Caloric Restriction and Exercise Increase Plasma ANGPTL4 Levels in Humans via Elevated Free Fatty Acids

Kersten, Sander; Lichtenstein, Laeticia; Steenbergen, Emma; Mudde, Karin; Hendriks, H.; Hesselink, Matthijs K.C.; Schrauwen, Patrick; Müller, Michael

doi:10.1161/atvbaha.108.182147

Cited by 180 publications

(211 citation statements)

References 34 publications

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“…The positive association between FFA and plasma ANGPTL4 was previously reported ( 21,23 ). Our data confi rm these results and strengthen them via the observed association with WHR.…”

Section: Effect Of Heparin On Human Angptl 3 and 4 In Vivo And In Vitrosupporting

confidence: 91%

“…To measure the concentration of human ANGPTL4 in circulation we have developed a noncompetitive direct ELISA using the DuoSet Elisa hANGPTL4 (RnD Systems) and the protocol described by Kersten et al with some modifi cations ( 21 ). We used the goat anti-human ANGPTL4 as a capture antibody to coat 96-well plates, 100 l/well (1.6 g/ml in PBS) overnight at 4°C.…”

Section: Determination Of Angptl4 Concentrationmentioning

confidence: 99%

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Quantitation of serum angiopoietin-like proteins 3 and 4 in a Finnish population sample

Robciuc

Tahvanainen

Jauhiainen

et al. 2010

Journal of Lipid Research

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Dysregulation of lipid metabolism is closely related with a number of pathological states including atherosclerosis, obesity, and insulin resistance. An extensive amount of data relates elevation of cholesterol and triglycerides (TG) in apolipoprotein (apo)B-containing particles such as VLDL and LDL to increased risk for atherosclerosis. Epidemiological and clinical studies have provided strong evidence that a low level of cholesterol in HDL is also a major risk factor for the development of atherosclerosis ( 4, 5 ). LPL is a key molecule involved in the hydrolysis of TG in VLDL and chylomicrons and in the clearance of these particles from circulation ( 6 ). In vitro observations as well as animal models have fi rmly established ANGPTL 3 and 4 as potent inhibitors of LPL ( 7,8 ). These studies are supported by genetic studies in humans that have associated mutations in these two proteins with circulating TG levels ( 9-11 ). Endothelial lipase (EL), a member of the triglyceride lipase gene family, has been demonstrated to infl uence the levels of HDL in circulation ( 12 ). Recently, it was shown that ANGPTL3 can inhibit EL and thereby increase the levels of HDL ( 13 ).Epidemiological studies clearly demonstrate that obesity has increased worldwide. Obesity increases the risk of diabetes, heart disease, fatty liver, and even some forms of cancer. It is therefore important to better understand the biological basis of obesity in order to aid its prevention and treatment. Several studies in mice have shown that ANGPTL4 can act as a powerful signal from adipose and other tissues to prevent fat storage and stimulate fat mobilization ( 14, 15 ). There is a large body of evidence demonstrating that ANGPTL 3 and 4 play major roles in rodent energy metabolism. However, there is limited information on the physiological roles of ANGPTL 3 and 4 in humans. The anthropometric and biochemical parameters of subjects were characterized in detail. ANGPTL 3 and 4 levels were determined using the developed ELISAs. The intraand inter-assay coeffi cients of variation for the assays were less than 15%. The average serum concentration of ANGPTL3 was 368 ± 168 ng/ml (mean ± SD) and for ANGPTL4 it was 18 ± 23 ng/ml (mean ± SD). ANGPTL4 serum levels displayed high variability between individuals ranging from 2 to 158 ng/ml. In post-heparin plasma, both ANGPTL 3 and 4 were increased. Low levels of ANGPTL3 were associated with decreased HDL-cholesterol and increased triglyceride levels. ANGPTL4 levels were positively correlated with FFAs ( P = 0.044) and waist-hip ratio ( P = 0.016). The developed ELISAs will be important tools to clarify the role of ANGPTL 3 and 4 in human energy metabolism and partitioning of triglycerides between sites of storage (adipose tissue) and oxidation (skeletal and cardiac muscle). Angiopoietin-like (ANGPTL) proteins 3 and 4 belong to a family of proteins that share a common modular structure consisting of an N-terminal signal sequence, a coiledcoil domain and a large fi brinogen/angiopoietin-like domain ( 1, 2 ...

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“…The positive association between FFA and plasma ANGPTL4 was previously reported ( 21,23 ). Our data confi rm these results and strengthen them via the observed association with WHR.…”

Section: Effect Of Heparin On Human Angptl 3 and 4 In Vivo And In Vitrosupporting

confidence: 91%

Section: Determination Of Angptl4 Concentrationmentioning

confidence: 99%

Quantitation of serum angiopoietin-like proteins 3 and 4 in a Finnish population sample

Robciuc

Tahvanainen

Jauhiainen

et al. 2010

Journal of Lipid Research

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“…4 A and B, Right), levels of which also increased during one-legged cycling (Fig. 4D) and which previously had been shown to induce Angptl4 mRNA potently in various cell types, including cultured myocytes (15)(16)(17)(18). In support of a role of plasma FFA in induction of ANGPTL4 gene expression in human muscle, raising plasma FFA levels by salbutamol treatment markedly increased muscle ANGPTL4 expression, and this increase was largely blunted when salbutamol was coadministered with the lipolysis inhibitor acipimox (Fig.…”

Section: Significancesupporting

confidence: 52%

Fatty acid-inducible ANGPTL4 governs lipid metabolic response to exercise

Catoire

Alex

Paraskevopulos

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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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-δ, 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.

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“…It is well known that fatty acids up-regulate Angptl4 gene expression via interaction with peroxisome proliferator-activated nuclear receptors (48,49). The observations in this study suggest that fatty acids may directly affect the ability of the Angptl4 protein to modulate the activity of LPL.…”

Section: Discussionsupporting

confidence: 52%

Fatty Acids Bind Tightly to the N-terminal Domain of Angiopoietin-like Protein 4 and Modulate Its Interaction with Lipoprotein Lipase

Robal

Larsson

Martin

et al. 2012

Journal of Biological Chemistry

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Background: Angiopoietin-like protein 4 regulates plasma triglyceride metabolism by modulating the activity of lipoprotein lipase. Results: Fatty acids bind tightly to the N-terminal domain of angiopoietin-like protein 4 and reduce its effect on lipoprotein lipase. Conclusion: Fatty acids play a role in modulating the effects of angiopoietin-like protein 4. Significance: A novel mechanism for regulation of the action of angiopoietin-like protein 4 is proposed.

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Caloric Restriction and Exercise Increase Plasma ANGPTL4 Levels in Humans via Elevated Free Fatty Acids

Cited by 180 publications

References 34 publications

Quantitation of serum angiopoietin-like proteins 3 and 4 in a Finnish population sample

Quantitation of serum angiopoietin-like proteins 3 and 4 in a Finnish population sample

Fatty acid-inducible ANGPTL4 governs lipid metabolic response to exercise

Fatty Acids Bind Tightly to the N-terminal Domain of Angiopoietin-like Protein 4 and Modulate Its Interaction with Lipoprotein Lipase

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