STRUCTURE AND FUNCTION OF APOLIPOPROTEIN A-IV

Wake Forest University Health Sciences, Winston-Salem NC

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Abstract

DESCRIPTION (Applicant's abstract): Apolipoprotein A-IV (apo A-IV) is a 46 Kd plasma glycoprotein that is synthesized by the mammalian intestine during lipid absorption and incorporated into the surface of nascent chylomicrons. Although apo A-IV has been implicated in many metabolic processes, a preponderance of evidence suggests that it evolved to play a specific role in intestinal lipid absorption. Using several novel approaches borrowed from the surfactant industry, we have found that apo A-IV possesses dynamic interfacial properties that are optimal for stabilizing surface tension and molecular packing at lipid/aqueous interfaces. We therefore hypothesize that apo A-IV plays a specific role in the growth stage of chylomicron formation by controlling the density of lipid packing at the expanding chylomicron surface, thereby modulating the access of cellular phospholipids and cholesterol to the surface and, ultimately, fractional intestinal cholesterol absorption. This hypothesis predicts that: 1) polymorphisms of human apo A-lV that alter its interfacial properties will affect cholesterol influx to lipid/aqueous interfaces; 2) fractional cholesterol absorption will be modulated by the level of intestinal apo A-IV synthesis in apo A-lV transgenic and knockout mice; 3) the impact of apo A-lV expression on cholesterol absorption will depend upon the fatty acyl species absorbed from the diet. To pursue these hypotheses we will: 1) use physical techniques to examine the impact of human genetic and recombinant apo A-lV polymorphisms on its molecular structure, interfacial properties, and the kinetics of its interaction with lipid surfaces; 2) use oil-drop tensiometer techniques as novel 3-dimensional models of chylomicron lipidation to examine how the interfacial properties of apo A-lV modulate cholesterol influx to the expanding chylomicron surface; 3) use apo A-IV transgenic and knock-out mice to examine the impact of apo A-lV expression, dietary fatty acids, and ACAT activity on intestinal cholesterol absorption. We believe that these studies will provide insight into the specific biological function of apo A-IV, a new avenue to examine the complex process of cholesterol absorption, and new knowledge on the biological impact of apo A-lV genetic polymorphisms relevant to the dietary control of atherosclerotic cardiovascular disease.