Oligomerization state-dependent hyperlipidemic effect of angiopoietin-like protein 4.
Angiopoietin-like protein 4 (Angptl4) is the second member of the angiopoietin-like family of proteins previously shown to increase plasma triglyceride (TG) levels in vivo. We recently reported that Angptl4 is a variable-sized oligomer formed by intermolecular disulfide bonds and undergoes regulated proteolytic processing upon secretion. We now show that adenoviral overexpression of Angptl4 potently increases plasma TG levels by a mechanism independent of food intake or hepatic VLDL secretion. We determined that cysteine residues at positions 76 and 80 of Angptl4, conserved among mouse, rat, and human, are required to form higher order structures. By generating adenoviral expression vectors of Angptl4 containing different epitope tags at both N and C termini, we show that loss of oligomerization results in decreased stability of the N-terminal coiled-coil domain of Angptl4 as well as decreased ability to increase plasma TG levels, suggesting that intermolecular disulfide bond formation plays important roles in determining the magnitude of the hyperlipidemic effect of Angptl4. Because Angptl4 is more potent than Angptl3 in increasing plasma TG levels in mice, inappropriate oligomerization of Angptl4 could be associated with disorders of lipid metabolism in vivo.
Touchstone Center for Diabetes Research, University of Texas Southwestern Medical Center, Dallas, TX 75390-8854, USA.
Hongfei
H
Ge
Guoqing
G
Yang
Xinxin
X
Yu
Tiffany
T
Pourbahrami
Cai
C
Li
D000256:Adenoviridae / Q000235:genetics; D000595:Amino Acid Sequence; D000075803:Angiopoietin-Like Protein 4; D042682:Angiopoietins; D000821:Animal Feed; D000818:Animals; D001798:Blood Proteins; D015152:Blotting, Northern; D003545:Cysteine / Q000737:chemistry; D004220:Disulfides / Q000737:chemistry; D000939:Epitopes / Q000737:chemistry; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000737:chemistry* / Q000378:metabolism; D050356:Lipid Metabolism; D008055:Lipids / Q000737:chemistry; D008074:Lipoproteins / Q000737:chemistry; D008079:Lipoproteins, VLDL / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008813:Mice, Inbred ICR; D008969:Molecular Sequence Data; D009154:Mutation; D011092:Polyethylene Glycols / Q000494:pharmacology; D016133:Polymerase Chain Reaction; D011485:Protein Binding; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D051381:Rats; D013997:Time Factors; D014280:Triglycerides / Q000097:blood*
C474772:ANGPTL4 protein, human; D000075803:Angiopoietin-Like Protein 4; D042682:Angiopoietins; C407088:Angptl4 protein, mouse; D001798:Blood Proteins; D004220:Disulfides; D000939:Epitopes; D036341:Intercellular Signaling Peptides and Proteins; D008055:Lipids; D008074:Lipoproteins; D008079:Lipoproteins, VLDL; D014280:Triglycerides; D011092:Polyethylene Glycols; D003545:Cysteine; C016811:tyloxapol