Disease relevance of ANGPTL3

• METHODS AND RESULTS: Angptl3-deficient mice showed low plasma HDL cholesterol and HDL phospholipid (PL), and which were increased by ANGPTL3 supplementation via adenovirus [1].

High impact information on ANGPTL3

• Furthermore, a cleavage-resistant mutant of ANGPTL3 was determined to be less active than wild-type ANGPTL3 in increasing mouse plasma triglyceride levels but not in inhibiting lipoprotein lipase activity [2].
• Protein region important for regulation of lipid metabolism in angiopoietin-like 3 (ANGPTL3): ANGPTL3 is cleaved and activated in vivo [2].
• Angiopoietin-like 3 (ANGPTL3) is a secreted protein that is mainly expressed in the liver and regulates lipid metabolism by inhibiting the lipolysis of triglyceriderich lipoproteins [2].
• Serial deletion and point mutation of Angptl3 promoter identified an LXR response element (LXRE) [3].
• By screening expressed sequence tag data bases for homologies to a consensus FBN-like motive, we have identified ANGPTL3, a liver-specific, secreted factor consisting of an N-terminal coiled-coil domain and the C-terminal FBN-like domain [4].

Biological context of ANGPTL3

• Murine ANGPTL3 is a 455-acid polypeptide encoded by seven exons on mouse chromosome 4, spanning about 11 kb of DNA [5].
• 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].
• 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].
• 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].
• In the present study, in order to clarify the regulation of ANGPTL3 gene expression in diabetic states, we examined mRNA and protein levels of ANGPTL3 in the livers of diabetic animals [7].

Anatomical context of ANGPTL3

• We conclude that ANGPTL3 is a liver-derived lipolytic factor targeting on adipocyte [8].
• Furthermore, the mRNA level of ANGPTL3 and -4 in liver and the mRNA level of ANGPTL4 in white adipose tissue were significantly higher in genetically obese pigs than in their lean counterparts [6].
• We evaluated the possible association between plasma ANGPTL3 level and carotid artery intima-media thickness (CA-IMT) and femoral artery intima-media thickness (FA-IMT) in healthy human subjects [9].

Associations of ANGPTL3 with chemical compounds

• Using deletion mutants of human ANGPTL3, we demonstrated that the N-terminal coiled-coil domain-containing fragment-(17-207) and not the C-terminal fibrinogen-like domain-containing fragment-(207-460) increased the plasma triglyceride levels in mice [2].
• Furthermore, ANGPTL3 activated the lipolysis to stimulate the release of FFA and glycerol from adipocytes [8].
• Taken together, our data demonstrate that ANGPTL3 is the first member of the angiopoietin-like family of secreted factors binding to integrin alpha(v)beta(3) and suggest a possible role in the regulation of angiogenesis [4].
• The level of ANGPTL3 mRNA was increased approximately 2.2-fold in the livers of streptozotocin (STZ) diabetic mice, and this effect was reversed by administration of insulin [7].
• The positive association between ANGPTL3 and CA-IMT remained significant after adjustment for age, sex, smoking, body mass index, systolic blood pressure, plasma glucose, insulin resistance index, triglyceride, and high-density and low-density lipoprotein cholesterol levels [9].

Regulatory relationships of ANGPTL3

• To elucidate the mechanism by which PPARbeta represses angptl3 promoter activity, reporter constructs were prepared and transfection analysis carried out [10].

Other interactions of ANGPTL3

• Angiopoietin-like protein 3 (ANGPTL3) is secreted by the liver and was recently postulated to be an important hormone regulating serum triglyceride levels [7].

Analytical, diagnostic and therapeutic context of ANGPTL3

• Co-immunoprecipitation experiments, however, failed to detect binding of ANGPTL3 to the Tie2 receptor [4].
• By radiation hybrid mapping and the use of surrounding genes, human ANGPTL3 maps to the 1p31 region [5].
• Multiple tissue Northern blots show that ANGPTL3 is expressed principally in the liver [5].
• This is the first report of molecular cloning and characterization of ANGPTL3 and -4 in pigs, which will be helpful for a better understanding of the role of ANGPTLs in lipid metabolism [6].
• Plasma ANGPTL3 was determined by a specific ELISA [9].

References