Potential Role of ANGPTL4 in the Cross Talk between Metabolism and Cancer through PPAR Signaling Pathway.

Laura La Paglia,Daniele Fanale,Viviana Bazan,Angela Listì,Valeria Amodeo,Stefano Caruso,Francesco Passiglia

doi:10.1155/2017/8187235

Abstract

The angiopoietin-like 4 (ANGPTL4) protein belongs to a superfamily of secreted proteins structurally related to factors modulating angiogenesis known as angiopoietins. At first, ANGPTL4 has been identified as an adipokine exclusively involved in lipid metabolism, because of its prevalent expression in liver and adipose tissue. This 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, ANGPTL4 has been shown to be involved in several nonmetabolic and metabolic conditions, both physiological and pathological, including angiogenesis and vascular permeability, cell differentiation, tumorigenesis, glucose homoeostasis, lipid metabolism, energy homeostasis, wound healing, inflammation, and redox regulation. The transcriptional regulation of ANGPTL4 can be modulated by several transcription factors, including PPARα, PPARβ/δ, PPARγ, and HIF-1α, and nutritional and hormonal conditions. Several studies showed that high levels of ANGPTL4 are associated with 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 ANGPTL4 in mediating the cross talk between metabolic syndromes, such as diabetes and obesity, and cancer through regulation of its expression by PPARs.

Highlights

Laura La Paglia,1 Angela Listì,2 Stefano Caruso,3 Valeria Amodeo,4 Francesco Passiglia,2 Viviana Bazan,2 and Daniele Fanale2
PPARα, the first Peroxisome proliferator-activated receptors (PPARs) to be cloned, is highly expressed in tissues characterized by elevated fatty acid oxidation such as liver, heart, skeletal muscle, brown adipose tissue, kidney, adrenal gland, and intestinal mucosa, where it plays a key role in the fatty acid catabolism [5, 6]
PPARRXR heterodimers are packed with a corepressor molecule in peroxisome proliferator response element (PPRE) and the binding with ligands causes an exchange of corepressors for coactivators

Summary

ANGPTL4: A Regulative Role in Glucose and Lipid Metabolism

Among the “pleiotropic” roles of ANGPTL4, greater attention was focused on its involvement in glucose and lipid metabolism regulation [81]. Mutant mice carrying a loss-of-function of ANGPTLs exhibited low plasma TG levels [32, 92,93,94], all three proteins show different tissue expression patterns and are regulated by different stimuli This has led to the hypothesis that they are active during different metabolic states. The model suggests that feeding can induce ANGPTL8, resulting in the activation of the ANGPTL3-8 pathway This causes LPL inhibition and increase in plasma levels of TG which can be stored in WAT. Other evidences concerning the ANGPTL4 role in glucose metabolism regulation were reported in different studies on transgenic mice, where the decrease of blood glucose, improvement of glucose tolerance, and induction of hyperlipidemia and hepatic steatosis have been linked to the protein [44, 98]. Other studies carried out on humans and animal models suggested the involvement of ANGPTL4 in nephrotic syndrome, revealing that ANGPTL4 acts by linking proteinuria and hypertriglyceridemia through negative feedback loops [99]

Role of ANGPTL4 in Cancer

Conclusions