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.
The ER-Associated Degradation Adaptor Protein Sel1L Regulates LPL Secretion and Lipid Metabolism
Sha, H. ; Sun, S. ; Francisco, A. ; Ehrhardt, N. ; Xue, Z.Q. ; Liu, L. ; Mattijssen, F.B.J. ; Kersten, A.H. - \ 2014
Cell Metabolism 20 (2014)3. - ISSN 1550-4131 - p. 458 - 470.
reticulum-associated-degradation - endoplasmic-reticulum - lipoprotein-lipase - caenorhabditis-elegans - membrane-protein - stress - deficiency - maturation - disease - liver
Sel1L is an essential adaptor protein for the E3 ligase Hrd1 in the endoplasmic reticulum (ER)-associated degradation (ERAD), a universal quality-control system in the cell; but its physiological role remains unclear. Here we show that mice with adipocyte-specific Sel1L deficiency are resistant to diet-induced obesity and exhibit postprandial hypertriglyceridemia. Further analyses reveal that Sel1L is indispensable for the secretion of lipoprotein lipase (LPL), independent of its role in Hrd1-mediated ERAD and ER homeostasis. Sel1L physically interacts with and stabilizes the LPL maturation complex consisting of LPL and lipase maturation factor 1 (LMF1). In the absence of Sel1L, LPL is retained in the ER and forms protein aggregates, which are degraded primarily by autophagy. The Sel1L-mediated control of LPL secretion is also seen in other LPL-expressing cell types including cardiac myocytes and macrophages. Thus, our study reports a role of Sel1L in LPL secretion and systemic lipid metabolism.
Fatty acid-inducible ANGPTL4 governs lipid metabolic response to exercise
Catoire, M. ; Alex, S. ; Paraskevopulos, N. ; Mattijssen, F.B.J. ; Mensink, M.R. ; Kersten, A.H. - \ 2014
Proceedings of the National Academy of Sciences of the United States of America 111 (2014)11. - ISSN 0027-8424 - p. E1043 - E1052.
human skeletal-muscle - angiopoietin-like protein-4 - lipoprotein-lipase - adipose-tissue - insulin-resistance - postprandial triacylglycerol - endurance exercise - in-vivo - expression - receptor
Physical activity increases energy metabolism in exercising muscle. Whether acute exercise elicits metabolic changes in nonexercising muscles remains unclear. We show that one of the few genes that is more highly induced in nonexercising muscle than in exercising human muscle during acute exercise encodes angiopoietin-like 4 (ANGPTL4), an inhibitor of lipoprotein lipase-mediated plasma triglyceride clearance. Using a combination of human, animal, and in vitro data, we show that induction of ANGPTL4 in nonexercising muscle is mediated by elevated plasma free fatty acids via peroxisome proliferator-activated receptor-d, presumably leading to reduced local uptake of plasma triglyceride-derived fatty acids and their sparing for use by exercising muscle. In contrast, the induction of ANGPTL4 in exercising muscle likely is counteracted via AMP-activated protein kinase (AMPK)-mediated down-regulation, promoting the use of plasma triglycerides as fuel for active muscles. Our data suggest that nonexercising muscle and the local regulation of ANGPTL4 via AMPK and free fatty acids have key roles in governing lipid homeostasis during exercise.
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.
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.
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.
Detailed transcriptomics analysis of the effect of dietary fatty acids on gene expression in the heart
Georgiadi, A. ; Boekschoten, M.V. ; Muller, M.R. ; Kersten, A.H. - \ 2012
Physiological genomics 44 (2012). - ISSN 1094-8341 - p. 352 - 361.
proliferator-activated receptors - ppar-alpha - heme oxygenase-1 - lipoprotein-lipase - cardiac myocytes - lipid-metabolism - transgenic mice - rat-heart - triglycerides - eicosanoids
Fatty acids comprise the primary energy source for the heart and are mainly taken up via hydrolysis of circulating triglyceride-rich lipoproteins. While most of the fatty acids entering the cardiomyocyte are oxidized, a small portion is involved in altering gene transcription to modulate cardiometabolic functions. So far, no in vivo model has been developed enabling study of the transcriptional effects of specific fatty acids in the intact heart. In the present study, mice were given a single oral dose of synthetic triglycerides composed of one single fatty acid. Hearts were collected 6 h thereafter and used for whole genome gene expression profiling. Experiments were conducted in wild-type and peroxisome proliferator-activated receptor (PPAR)a-/- mice to allow exploration of the specific contribution of PPARa. It was found that: 1) C18:3 had the most pronounced effect on cardiac gene expression. 2) The largest similarity in gene regulation was observed between C18:2 and C18:3. Large similarity was also observed between PPARa agonist Wy14643 and C22:6. 3) Many genes were regulated by one particular treatment only. Genes regulated by one particular treatment showed large functional divergence. 4) The majority of genes responding to fatty acid treatment were regulated in a PPARa-dependent manner, emphasizing the importance of PPARa in mediating transcriptional regulation by fatty acids in the heart. 5) Several genes were robustly regulated by all or many of the fatty acids studied, mostly representing well-described targets of PPARs (e.g., Acot1, Angptl4, Ucp3) but also including Zbtb16/PLZF, a transcription factor crucial for natural killer T cell function. 6) Deletion and activation of PPARa had a major effect on expression of numerous genes involved in metabolism and immunity. Our analysis demonstrates the marked impact of dietary fatty acids on gene regulation in the heart via PPARa
Induction of cardiac Angpt14 by dietary fatty acids Is mediated by peroxisome proliferator-activated receptor ß/d and protects against fatty acid-induced oxidative stress
Georgiadi, A. ; Lichtenstein, L.L. ; Degenhardt, T. ; Boekschoten, M.V. ; Bilsen, M. van; Desvergne, B. ; Müller, M.R. ; Kersten, A.H. - \ 2010
Circulation Research 106 (2010). - ISSN 0009-7330 - p. 1712 - 1721.
angiopoietin-like protein-4 - lipoprotein-lipase - gene-expression - ppar-gamma - lipotoxic cardiomyopathy - triglyceride-metabolism - target genes - mouse heart - plasma - alpha
Rationale: Although dietary fatty acids are a major fuel for the heart, little is known about the direct effects of dietary fatty acids on gene regulation in the intact heart. Objective: To study the effect of dietary fatty acids on cardiac gene expression and explore the functional consequences. Methods and Results: Oral administration of synthetic triglycerides composed of one single fatty acid altered cardiac expression of numerous genes, many of which are involved in the oxidative stress response. The gene most significantly and consistently upregulated by dietary fatty acids encoded Angiopoietin-like protein (Angptl)4, a circulating inhibitor of lipoprotein lipase expressed by cardiomyocytes. Induction of Angptl4 by the fatty acid linolenic acid was specifically abolished in peroxisome proliferator-activated receptor (PPAR)beta/delta(-/-) and not PPAR alpha(-/-) mice and was blunted on siRNA-mediated PPAR beta/delta knockdown in cultured cardiomyocytes. Consistent with these data, linolenic acid stimulated binding of PPAR beta/delta but not PPAR alpha to the Angptl4 gene. Upregulation of Angptl4 resulted in decreased cardiac uptake of plasma triglyceride-derived fatty acids and decreased fatty acid-induced oxidative stress and lipid peroxidation. In contrast, Angptl4 deletion led to enhanced oxidative stress in the heart, both after an acute oral fat load and after prolonged high fat feeding. Conclusions: Stimulation of cardiac Angptl4 gene expression by dietary fatty acids and via PPAR beta/delta is part of a feedback mechanism aimed at protecting the heart against lipid overload and consequently fatty acid-induced oxidative stress. (Circ Res. 2010; 106: 1712-1721.)
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
Fasting-induced adipose factor/angiopoietin-like protein 4: a potential target for dyslipidemia?
Zandbergen, F.J. ; Dijk, S. van; Müller, M.R. ; Kersten, A.H. - \ 2006
Future Lipidology 1 (2006)2. - ISSN 1746-0875 - p. 227 - 236.
lipoprotein-lipase - ppar-alpha - in-vivo - receptor - gene - angiogenesis - angptl3 - mice - metabolism - inhibition
Recently, several proteins with homology to angiopoietins have been discovered. Three members of this new group, designated angiopoietin-like proteins (ANGPTLs), have been linked to regulation of energy metabolism. This review will focus on the fasting-induced adipose factor (FIAF)/ANGPTL4 as an important modulator of plasma lipid metabolism. FIAF/ANGPTL4 is a direct target of the insulin-sensitizing thiazolidinediones and hypolipidemic fibrate drugs. The collective data suggests that FIAF/ANGPTL4 plays an important role in the systemic partitioning of fatty acids, especially under fasting conditions. FIAF/ANGPTL4 prevents the clearance of plasma triglycerides and appears to stimulate adipose tissue lipolysis, resulting in lipids being redirected from storage to the circulation. FIAF/ANGPTL4 thus represents an interesting candidate for therapeutic targeting of dyslipidemia. It can be hypothesized that alterations in FIAF/ANGPTL4 signaling might be involved in dyslipidemia. While the importance of FIAF/ANGPTL4 in lipoprotein metabolism is well established, the effects of FIAF/ANGPTL4 on glucose homeostasis currently remain ambiguous
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
The Direct Peroxisome Proliferator-activated Receptor Target Fasting-induced Adipose Factor (FIAF/PGAR/ANGPTL4) Is Present in Blood Plasma as a Truncated Protein That Is Increased by Fenofibrate Treatment
Mandard, S.J. ; Zandbergen, F.J. ; Tan, N.S. ; Escher, P. ; Patsouris, D.A. ; Müller, M.R. ; Kersten, A.H. - \ 2004
Journal of Biological Chemistry 279 (2004)33. - ISSN 0021-9258 - p. 34411 - 34420.
angiopoietin-like protein-4 - necrosis-factor-alpha - adipocyte differentiation - proprotein convertases - lipoprotein-lipase - lipid-metabolism - secretory factor - in-vivo - gene - expression
The fasting-induced adipose factor (FIAF, ANGPTL4, PGAR, HFARP) was previously identified as a novel adipocytokine that was up-regulated by fasting, by peroxisome proliferator-activated receptor agonists, and by hypoxia. To further characterize FIAF, we studied regulation of FIAF mRNA and protein in liver and adipose cell lines as well as in human and mouse plasma. Expression of FIAF mRNA was up-regulated by peroxisome proliferator-activated receptor alpha( PPARalpha) and PPARbeta/delta agonists in rat and human hepatoma cell lines and by PPARgamma and PPARbeta/delta agonists in mouse and human adipocytes. Transactivation, chromatin immunoprecipitation, and gel shift experiments identified a functional PPAR response element within intron 3 of the FIAF gene. At the protein level, in human and mouse blood plasma, FIAF was found to be present both as the native protein and in a truncated form. Differentiation of mouse 3T3-L1 adipocytes was associated with the production of truncated FIAF, whereas in human white adipose tissue and SGBS adipocytes, only native FIAF could be detected. Interestingly, truncated FIAF was produced by human liver. Treatment with fenofibrate, a potent PPARalpha agonist, markedly increased plasma levels of truncated FIAF, but not native FIAF, in humans. Levels of both truncated and native FIAF showed marked interindividual variation but were not associated with body mass index and were not influenced by prolonged semistarvation. Together, these data suggest that FIAF, similar to other adipocytokines such as adiponectin, may partially exert its function via a truncated form.
|Lipase in milk, curd and cheese
Geurts, T.J. ; Lettink, F.J. ; Wouters, J.T.M. - \ 2003
Milchwissenschaft-Milk Science International 58 (2003). - ISSN 0026-3788 - p. 62 - 66.
lipoprotein-lipase - flavor compounds - lipolysis - goats - raw
Presence of lipase in milk, curd, whey and cheese was studied. A small amount of the product was added to a large volume of lipase-free whole milk that had been made sensitive to lipolysis by homogenization. Increase of the acidity of the fat in the mixture, determined after incubation, was interpreted as enzyme activity being present in the product concerned. Results obtained in this way showed that lipase was present in raw milk and in the curd and whey made of it, but that the bulk of the enzyme disappeared quickly from the curd during Gouda cheese making, as a result of several factors including scalding of the curd, whey removal and pH decrease. By using this method no lipase could be detected in ripened Gouda cheese, made of raw milk. Furthermore, no potential lipolytic activity was measured in ripened danish blue cheese, but it was in ripened Camembert and Brie, all of these cheeses being made of pasteurized milk. Obviously, the presence of active milk lipase in ripening cheese is by no means self-evident.