Induction of Cardiac Angptl4 by Dietary Fatty Acids Is Mediated by Peroxisome Proliferator-Activated Receptor β/δ and Protects Against Fatty Acid–Induced Oxidative Stress

Georgiadi, Anastasia; Lichtenstein, Laeticia; Degenhardt, Tatjana; Boekschoten, Mark V.; Bilsen, Marc van; Desvergne, Béatrice; Müller, Michael; Kersten, Sander

doi:10.1161/circresaha.110.217380

Cited by 124 publications

(90 citation statements)

References 52 publications

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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: 57%

“…After three washing steps with PBS, sections were incubated for 45 min at room temperature with the appropriate fluorescent-labeled secondary antibodies. The specificity of the antibody for ANGPTL4 was demonstrated previously via immunoblot of human plasma using appropriate peptide controls and was corroborated by immunochemical and immunofluorescence staining of ANGPTL4 in human heart, intestine, and skin wounds, using appropriate negative controls (15,47,48).…”

Section: Methodsmentioning

confidence: 53%

“…Although the abundant plasma FFA are oxidized efficiently in exercising muscle, their increase leads to elevated intramuscular fat storage in nonexercising muscle, possibly leading to lipotoxicity (27). Previously, we found that ANGPTL4 functions as a fatty acid-inducible antilipotoxic factor in cardiomyocytes and macrophages (15,28). The present work suggests that the exercise-induced increase in plasma FFA stimulates ANGPTL4 synthesis in nonexercising human muscle, leading to local inhibition of LPL activity and diminished uptake of fatty acids derived from plasma TG in compensation for elevated uptake of plasma FFA, presumably to mitigate lipid overload and associated lipotoxicity in nonexercising muscle during prolonged exercise.…”

Section: Discussionmentioning

confidence: 96%

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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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123

165

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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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Section: Significancesupporting

confidence: 57%

Section: Methodsmentioning

confidence: 53%

Section: Discussionmentioning

confidence: 96%

See 1 more Smart Citation

Fatty acid-inducible ANGPTL4 governs lipid metabolic response to exercise

Catoire

Alex

Paraskevopulos

et al. 2014

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

Self Cite

123

165

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show abstract

“…The expression of angptl4 is up-regulated by per-oxisome proliferator-activated receptors, which in turn are activated by free fatty acids and other ligands (27,28). Angptl4 is a strong candidate for the tissue-specific, post-translational regulation of LPL activity that is necessary for directing uptake of blood lipids according to the needs of different tissues of the body (2,29) and for protecting tissues against deleterious effects of lipid overload (27,28).…”

mentioning

confidence: 99%

Apolipoproteins C-I and C-III Inhibit Lipoprotein Lipase Activity by Displacement of the Enzyme from Lipid Droplets

Larsson

Vorrsjö

Talmud

et al. 2013

Journal of Biological Chemistry

147

128

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Background: Apolipoproteins (apo) C-I and C-III regulate plasma triglyceride metabolism by inhibition of lipoprotein lipase (LPL) activity. Results: ApoC-I or apoC-III prevents LPL from binding to lipid droplets. This results in inhibition of LPL. Conclusion: Inhibition of LPL activity by apoC-I and apoC-III is due to displacement of LPL from lipid droplets. Significance: Our proposed mechanism explains several effects of these apolipoproteins on lipoprotein metabolism.

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“…PPARδ also has protective effect against fatty acid-induced oxidative stress and lipid peroxidation by affecting expression of the gene encoding angiopoietin-like protein (Angptl) 4, a circulating inhibitor of lipoprotein lipase. 15 Therefore, PPARD rs7770619 and MDA levels may be connected by regulating the effects of PPARδ on Angptl4. However, exact mechanisms of the association between PPARD rs7770619 and MDA levels through endogenous antioxidants or Angptl4 need to be further investigated.…”

Section: Diabetes and Vascular Disease Research 15(4)mentioning

confidence: 99%

PPARD rs7770619 polymorphism in a Korean population: Association with plasma malondialdehyde and impaired fasting glucose or newly diagnosed type 2 diabetes

Kim

Yoo

Sun

et al. 2018

Diabetes and Vascular Disease Research

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Both the peroxisome proliferator-activated receptor delta gene (PPARD) and malondialdehyde plasma concentrations may play a role in impaired glucose metabolism. The aim of this work was to determine whether PPARD is a candidate gene for impaired fasting glucose or type 2 diabetes and whether a particular genetic variant shows association with plasma malondialdehyde levels. Among the 10 single-nucleotide polymorphisms that were most strongly associated with malondialdehyde, the rs7770619 polymorphism in PPARD was analysed in 1798 subjects with normal fasting glucose, impaired fasting glucose and newly diagnosed type 2 diabetes. Our data demonstrate that the CT genotype of the rs7770619 is associated with a lower risk of impaired fasting glucose or type 2 diabetes together with lower plasma levels of malondialdehyde in both groups (p < 0.05). Glucose levels and the rs7770619 are significantly associated in individuals with normal fasting glucose, and a trend towards an association between glucose levels and rs7770619 is also observed in individuals with impaired fasting glucose or type 2 diabetes. In conclusion, PPARD rs7770619 is a novel candidate variant for impaired fasting glucose and type 2 diabetes and shows association with malondialdehyde levels. Future work is required to understand the mechanisms for these associations and the clinical implications of our findings.

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Induction of Cardiac Angptl4 by Dietary Fatty Acids Is Mediated by Peroxisome Proliferator-Activated Receptor β/δ and Protects Against Fatty Acid–Induced Oxidative Stress

Cited by 124 publications

References 52 publications

Fatty acid-inducible ANGPTL4 governs lipid metabolic response to exercise

Fatty acid-inducible ANGPTL4 governs lipid metabolic response to exercise

Apolipoproteins C-I and C-III Inhibit Lipoprotein Lipase Activity by Displacement of the Enzyme from Lipid Droplets

PPARD rs7770619 polymorphism in a Korean population: Association with plasma malondialdehyde and impaired fasting glucose or newly diagnosed type 2 diabetes

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