Review
Regulation of lipoprotein lipase by Angptl4

https://doi.org/10.1016/j.tem.2013.12.005Get rights and content

Highlights

  • Angptl4 is a main regulator of LPL activity in a variety of tissues during different physiological situations, including fasting.

  • Angptl4 inhibits LPL activity via a mechanism that involves dimer-to-monomer conversion of the LPL protein and/or competitive inhibition.

  • Cleavage and oligomerization of Angptl4 may alter the capacity of Angptl4 to inhibit LPL activity.

  • Angptl4 is under sensitive transcriptional control of fatty acids and the fatty acid-activated PPARs.

Triglyceride (TG)-rich chylomicrons and very low density lipoproteins (VLDL) distribute fatty acids (FA) to various tissues by interacting with the enzyme lipoprotein lipase (LPL). The protein angiopoietin-like 4 (Angptl4) is under sensitive transcriptional control by FA and the FA-activated peroxisome proliferator activated receptors (PPARs), and its tissue expression largely overlaps with that of LPL. Growing evidence indicates that Angptl4 mediates the physiological fluctuations in LPL activity, including the decrease in adipose tissue LPL activity during fasting. This review focuses on the major ambiguities concerning the mechanism of LPL inhibition by Angptl4, as well as on the physiological role of Angptl4 in lipid metabolism, highlighting its function in a variety of tissues, and uses this information to make suggestions for further research.

Section snippets

Regulation of plasma TG clearance

FA are a principal fuel for numerous cell types and serve as substrate for energy storage in fat tissue. A major portion of FA taken up by cells is transported through the blood as TG within chylomicrons and VLDL (see Glossary). Chylomicrons are formed from dietary TG and cholesterol in enterocytes and reach the bloodstream after passing through the splanchnic lymphatic system. VLDL are assembled from TG synthesized in liver and are secreted directly into the blood. In the circulation,

Structure of Angptl4

Similarly to other family members, Angptl4 can be divided into distinct regions: an N-terminal signal peptide, a region containing two separate coiled-coil domains, a linker region, and a large C-terminal fibrinogen-like domain 19, 20. During evolution, the C-terminal and N-terminal regions were present separately in different organisms, suggesting that the different domains of Angptl4 may have distinct physiological functions [20]. In agreement with that notion, full-length Angptl4 (flAngptl4,

Role of Angptl4 in physiological regulation of lipid metabolism

LPL and Angptl4 are regulated by changes in nutritional state in a tissue-specific manner, reflecting the different functions of these tissues and the corresponding variations in physiological requirements for lipids 13, 14, 46. Below, we discuss current knowledge on the regulation of Angptl4 and LPL in response to various physiological stimuli and address the importance of Angptl4 in lipid uptake. An overview of the role of Angptl4 in physiological regulation of lipid metabolism is presented

Clinical perspectives of Angptl4

In support of the mouse studies, genetic studies have provided support for a similar function of Angptl4 in humans. Specifically, a genetic loss-of-function variant of ANGPTL4 (E40K) that is found in 3% of European Americans is associated with reduced plasma TG levels [86]. Remarkably, none of the genome-wide association studies performed so far have linked single-nucleotide polymorphisms (SNPs) in or near the ANGPTL4 gene to plasma TG levels. Likewise, so far no positive correlation has been

Concluding remarks and future perspectives

In the past decade, angiopoietin-like proteins have been demonstrated to regulate plasma TG levels powerfully in mice and humans. The elucidation of these proteins as inhibitors of LPL activity has led to a paradigm shift in how clearance of circulating TG and thereby tissue uptake of FA are regulated. Most of our understanding of angiopoietin-like proteins has resulted from detailed study of Angptl4. It is becoming increasingly clear that a major portion of the physiological variation in LPL

Acknowledgments

We would like to thank Gunilla Olivecrona for fruitful discussion. This study was supported by grant 12CVD04 from the Fondation Leducq and by The Netherlands Organisation for Health Research and Development (NWO ZonMW).

Glossary

Angiopoietin-like 4 (Angptl4)
a ∼45–65 kDa glycosylated and secreted protein, a member of the angiopoietin-like gene family. Angptl4 contains a coiled-coil N-terminal domain and a fibrinogen-like C-terminal domain and is directly involved in the regulation of lipid metabolism via the inhibition of LPL activity. Angptl4 has also been linked to endothelial function, tumor biology, and wound healing.
Chylomicrons
large lipoproteins with high TG content that transport dietary lipids from the intestines

References (102)

  • H. Ge

    Oligomerization state-dependent hyperlipidemic effect of angiopoietin-like protein 4

    J. Lipid Res.

    (2004)
  • S. Mandard

    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

    J. Biol. Chem.

    (2004)
  • S.K. Koliwad

    Angiopoietin-like 4 (ANGPTL4, fasting-induced adipose factor) is a direct glucocorticoid receptor target and participates in glucocorticoid-regulated triglyceride metabolism

    J. Biol. Chem.

    (2009)
  • T. Robal

    Fatty acids bind tightly to the N-terminal domain of angiopoietin-like protein 4 and modulate its interaction with lipoprotein lipase

    J. Biol. Chem.

    (2012)
  • E. Makoveichuk

    Inactivation of lipoprotein lipase occurs on the surface of THP-1 macrophages where oligomers of angiopoietin-like protein 4 are formed

    Biochem. Biophys. Res. Commun.

    (2012)
  • M. Brands

    Omega-3 long-chain fatty acids strongly induce angiopoietin-like 4 in humans

    J. Lipid Res.

    (2013)
  • K. Yoshida

    Angiopoietin-like protein 4 is a potent hyperlipidemia-inducing factor in mice and inhibitor of lipoprotein lipase

    J. Lipid Res.

    (2002)
  • E. Makoveichuk

    Inactivation of lipoprotein lipase in 3T3-L1 adipocytes by angiopoietin-like protein 4 requires that both proteins have reached the cell surface

    Biochem. Biophys. Res. Commun.

    (2013)
  • M.J. Lafferty

    Angiopoietin-like protein 4 inhibition of lipoprotein lipase: Evidence for reversible complex formation

    J. Biol. Chem.

    (2013)
  • A.P. Beigneux

    Glycosylphosphatidylinositol-anchored high-density lipoprotein-binding protein 1 plays a critical role in the lipolytic processing of chylomicrons

    Cell Metab.

    (2007)
  • B.S.J. Davies

    GPIHBP1 is responsible for the entry of lipoprotein lipase into capillaries

    Cell Metab.

    (2010)
  • P. Gin

    The acidic domain of GPIHBP1 is important for the binding of lipoprotein lipase and chylomicrons

    J. Biol. Chem.

    (2008)
  • W.K. Sonnenburg

    GPIHBP1 stabilizes lipoprotein lipase and prevents its inhibition by angiopoietin-like 3 and angiopoietin-like 4

    J. Clin. Nutr.

    (2009)
  • S.K. Nilsson

    Triacylglycerol-rich lipoproteins protect lipoprotein lipase from inactivation by ANGPTL3 and ANGPTL4

    Biochim. Biophys. Acta

    (2012)
  • Y.Y. Goh

    Angiopoietin-like 4 interacts with integrins beta1 and beta5 to modulate keratinocyte migration

    Am. J. Pathol.

    (2010)
  • T. Yamada

    Insulin downregulates angiopoietin-like protein 4 mRNA in 3T3-L1 adipocytes

    Biochem. Biophys. Res. Commun.

    (2006)
  • M.R. Robciuc

    Serum angiopoietin-like 4 protein levels and expression in adipose tissue are inversely correlated with obesity in monozygotic twins

    J. Lipid Res.

    (2011)
  • Q. Yao

    Effect of chronic intermittent hypoxia on triglyceride uptake in different tissues

    J. Lipid Res.

    (2013)
  • H. Ge

    Differential regulation and properties of angiopoietin-like proteins 3 and 4

    J. Lipid Res.

    (2005)
  • D.W. Quig

    The influence of starvation and refeeding on the lipoprotein lipase activity of skeletal muscle and adipose tissue of lean and obese Zucker rats

    J. Nutr.

    (1983)
  • T.B.M. Hakvoort

    Interorgan coordination of the murine adaptive response to fasting

    J. Biol. Chem.

    (2011)
  • A.J. Evans

    Evidence that cholesteryl ester and triglyceride accumulation in J774 macrophages induced by very low density lipoprotein subfractions occurs by different mechanisms

    J. Lipid Res.

    (1993)
  • H. Adachi

    Angptl 4 deficiency improves lipid metabolism, suppresses foam cell formation and protects against atherosclerosis

    Biochem. Biophys. Res. Commun.

    (2009)
  • L. Lichtenstein

    Angptl4 protects against severe proinflammatory effects of saturated fat by inhibiting fatty acid uptake into mesenteric lymph node macrophages

    Cell Metab.

    (2010)
  • J.T. Jonker

    Dietary modulation of plasma angiopoietin-like protein 4 concentrations in healthy volunteers and in patients with type 2 diabetes

    J. Clin. Nutr.

    (2013)
  • M.R. Robciuc

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

    J. Lipid Res.

    (2010)
  • A. Lookene

    Rapid subunit exchange in dimeric lipoprotein lipase and properties of the inactive monomer

    J. Biol. Chem.

    (2004)
  • L. Zhang

    Calreticulin promotes folding/dimerization of human lipoprotein lipase expressed in insect cells (sf21)

    J. Biol. Chem.

    (2003)
  • O. Ben-Zeev

    Maturation of lipoprotein lipase in the endoplasmic reticulum. Concurrent formation of functional dimers and inactive aggregates

    J. Biol. Chem.

    (2002)
  • S. Enerbäck

    Tissue-specific regulation of guinea pig lipoprotein lipase; effects of nutritional state and of tumor necrosis factor on mRNA levels in adipose tissue, heart and liver

    Gene

    (1988)
  • H. Wang et al.

    Lipoprotein lipase: from gene to obesity

    Am. J. Physiol. Endocrinol. Metab.

    (2009)
  • S.G. Young et al.

    Biochemistry and pathophysiology of intravascular and intracellular lipolysis

    Genes Dev.

    (2013)
  • B. Klop

    Dyslipidemia in obesity: mechanisms and potential targets

    Nutrients

    (2013)
  • A. Köster

    Transgenic angiopoietin-like (angptl)4 overexpression and targeted disruption of angptl4 and angptl3: regulation of triglyceride metabolism

    Endocrinology

    (2005)
  • U. Desai

    Lipid-lowering effects of anti-angiopoietin-like 4 antibody recapitulate the lipid phenotype found in angiopoietin-like 4 knockout mice

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

    (2007)
  • Y. Wang

    Mice lacking ANGPTL8 (Betatrophin) manifest disrupted triglyceride metabolism without impaired glucose homeostasis

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

    (2013)
  • F. Quagliarini

    Atypical angiopoietin-like protein that regulates ANGPTL3

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

    (2012)
  • F. Zandbergen

    Fasting-induced adipose factor/angiopoietin-like protein 4: a potential target for dyslipidemia?

    Future Lipidol.

    (2006)
  • J.C. Yoon

    Peroxisome proliferator-activated receptor γ target gene encoding a novel angiopoietin-related protein associated with adipose differentiation

    Mol. Cell. Biol.

    (2000)
  • I. Kim

    Hepatic expression, synthesis and secretion of a novel fibrinogen/angiopoietin-related protein that prevents endothelial-cell apoptosis

    Biochem. J.

    (2000)
  • Cited by (146)

    View all citing articles on Scopus
    View full text