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Structure-Function Analysis of Apolipoprotein A-V: Insight into Plasma Triglyceride Homeostasis


Coronary heart disease is the leading cause of death in the United States, and epidemiological studies have shown that an elevated plasma triglyceride level is an independent risk factor for cardiovascular disease. In 2001, a new member of the exchangeable apolipoprotein (apo) family, apoA-V, was discovered using comparative genomics. Studies with transgenic mice over-expressing human apoA-V and apoA-V knock-out mice have shown that there exists a negative correlation between apoA-V levels and plasma triglyceride concentrations. Such findings have also been observed in humans, where single nucleotide polymorphisms within the APOA5 gene have been associated with hypertriglyceridemia. These physiological findings suggest that apoA-V plays a major role in the regulation of triglyceride metabolism, and elucidating the mechanism by which apoA-V functions could yield therapeutic effects.

Several features of apoA-V, including an extremely low plasma concentration, a lack of correlation with cholesterol levels despite its association with high density lipoprotein, and its insolubility at neutral pH in the absence of lipid, are unlike other exchangeable apolipoproteins. Findings indicate apoA-V is comprised of two independently folded structural domains, with the amino-terminal domain forming an amphipathic alpha-helix bundle in the absence of lipid. In the presence of lipid, the helix bundle motif is postulated to unfurl, exposing hydrophobic residues for lipid interaction. The carboxy-terminal region plays a key function in apoA-V lipid binding, consistent with its known association with plasma lipoproteins.

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