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.
Angptl4 Protects against Severe Proinflammatory Effects of Saturated Fat by Inhibiting Fatty Acid Uptake into Mesenteric Lymph Node Macrophages
Lichtenstein, L.L. ; Mattijssen, F.B.J. ; Wit, N.J.W. de; Georgiadi, A. ; Hooiveld, G.J.E.J. ; Meer, R. van der; He, Y. ; Qi, L. ; Köster, A. ; Tamsma, J.T. ; Tan, N.S. ; Müller, M.R. ; Kersten, A.H. - \ 2010
Cell Metabolism 12 (2010)6. - ISSN 1550-4131 - p. 580 - 592.
endoplasmic-reticulum stress - mouse peritoneal-macrophages - angiopoietin-like protein-4 - low-density lipoproteins - induced adipose factor - insulin-resistance - target gene - lipase - obesity - activation
Dietary saturated fat is linked to numerous chronic diseases, including cardiovascular disease. Here we study the role of the lipoprotein lipase inhibitor Angptl4 in the response to dietary saturated fat. Strikingly, in mice lacking Angptl4, saturated fat induces a severe and lethal phenotype characterized by fibrinopurulent peritonitis, ascites, intestinal fibrosis, and cachexia. These abnormalities are preceded by a massive acute phase response induced by saturated but not unsaturated fat or medium-chain fat, originating in mesenteric lymph nodes (MLNs). MLNs undergo dramatic expansion and contain numerous lipid-laden macrophages. In peritoneal macrophages incubated with chyle, Angptl4 dramatically reduced foam cell formation, inflammatory gene expression, and chyle-induced activation of ER stress. Induction of macrophage Angptl4 by fatty acids is part of a mechanism that serves to reduce postprandial lipid uptake from chyle into MLN-resident macrophages by inhibiting triglyceride hydrolysis, thereby preventing macrophage activation and foam cell formation and protecting against progressive, uncontrolled saturated fat-induced inflammation
Angiopoietin-Like 4 Interacts with Integrins ß1 and ß5 to Modulate Keratinocyte Migration
Goh, Y.Y. ; Pal, M. ; Chong, H.C. ; Zhu, P. ; Tan, M.J. ; Punugu, L. ; Lam, C.R.I. ; Yau, Y.H. ; Tan, C.K. ; Huang, R.L. ; Tan, S. ; Yang Tang, M.B. ; Ling Ding, J. ; Kersten, A.H. ; Tan, N.S. - \ 2010
American Journal of Pathology 177 (2010)6. - ISSN 0002-9440 - p. 2791 - 2803.
induced adipose factor - cell-migration - alpha-6-beta-4 integrin - in-vivo - protein - kinase - expression - repair - metastasis - inhibition
Adipose tissue secretes adipocytokines for energy homeostasis, but recent evidence indicates that some adipocytokines also have a profound local impact on wound healing. Upon skin injury, keratinocytes use various signaling molecules to promote reepithelialization for efficient wound closure. In this study, we identify a novel function of adipocytokine angiopoietin-like 4 (ANGPTL4) in keratinocytes during wound healing through the control of both integrin-mediated signaling and internalization. Using two different in vivo models based on topical immuno-neutralization of ANGPTL4 as well as ablation of the ANGPTL4 gene, we show that ANGPTL4-deficient mice exhibit delayed wound reepithelialization with impaired keratinocyte migration. Human keratinocytes in which endogenous ANGPTL4 expression was suppressed by either siRNA or a neutralizing antibody show impaired migration associated with diminished integrin-mediated signaling. Importantly, we identify integrins ß1 and ß5, but not ß3, as novel binding partners of ANGPTL4. ANGPTL4-bound integrin ß1 activated the FAK-Src-PAK1 signaling pathway, which is important for cell migration. The findings presented herein reveal an unpredicted role of ANGPTL4 during wound healing and demonstrate how ANGPTL4 stimulates intracellular signaling mechanisms to coordinate cellular behavior. Our findings provide insight into a novel cell migration control mechanism and underscore the physiological importance of the modulation of integrin activity in cancer metastasis
Modulation of plasma TG lipolysis by Angiopoietin-like proteins and GPIHBP1
Lichtenstein, L.L. ; Kersten, A.H. - \ 2010
Biochimica et Biophysica Acta. Molecular and Cell Biology of Lipids 1801 (2010)4. - ISSN 1388-1981 - p. 415 - 420.
induced adipose factor - lipoprotein-lipase activity - endothelial-cell adhesion - activated receptor-alpha - ppar-gamma activators - coiled-coil domain - in-vivo - lipid concentrations - genetic-variation - target gene
There is evidence that elevated plasma triglycerides (TG) serve as an independent risk factor for coronary heart disease. Plasma TG levels are determined by the balance between the rate of production of chylomicrons and VLDL in intestine and liver, respectively, and their rate of clearance in peripheral tissues. Lipolytic processing of TG-rich lipoproteins is mediated by the enzyme lipoprotein lipase (LPL), which is tethered to the capillary endothelium via heparin sulphate proteoglycans. In recent years the Angiopoietin-like proteins ANGPTL3 and ANGPTL4 have emerged as novel modulators of LPL activity. Studies in transgenic animals supported by in vitro experiments have demonstrated that ANGPTL3 and ANGPTL4 impair plasma TG clearance by inhibiting LPL activity. In humans, genetic variation within the ANGPTL3 and ANGPTL4 genes contributes to variation in plasma TG and HDL levels, thereby validating the importance of ANGPTLs in the regulation of lipoprotein metabolism in humans. Combined with the discovery of GPIHBP1 as a likely LPL anchor, these findings have led to a readjustment of the mechanism of LPL function. This review provides an overview of our current understanding of the role and regulation of ANGPTL3, ANGPTL4 and GPIHBP1, and places the newly acquired knowledge in the context of the established function and mechanism of LPL-mediated lipolysis