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Papers In Press, published online ahead of print August 1, 2004
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Physiology and Internal Medicine, UT Southwestern Medical Center, Dallas, TX 75390-8854
Corresponding Author: Cai.Li{at}UTSouthwestern.edu
Angiopoietin-like protein 4 (Angptl4) is the second member of the angiopoietin-like family of proteins previously shown to raise 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 over-expression of Angptl4 potently raises plasma triglyceride 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 amino and carboxyl 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 raise plasma TG levels, suggesting that intermolecular disulfide bond formation plays important roles in determining the hyperlipidemic effect of Angptl4. Because Angptl4 is more potent than Angptl3 in raising plasma TG levels in mice, inappropriate oligomerization of Angptl4 could be associated with disorders of lipid metabolism in vivo.
Revised on July 27, 2004
Accepted on July 30, 2004
Oligomerization state-dependent hyperlipidemic effect of angiopoietin-like protein 4
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