APOA4 resides onchromosome 11 in close linkage toAPOA1 andAPOC3. APOA4 contains 3exons separated by twointrons, and ispolymorphic, although most of the reported sequence polymorphisms occur in exon 3. The best validated and studied non-synonymousSNPs are aglutamine →histidine substitution atcodon 360 and athreonine →serine substitution at codon 347; a sequence polymorphism has also been identified in the 3'UTR of the third exon.[7] Intra-species comparative gene sequence analysis suggests that the APOA4 gene arose from APOA1 by gene duplication approximately 270MYA.[8]
The primary translation product of the APOA4 gene is a 396-residue preprotein, which undergoes proteolytic processing to yield apo A-IV, a 376-residue mature O-linked glycoprotein. In most mammals, including humans, apo A-IV synthesis is confined to theintestine; however in mice and rats hepatic synthesis also occurs. Apo A-IV is secreted into circulation on the surface of newly synthesizedchylomicron particles. Intestinal fat absorption dramatically increases the synthesis and secretion of apo A-IV. Although its primary function in human lipid metabolism has not been established, apo A-IV has been found to:
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