Proapolipoprotein A-I Metabolism in the Human and the Rat

Abstract

Apolipoprotein A-I (apoA-I) is the major protein constituent of HDL and is polymorphic in plasma consisting of a series of isoforms denoted apoA-I-¹ through apoA-I⁵. Human apoA-I is secreted primarily by the liver and the small intestine^{1 - 5} Initial studies on the in vitro biosynthesis of human apoA-I by fetal and adult intestine, fetal liver and a hepatoma cell line indicated that newly secreted apoA-I was a more basic isoprotein than plasma apoA-I.^6-8 Thus it was suggested that the conversion of the newly secreted apoA-I to the circulating mature apoA-I takes place in the plasma; however, the nature of this conversion process, which resulted in a net change of two positive charges, was unknown. Recent advances in our understanding of the biosynthesis of human apoA-I have allowed a more definitive analysis of the processing and metabolism of plasma apoA-I. Initial studies have revealed that apoA-I is biosynthesized as a 267 amino acid precursor protein, preproapoA-I.^9-11 The presegment is 18 amino acids long and cotranslational cleavage of preproapoA-I to proapoA-I occurs intracellularly during vectoral translocation into the lumen of the rough endoplasmic reticulum. Human proapoA-I contains six amino acids, Arg-His-Phe-Trp-Gln-G1n, attached to the amino terminal end of the mature apoA-I. In more recent studies proapoA-I has been isolated from human plasma and lymph and correspond to the apoA-I-¹ isoform on isoelectrofocusing¹² plasma, proapoA-I accounts for less than 5% of the total mass of circulating apoA-I.¹²