had no effect on very low density lipoprotein production. The effects of FIAF overexpression were amplified by a high fat diet, resulting in markedly elevated plasma and liver triglycerides, plasma free fatty acids, and plasma glycerol levels, and impaired glucose tolerance in FIAF transgenic mice fed a high fat diet. Remarkably, in mice the full-length form of FIAF was physically associated with HDL, whereas truncated FIAF was associated with low density lipoprotein. In human both full-length and truncated FIAF were associated with HDL. The composite data suggest that via physical association with plasma lipoproteins, FIAF acts as a powerful signal from fat and other tissues to prevent fat storage and stimulate fat mobilization. Our data indicate that disturbances in FIAF signaling might be involved in dyslipidemia.
    Regulation of lipid metabolism via angiopoietin-like proteins
    Kersten, A.H. - \ 2005
    Biochemical Society Transactions 33 (2005)5. - ISSN 0300-5127 - p. 1059 - 1062.
    lipoprotein-lipase - target gene - in-vivo - receptor - expression - mice - angiogenesis - inhibition - angptl3 - hyperlipidemia
    Regulation of mammalian energy metabolism is an intricate process involving numerous hormones, transcription factors and signal transduction cascades. Much of the regulation occurs via secreted factors that relay information from one organ to another. One group of secreted factors that recently emerged as having a major impact on lipid and possibly glucose metabolism are the ANGPTLs (angiopoietin-like proteins). This includes ANGPTL3, ANGPTL4/FIAF (fasting-induced adipose factor), and ANGPTL6/AGF (angiopoietin-related growth factor). Although the receptors for these proteins have yet to be identified, it is nevertheless increasingly clear that these proteins have important effects on plasma triacylglycerol clearance, adipose tissue lipolysis, and adiposity. This review summarizes contemporary data on ANGPTLs with emphasis on the connection with energy metabolism
    Angiopoietin-like-4 is a potential angiogenic mediator in arthritis
    Hermann, L.M. ; Pinkerton, M. ; Jennings, K. ; Yang, L. ; Grom, A. ; Sowders, D. ; Kersten, A.H. ; Witte, D.P. ; Hirsch, R. ; Thornton, S. - \ 2005
    Clinical Immunology 115 (2005)1 sp. is.. - ISSN 1521-6616 - p. 93 - 101.
    collagen-induced arthritis - endothelial growth-factor - necrosis-factor-alpha - rheumatoid-arthritis - gene-transfer - target gene - expression - inhibition - protein - vegf
    Our previous studies of gene expression profiling during collagen-induced arthritis (CIA) indicated that the putative angiogenic factor Angptl4 was one of the most highly expressed mRNAs early in disease. To investigate the potential involvement of Angptl4 in CIA pathogenesis, Angptl4 protein levels were assessed at early stages of disease and its cellular sources were determined. In addition, the functional effects of mouse Angptl4 on endothelial cells were assessed. Angptl4 protein levels were higher in arthritic joints as compared to normal joints. In situ hybridization localized Angptl4 mRNA to stromal fibroblast-like cells within the inflamed synovium. Temporal expression of Angptl4 mRNA during CIA was similar to that of key angiogenic factors, including structurally related angiopoietin 1. Recombinant mouse Angptl4 promoted endothelial cell survival and formation of tubule-like structures. These functional effects of Angptl4, combined with very high expression at early stages of CIA, suggest a role for Angptl4 in angiogenesis in arthritis
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