Disease relevance of ANGPTL4

• We showed that the levels of both mRNA and protein for ANGPTL4 increased in response to hypoxia [1].
• We observed particularly high levels of ANGPTL4 mRNA in tumor cells of conventional renal cell carcinoma [1].
• In human pathology, ANGPTL4 mRNA is produced in ischemic tissues, in conditions such as critical leg ischemia [1].
• Adenovirus-mediated expression of ANGPTL4 potently decreased blood glucose and improved glucose tolerance, whereas it induced hyperlipidemia, fatty liver, and hepatomegaly in C57 mice [2].
• Here, we investigated whether ANGPTL4 might affect tumor growth as well as metastasis [3].

High impact information on ANGPTL4

• We demonstrate here that the N-terminal coiled-coil domain of Angptl-4 binds transiently to LPL and that the interaction results in conversion of the enzyme from catalytically active dimers to inactive, but still folded, monomers with decreased affinity for heparin [4].
• Angiopoietin-like 4 (ANGPTL4), a secreted protein of the angiopoietin-like family, is induced by hypoxia in both tumor and endothelial cells as well as in hypoxic perinecrotic areas of numerous cancers [3].
• Expression of ANGPTL4 induced reorganization of the actin cytoskeleton through inhibition of actin stress fiber formation and vinculin localization at focal contacts [3].
• Together, these results show that ANGPTL4, through its action on both vascular and tumor compartments, prevents the metastatic process by inhibiting vascular activity as well as tumor cell motility and invasiveness [3].
• We conclude that Angptl-4 is a fasting-induced controller of LPL in adipose tissue, acting extracellularly on the native conformation in an unusual fashion, like an unfolding molecular chaperone [4].

Chemical compound and disease context of ANGPTL4

• Bacillus subtilis ribonuclease P protein (P protein) is predominantly unfolded (D) at physiological pH and low ionic strength; however, small molecule anionic ligands (e.g., sulfate) directly bind to and stabilize the folded state (NL2) [5].

Biological context of ANGPTL4

• These results collectively indicate that ANGPTL4 exerts distinct effects on glucose and lipid metabolism, and that its beneficial effect on glucose homeostasis might be useful for the treatment of diabetes [2].
• Here we provide evidence that ANGPTL4 is a blood-borne hormone directly involved in regulating glucose homeostasis, lipid metabolism, and insulin sensitivity [2].
• Serum levels of ANGPTL4 in human subjects inversely correlated with plasma glucose concentrations and HOMA IR, the homeostasis model assessment of insulin resistance [2].
• Ex vivo studies on primary rat hepatocytes revealed that ANGPTL4 significantly decreased hepatic glucose production and enhanced insulin-mediated inhibition of gluconeogenesis [2].
• Porcine ANGPTL3 deduced amino acid sequence shares 83% and 73.7% identity with human and mouse, respectively, and ANGPTL4 shares 79.4% and 77.7% amino acid identity with human and mouse, respectively [6].

Anatomical context of ANGPTL4

• When tested in the chicken chorioallantoic membrane assay, ANGPTL4 induced a strong proangiogenic response, independently of vascular endothelial growth factor [1].
• Angiopoietin-like protein 4 (ANGPTL4) is a circulating protein predominantly expressed in adipose tissue and liver [2].
• Several recent studies demonstrated that ANGPTL4 is the target gene of peroxisome proliferation activators, the agonists of which are widely used as the antidiabetic and lipid-lowering drugs [2].
• We identified human angiopoietin-like 4 (angptl4) as a gene with hypoxia-induced expression in endothelial cells [1].
• U94 alters FN1 and ANGPTL4 gene expression and inhibits tumorigenesis of prostate cancer cell line PC3 [7].

Associations of ANGPTL4 with chemical compounds

• Competition and direct binding assays indicate that the strong interaction of ANGPTL4 with the ECM is heparin/heparan sulfate proteoglycan dependent [8].
• PGAR expression was also increased by desferrioxamine and CoCl(2), but not by sodium cyanide, results consistent with the pharmacological features of hypoxia-responsive genes [9].

Other interactions of ANGPTL4

• ANGPTL4, originally identified as a peroxisome proliferator-activated receptor alpha and gamma target gene, has potential for use as a new diagnostic tool and a potential therapeutic target, modulating angiogenesis both in tumors and in ischemic tissues [1].
• Tissue distribution analysis indicated that porcine ANGPTL3 mRNA was exclusively expressed in liver, and porcine ANGPTL4 was ubiquitously expressed with the highest abundance in white adipose tissue [6].
• High level of induction, however, was observed with the PPAR-gamma-induced angiopoietin-related gene, PGAR [10].
• Hypoxia up-regulates expression of peroxisome proliferator-activated receptor gamma angiopoietin-related gene (PGAR) in cardiomyocytes: role of hypoxia inducible factor 1alpha [9].
• Furthermore, we show that Angptl-4 mRNA in rat adipose tissue turns over rapidly and that changes in the Angptl-4 mRNA abundance are inversely correlated to LPL activity, both during the fed-to-fasted and fasted-to-fed transitions [4].

Analytical, diagnostic and therapeutic context of ANGPTL4

• Sequence analysis shows that ANGPTL3 contains an open reading frame of 1,389 bp, which encodes 462 amino acids, and ANGPTL4 contains a coding region of 1,239 bp, which encodes 412 amino acids [6].
• The expression of ANGPTL4 mRNA in HepG2-ANGPTL4 cells was investigated using RT-PCR [11].
• The differential expression of ANGPTL4 and COL1A1 and other genes was confirmed by quantitative PCR [12].
• Site-specific mutagenesis and generation of deletions were then used to show that Arp4 derivatives lacking different parts of the putative IgA-binding region had lost the ability to bind IgA [13].
• Strikingly, however, both DNase I footprinting and electrophoretic mobility shift assays showed that NL3, but not NL1 or NL2, has high binding affinity to Nurr1 [14].

References