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Review Article Potential Role of ANGPTL4 in the Cross Talk Between Metabolism and Cancer Through PPAR Signaling Pathway

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Review Article Potential Role of ANGPTL4 in the Cross Talk Between Metabolism and Cancer Through PPAR Signaling Pathway Hindawi PPAR Research Volume 2017, Article ID 8187235, 15 pages https://doi.org/10.1155/2017/8187235 Review Article Potential Role of ANGPTL4 in the Cross Talk between Metabolism and Cancer through PPAR Signaling Pathway Laura La Paglia,1 Angela Listì,2 Stefano Caruso,3 Valeria Amodeo,4 Francesco Passiglia,2 Viviana Bazan,2 and Daniele Fanale2 1 ICAR-CNR, National Research Council of Italy, 90146 Palermo, Italy 2Department of Surgical, Oncological and Oral Sciences, Section of Medical Oncology, University of Palermo, 90127 Palermo, Italy 3Genomique´ Fonctionnelle des Tumeurs Solides, INSERM, UMR 1162,75010 Paris, France 4Samantha Dickson Brain Cancer Unit, UCL Cancer Institute, University College London, London WC1E6DD, UK Correspondence should be addressed to Daniele Fanale; [email protected] Received 20October 2016; Accepted 19 December 2016; Published 15January 2017 Academic Editor: Stephane´ Mandard Copyright © 2017 Laura La Paglia et al. Tis is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Te angiopoietin-like 4(ANGPTL4) protein belongs to a superfamily of secreted proteins structurally related to factors modulating angiogenesis known as angiopoietins. At frst, ANGPTL4has been identifed as an adipokine exclusively involved in lipid metabolism, because of its prevalent expression in liver and adipose tissue. Tis protein regulates lipid metabolism by inhibiting lipoprotein lipase (LPL) activity and stimulating lipolysis of white adipose tissue (WAT), resulting in increased levels of plasma triglycerides (TG) and fatty acids. Subsequently, ANGPTL4has been shown to be involved in several nonmetabolic and metabolic conditions, both physiological and pathological, includingangiogenesisandvascularpermeability,celldiferentiation, tumorigenesis, glucose homoeostasis, lipid metabolism, energy homeostasis, wound healing, infammation, and redox regulation. Te transcriptional regulation of ANGPTL4can be modulated by several transcription factors, including PPAR ,PPAR / ,PPAR , and HIF-1 ,andnutritionalandhormonalconditions.SeveralstudiesshowedthathighlevelsofANGPTL4areassociatedwith poor prognosis in patients with various solid tumors, suggesting an important role in cancer onset and progression,! " metastasis,# $ and anoikis! resistance. Here, we have discussed the potential role of ANGPTL4in mediating the cross talk between metabolic syndromes, such as diabetes and obesity, and cancer through regulation of its expression by PPARs. 1. Peroxisome Proliferator-Activated actions are limited to specifc tissue types [3,4]. PPAR , Receptors (PPARs): Structure and Functions the frst PPAR to be cloned, is highly expressed in tissues characterized by elevated fatty acid oxidation such as liver,! Peroxisome proliferator-activated receptors (PPARs) are heart, skeletal muscle, brown adipose tissue, kidney, adrenal ligand-activated transcription factors belonging to the steroid gland, and intestinal mucosa, where it plays a key role in the hormone receptor superfamily, identifed for the frst time fatty acid catabolism [5,6]. PPAR / is expressed in most in 1990 by Issemann and Green [1].Tere are three distinct of human tissues, mainly in the liver, adipose tissue, skeletal PPAR subtypes, PPAR ,PPAR / (also known as PPAR or muscle, heart, brain, kidney, skin, and" # intestine, characterized PPAR ), and PPAR ,encodedbyspecifcgeneslocatedon by an increased lipid metabolism. However, the function of diferent chromosomes.! Although" # these three members show" this isoform remains to be elucidated [7–10]. PPAR is highly a signi#fcant homology,$ they difer from each other for tissue expressed in white and brown adipose tissue (WAT and BAT) distribution, afnity for ligands, and biological functions and plays a pivotal role in the regulation of adipogenesis,$ fat [2]. All subtypes are activated by endogenous ligands and storage, and glucose metabolism [11–15]. In addition, PPAR participate in the regulation of several genes involved in also regulates the expression of proinfammatory cytokines, glucose and lipid metabolism. However, other specifc PPAR such as tumor necrosis factor- (TNF- ), as well as genes$ ! ! 2 PPAR Research involved in insulin sensitivity. For this reason, PPAR is the fbrinogen-like globular domain and an N-terminal coiled- main target of thiazolidinediones (TZDs), a class of drugs coil domain [35] except for ANGPTL8. Indeed, this last used to improve lipid and glucose metabolism in$ type 2 ANGPTL family member is considered an atypical member, diabetes [16,17]. since it lacks the main structural features present in all other PPARs show a DNA binding domain (DBD) in the N- proteins of the group, such as the fbrinogen-like domain, terminal and a ligand binding domain (LBD) in the C-ter- glycosylation sites, and amino acids requested for formation minal separated by a hinge region acting as a docking site of disulfde bonds [32] (Figure 2). Unlike the angiopoietins, for cofactors [18]. Tree PPAR isoforms exhibit an 80% ANGPTLs are considered orphan ligands, as they do not bind homology and are more divergent in the LBD, confrming to either the angiopoietin receptor tyrosine kinase Tie2or the their diferent response to various ligands. Afer activation by related protein Tie1[36–38]. endogenous or synthetic ligands, PPARs undergo a confor- Tefrst four family members (ANGPTL1-4) and mational change that causes the translocation to the nucleus ANGPTL6/angiopoietin-related growth factor (AGF) have and the heterodimerization with another nuclear receptor, been shown to modulate angiogenesis. ANGPTLs 3,4,5, and the retinoid X receptor (RXR) [19]. Te PPAR-RXR het- 8andANGPTL6/AGFseemtobeinvolvedalsoinregulation erodimer then binds a DNA portion in the promoter region of of other processes such as lipid metabolism and glucose and target genes, called peroxisome proliferator response element energy homeostasis [39–46]. Another study showed that (PPRE), modulating the expression of several genes involved ANGPTLs 3and 4control lipid metabolism by inhibiting in diferent physiological or pathological processes [20]. the activity of lipoprotein lipase (LPL) [47], an enzyme Interestingly, the PPAR functions also depend on the binding responsible for hydrolysis of triglycerides (TG) contained with diferent coactivator and corepressor proteins [21]. in lipoproteins, such as chylomicrons and very low-density Indeed, afer interaction with agonists, the conformational lipoproteins (VLDL), fatty acids, and cholesterol, whereas change of the PPAR structure causes also the attachment of ANGPTL6/AGF antagonizes obesity and related metabolic coactivators and detachment of corepressors. Usually, PPAR- diseases, including insulin resistance, by enhancing systemic RXR heterodimers are packed with a corepressor molecule energy expenditure [45]. in PPRE and the binding with ligands causes an exchange ANGPTLs show diferent tissue expression patterns. of corepressors for coactivators. One of the more studied ANGPTL1is mostly detected in liver, heart, skeletal muscle, PPAR corepressors is histone deacetylase (HDAC). Among kidney, and vessel-rich endocrine organs (adrenal glands, the diferent coactivators, there are PGC-1, p300, and CREB thyroid, and pituitary gland) but also to a lesser extent in that are involved in regulation of metabolism as well as in uterus and gastrointestinal tract [48]. ANGPTL2shows high cancer development [22,23] (Figure 1). expression levels in heart, stomach, adipose tissue, skeletal muscle, and uterus [49], whereas ANGPTL3is predomi- nantly expressed in liver [50,51]. ANGPTL4shows 30% of 2. Angiopoietin-Like 4 (ANGPTL4): Structure sequence homology with ANGPTL3. It is abundantly present and Expression Patterns in the liver, adipose tissue, and skeletal muscle and, to∼ a lesser extent, in placenta, small intestine, heart, and pituitary gland Te angiopoietin-like 4(ANGPTL4) protein was discovered [52–56]. ANGPTL5is mainly expressed in adult human heart for the frst time in 2000 by three independent research [57], whereas ANGPTL6/AGF expression is restricted to liver groups. Tey simultaneously identifed this molecule as a and plasma [58]. Lastly, ANGPTL7exhibits high expression fasting-induced adipose factor (Fiaf) in diferent tissues. levels in the cornea, neural tissues, and trabecular meshwork ANGPTL4is mainly expressed in liver and adipose tissue, as as well as uterine endometrial cancer and melanoma [59]. shown by Kersten et al. [24] that highlighted its upregulation Te human gene encoding ANGPTL4is evolutionarily in these tissues during fasting and a PPAR-dependent mRNA conserved among species and shares a sequence homology of regulation, using PPAR / wild-type and mutant mice. Also, 77% with mouse. It is located on chromosome 19p13.3and Kim et al. [25] identifed a novel angiopoietin-like protein consists of seven exons encoding a 406-amino acid glycopro- mainly expressed in hepatocytes. Finally, ClifYoon et al. ! $ tein. Like other proteins of the ANGPTL family, ANGPTL4 [26] proved the regulative relation between PPAR proteins ∼ contains a C-terminal fbrinogen-like domain (cANGPTL4) and ANGPTL4, demonstrating that ANGPTL4is a target of and an N-terminal coiled-coil folding domain (nANGPTL4), PPAR in adipose tissue. ANGPTL4belongs to a superfamily of secreted pro- in which a highly hydrophobic region that acts as a signal peptide for protein secretion is present. In addition,
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