Circulating angiopoietin-like 4 links proteinuria with hypertriglyceridemia in nephrotic syndrome
Clement, L.C. ; Mace, C. ; Avila-Casado, C. ; Joles, J.A. ; Kersten, A.H. ; Chugh, S.S. - \ 2014
Nature Medicine 20 (2014)1. - ISSN 1078-8956 - p. 37 - 46.
lipoprotein-lipase - fatty-acids - gene-expression - adipose-tissue - angptl4 - disease - serum - rats - mice - glomeruli
The molecular link between proteinuria and hyperlipidemia in nephrotic syndrome is not known. We show in the present study that plasma angiopoietin-like 4 (Angptl4) links proteinuria with hypertriglyceridemia through two negative feedback loops. In previous studies in a rat model that mimics human minimal change disease, we observed localized secretion by podocytes of hyposialylated Angptl4, a pro-proteinuric form of the protein. But in this study we noted high serum levels of Angptl4 (presumably normosialylated based on a neutral isoelectric point) in other glomerular diseases as well. Circulating Angptl4 was secreted by extrarenal organs in response to an elevated plasma ratio of free fatty acids (FFAs) to albumin when proteinuria reached nephrotic range. In a systemic feedback loop, these circulating pools of Angptl4 reduced proteinuria by interacting with glomerular endothelial alpha(v)beta(5) integrin. Blocking the Angptl4-beta(5) integrin interaction or global knockout of Angptl4 or beta(5) integrin delayed recovery from peak proteinuria in animal models. But at the same time, in a local feedback loop, the elevated extrarenal pools of Angptl4 reduced tissue FFA uptake in skeletal muscle, heart and adipose tissue, subsequently resulting in hypertriglyceridemia, by inhibiting lipoprotein lipase (LPL)-mediated hydrolysis of plasma triglycerides to FFAs. Injecting recombinant human ANGPTL4 modified at a key LPL interacting site into nephrotic Buffalo Mna and Zucker Diabetic Fatty rats reduced proteinuria through the systemic loop but, by bypassing the local loop, without increasing plasma triglyceride levels. These data show that increases in circulating Angptl4 in response to nephrotic-range proteinuria reduces the degree of this pathology, but at the cost of inducing hypertriglyceridemia, while also suggesting a possible therapy to treat these linked pathologies.
Dietary modulation of plasma angiopoietin-like protein 4 concentrations in healthy volunteers and in patients with type 2 diabetes
Jonker, J.T. ; Smit, J.W.A. ; Hammer, S. ; Snel, M. ; Meer, R. van der; Lamb, H.J. ; Mattijssen, F.B.J. ; Mudde, C.M. ; Jazet, I.M. ; Dekkers, O.M. ; Roos, A. de; Romijn, J.A. ; Kersten, A.H. ; Rensen, P.C.N. - \ 2013
American Journal of Clinical Nutrition 97 (2013)2. - ISSN 0002-9165 - p. 255 - 260.
myocardial triglyceride content - free fatty-acids - lipoprotein-lipase - caloric restriction - diastolic function - angptl4 - mice - hyperlipidemia - inhibition - humans
Background: Angiopoietin-like protein 4 (ANGPTL4) has been identified as an inhibitor of lipoprotein lipase. Preliminary data suggest that plasma nonesterified fatty acids (NEFAs) raise plasma ANGPTL4 concentrations in humans. Objective: The objective was to assess plasma ANGPTL4 concentrations after various nutritional interventions that increase NEFA concentrations in healthy subjects and in patients with type 2 diabetes mellitus. Design: We studied 4 groups, both at baseline and after 3 d of either fasting (n = 22 healthy men), a very-low-calorie diet (VLCD; n = 10 healthy men and n = 10 patients with diabetes), or a high-fat, high-energy diet (HFED; n = 15 healthy men). Plasma ANGPTL4, NEFA, and triglyceride concentrations were measured. Results: In healthy men, a VLCD increased ANGPTL4 from 13.2 (IQR: 8.1-24.2) at baseline to 18.2 (16.7-33.4) ng/mL (P <0.05), fasting increased ANGPTL4 from 10.6 (7.6-17.6) to 28.0 (23.1-35.0) ng/mL (P <0.05), and an HFED increased ANGPTL4 from 13.9 (8.2-22.0) to 17.2 (11.2-23.6) ng/mL (P <0.05). In men with diabetes, a VLCD also increased ANGPTL4, from 10.9 +/- 2.4 to 19.2 +/- 3.2 ng/mL (P <0.05). All interventions significantly increased plasma NEFAs in both healthy men and patients with diabetes. The change in ANGPTL4 positively correlated with the change in NEFA concentrations (beta = 0.048, P <0.001) and negatively correlated with the change in plasma triglycerides (beta = -0.051, P = 0.01). Conclusions: Three days of either fasting, a VLCD, or an HFED increased plasma ANGPTL4 concentrations in healthy men, concomitantly with increased plasma NEFA concentrations. Similarly, a VLCD in patients with diabetes increased ANGPTL4 concentrations, concomitantly with increased NEFA concentrations. Am J Clin Nutr 2013;97:255-60.
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.
Overexpression of angiopoietin-like protein 4 protects against atherosclerosis development
Georgiadi, A. ; Wang, Y. ; Stienstra, R. ; Tjeerdema, N. ; Janssen, A. ; Stalenhoef, A. ; Vliet, A. van der; Roos, J.A. de; Tamsma, J.T. ; Smit, J.W. ; Tan, N.S. ; Müller, M.R. ; Rensen, P.C. ; Kersten, A.H. - \ 2013
Arteriosclerosis Thrombosis and Vascular Biology 33 (2013)7. - ISSN 1079-5642 - p. 1529 - 1537.
low-density-lipoprotein - mouse peritoneal-macrophages - foam cell-formation - transgenic mice - lipase - angptl4 - expression - gene - hyperlipoproteinemia - hyperlipidemia
Objective—Macrophage foam cells play a crucial role in several pathologies including multiple sclerosis, glomerulosclerosis, and atherosclerosis. Angiopoietin-like protein 4 (Angptl4) was previously shown to inhibit chyle-induced foam cell formation in mesenteric lymph nodes. Here we characterized the regulation of Angptl4 expression in macrophages and examined the impact of Angptl4 on atherosclerosis development. Approach and Results—Macrophage activation elicited by pathogen-recognition receptor agonists decreased Angptl4 expression, whereas lipid loading by intralipid and oxidized low-density lipoprotein increased Angptl4 expression. Consistent with an antilipotoxic role of Angptl4, recombinant Angptl4 significantly decreased uptake of oxidized low-density lipoprotein by macrophages, via lipolysis-dependent and -independent mechanisms. Angptl4 protein was detectable in human atherosclerotic lesions and localized to macrophages. Transgenic overexpression of Angptl4 in atherosclerosis-prone apolipoprotein E*3-Leiden mice did not significantly alter plasma cholesterol and triglyceride levels. Nevertheless, Angptl4 overexpression reduced lesion area by 34% (P
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.
Stabilizing lipoprotein lipase
Kersten, A.H. ; Bensadoun, A. - \ 2009
Journal of Lipid Research 50 (2009)12. - ISSN 0022-2275 - p. 2335 - 2336.
angiopoietin-like protein-4 - metabolism - angptl4 - mice - hyperlipidemia - chylomicrons - lipolysis - gpihbp1 - binding