Apolipoprotein A-IV genotype and the response to dietary cholesterol

The variant allele, apolipoprotein A-IV-2 alters the in vitro structure and function of apolipoprotein A-TV, and in some populations is associated with alterations in plasma lipids. We examined the effect of the apolipoprotein A-IV-2 allele on the response to dietary cholesterol in a group of II apolipoprotein A-IV-1/2 heterozygotes and a matched group of 12 apolipoprotein A-IV-1/1 homozygotes. After three weeks on a high-cholesterol (similar to 1100 mg/day) diet, the apolipoprotein A-IV-1/2 heterozygotes, unlike the apolipoprotein A-IV-1/1 homozygote controls, showed no increase in plasma low-density lipoprotein levels. Candidate mechanisms for the apolipoprotein A-TV-2 allele effect include reduced fractional absorption of dietary cholesterol, delayed chylomicron clearance, and accelerated reverse cholesterol transport. The geographic distribution of the apolipoprotein A-TV-2 allele frequency suggests that it may have originated in an ancient population that consumed a high-cholesterol diet. We conclude that the apolipoprotein A-IV-2 allele attenuates the hypercholesterolemic response to dietary cholesterol and may partially account for the heterogeneous response to dietary cholesterol in humans.