Review ArticlesThe Role of Angiopoietin-Like Proteins in Angiogenesis and Metabolism
Introduction
Seven molecules containing both an N-terminal coiled-coil domain and a C-terminal fibrinogen-like domain, domains also seen in angiopoietins, were identified (Oike et al. 2003, Ito et al. 2003, Kim et al. 1999a, Kim et al. 1999b, Kim et al. 2000, Kersten et al. 2000, Koishi et al. 2002, Yoon et al. 2000, Camenisch et al. 2002, Dhanabal et al. 2002, Le Jan et al. 2003). These similarities suggest that the seven proteins function as Tie receptor ligands. However, none of these proteins bind to either Tie2 or Tie1, and they are still considered orphan ligands (Kim et al. 1999b, Kim et al. 2000, Camenisch et al. 2002, Oike et al. 2004a, Katoh and Kato, 2006). Different groups of investigators have named these proteins; however, a nomenclature committee recently designated them “Angiopoietin-like proteins” (Angptls). Several studies show that Angptls potently regulate angiogenesis (Dhanabal et al. 2002, Kim et al. 1999b, Camenisch et al. 2002, Le Jan et al. 2003, Oike et al. 2004a) as do angiopoietins. In addition, some Angptls potently regulate lipid, glucose, and energy metabolism (Ono et al. 2003, Shimamura et al. 2007, Wang et al. 2007, Xu et al. 2005, Oike et al. 2003, Oike et al. 2005b). Here, we review the currently available information on the role of Angptls in both processes.
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Molecular Characteristics of Angptls
Angiopoietins bind receptors through a fibrinogen-like domain in the C-terminus. Because Angptls apparently bind to different receptors, we compared the deduced amino acid sequence of Angptls in the C-terminus with that of angiopoietins. Only four of six cysteines present in angiopoietins were conserved in all Angptls (Figure 1A, and Oike et al. 2004b), suggesting that conformational differences due to fewer cysteines might account for Angptls' inability to bind to Tie1 or Tie2. A phylogenetic
Angptl Expression Patterns and Regulation
Angptl messenger RNA (mRNA) expression in human and murine tissues has been well characterized. Angptl1 is expressed in vessel-rich endocrine organs (thyroid, pituitary gland, adrenal glands), heart, kidney, liver, and skeletal muscle and is also weakly detectable in the gastrointestinal tract and uterus (Kim et al. 1999a, Lai et al. 2007). Recently, developmental expression of mouse Angptl1 was analyzed by gene-targeted inactivation of Angptl1 by insertion of a LacZ reporter gene (Lai et al.
Role of Angptls in Angiogenesis
Several in vivo and in vitro studies indicate that Angptls do function to modulate angiogenesis, and that data are summarized in Table 1.
Kim et al. (1999a, 1999b) reported that both Angptl1 and Angptl2 exert a weak stimulatory effect on endothelial cell sprouting in vitro. Therefore, to investigate Angptl1 and Angptl2 function in vivo, we generated transgenic mice expressing these Angptls under the control of the keratinocyte-specific promoter (K14 promoter; K14-Angptl1, K14-Angptl2 mice) and
Role of Angptls in Metabolism
Metabolic syndrome characterized by obesity, disturbances in glucose and lipid metabolism, and hypertension is an increasingly prevalent medical and social problem and an important risk factor for cardiovascular disease and mortality (Yach et al. 2006, Wyatt et al. 2006, McTigue et al. 2006, Asia Pacific Cohort Studies Collaboration, 2007). Consequently, identification of effective pharmacologic targets for metabolic syndrome is required; in this regard, the roles of Angptls, particularly
Concluding Remarks
In this review, we have summarized current knowledge about the role of Angptls in angiogenesis and metabolism. It is now clear that Angptls are important modulators of angiogenesis and that they function in the pathogenesis of angiogenesis-related diseases, including tumorigenesis and obesity. Some Angptls also apparently regulate lipid and glucose metabolism independently of angiogenic effects. More detailed understanding of Angptl function requires identification of both cognate receptors and
Acknowledgments
This work was supported by grants-in-aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan, and by research grants from the Astellas Foundation for Research on Metabolic Disorders, the Mitsui Life Social Welfare Foundation, the Japan Heart Foundation, and the Takeda Science Foundation.
References (86)
- et al.
Peroxidase proliferator-activated receptor β/δ regulates very low density lipoprotein production and catabolism in mice on a western diet
J Biol Chem
(2004) - et al.
A decreased expression of angiopoietin-like 3 is protective against atherosclerosis in apoE-deficient mice
J Lipid Res
(2003) - et al.
Coiled coils: a highly versatile protein folding motif
Trends Cell Biol
(2001) - et al.
ANGPLT3 stimulates endothelial cell adhesion and migration via integrin αvβ3 and induces blood vessel formation in vivo
J Biol Chem
(2002) - et al.
Direct cell adhesion to the angiopoietins mediated by integrins
J of Biol Chem
(2001) - et al.
PPARs and the complex journey to obesity
Nat Med
(2004) - et al.
The lipoprotein lipase inhibitor ANGPTL3 is negatively regulated by thyroid hormone
J Biol Chem
(2006) - et al.
Oligomerization and regulated proteolytic processing of angiopoietin-like protein 4
J Biol Chem
(2004) - et al.
Oligomerization state-dependent hyperlipidemic effect of angiopoietin-like protein 4
J Lipid Res
(2004) - et al.
Differential regulation and properties of angiopoietin-like proteins 3 and 4
J Lipid Res
(2005)
HIF and c-Myc: sibling rivals for control of cancer cell metabolism and proliferation
Cancer Cell
Regulation of angiogenesis by hypoxia and hypoxia-inducible factors
Curr Top Dev Biol
Angiopoietin-like protein 3 mediates hypertriglyceridemia induced by the liver X receptor
J Biol Chem
ANGPTL3 is increased in both insulin-deficient and -resistant diabetic states
Biochem Biophys Res Commun
Hepatic proprotein convertases modulate HDL metabolism
Cell Metab
Regulation of the angiopoietin-like protein 3 gene by LXR
J Lipid Res
Characterization of the fasting induced adipose factor FIAF, a novel peroxisome proliferator-activated receptor target gene
J Biol Chem
Molecular cloning and characterization of a novel angiopoietin family protein, angiopoietin-3
FEBS Lett
Molecular cloning, expression, and characterization of angiopoietin-related protein
J Biol Chem
Locating Ath8, a locus for murine atherosclerosis susceptibility and testing several of its candidate genes in mice and humans
Atherosclerosis
Isolation and expression patterns of genes for three angiopoietin-like proteins, Angitp1, 2, and 6 in zebrafish
Gene Expr Patterns
Angiopoietin-like 4 is a proangiogenic factor produced during ischemia and in conventional renal cell carcinoma
Am J Pathol
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
The fasting-induced adipose factor/angiopoietin-like protein 4 is physically associated with lipoproteins and governs plasma lipid levels and adiposity
J Biol Chem
Angiopoietin-like proteins: potential new targets for therapy of metabolic syndrome
Trends Mol Med
Protein region important for regulation of lipid metabolism in angiopoietin-like 3 (ANGPTL3): ANGPTL3 is cleaved and activated in vivo
J Biol Chem
Cross-talk between epidermal growth factor receptor and hypoxia-inducible factor-1alpha signal pathways increases resistance to apoptosis by up-regulating survivin gene expression
J Biol Chem
Oncogenes and tumor angiogenesis: the question of vascular “supply” and vascular “demand”
Semin Cancer Biol
Leptin and insulin down-regulate angiopoietin-like protein 3, a plasma triglyceride-increasing factor
Biochem Biophys Res Commun
Angiopoietin-like protein 3, a hepatic secretory factor, activates lipolysis in adipocytes
Biochem Biophys Res Commun
ANGPTL3 decreases very low density lipoprotein triglyceride clearance by inhibition of lipoprotein lipase
J Biol Chem
The Dallas Heart Study: a population-based probability sample for the multidisciplinary study of ethnic differences in cardiovascular health
Am J Cardiol
Prox-1 function is required for the development of murine lymphatic system
Cell
Overweight and obesity: prevalence, consequences, and causes of a growing publish health problem
Am J Med Sci
Angiopoietin-like protein 4 is a potent hyperlipidemia-inducing factor in mice and inhibitor of lipoprotein lipase
J Lipid Res
The burden of overweight and obesity in the Asia-Pacific region
Obes Rev
Postnatal lymphatic partitioning from the blood vasculature in the small intestine requires fasting-induced adipose factor
Proc Natl Acad Sci U S A
Mechanisms underlying the resistance to diet-induced obesity in germ-free mice
Proc Natl Acad Sci U S A
The gut microbiota as an environmental factor that regulate fat storage
Proc Natl Acad Sci U S A
PPAR gamma activation in human endothelial cells increases plasminogen activator inhibitor type-1 expression: PPAR gamma as a potential mediator in vascular disease
Arterioscler Thromb Vasc Biol
Prevalence of hepatic steatosis in an urban population in the United States: impact of ethnicity
Hepatology
Extracellular matrix-bound angiopoietin-like 4 inhibits endothelial cell adhesion, migration, and sprouting and alters actin cytoskeleton
Circ Res
COMP-Ang1: a designed angiopoietin-1 variant with nonleaky angiogenic activity
Proc Natl Acad Sci U S A
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