Introduction Directory UMM :Data Elmu:jurnal:A:Atherosclerosis:Vol153.Issue1.Nov2000:

Atherosclerosis 153 2000 209 – 217 The apolipoprotein A-IV-360His polymorphism determines the dietary fat clearance in normal subjects Maria A. Ostos a , Jose Lopez-Miranda a,b , Carmen Marin a , Pedro Castro a , Purificacion Gomez a , Elier Paz a , Jose´ A. Jime´nez Perepe´rez a , Jose M. Ordovas c , Francisco Perez-Jimenez a, a Unidad de Lı´pidos y Arteriosclerosis, Hospital Uni6ersitario ‘ Reina Sofı´a ’ , A6da Mene´ndez Pidal, sn. 14004 Co´rdoba, Spain b Ser6icio de Medicina Interna, Hospital Alto Guadalqui6ir, Andujar, Spain c Lipid Metabolism Laboratory, USDA Human Nutrition Research Center on Aging at Tufts Uni6ersity, Boston, MA, USA Received 2 August 1999; received in revised form 13 December 1999; accepted 14 January 2000 Abstract Apolipoprotein IV apo A-IV has been related to fat absorption and to the activation of some of the enzymes involved in lipid metabolism. Several polymorphic sites within the gene locus for apo A-IV have been detected. Previous studies have shown that the A-IV-2 isoform produces a different plasma lipid response after the consumption of diets with different fat and cholesterol content. The present study was designed to evaluate whether the apo A-IV 360His polymorphism could explain, at least in part, the interindividual variability observed during postprandial lipemia. Fifty-one healthy male volunteers 42 homozygous for the apo A-IV 360Gln allele GlnGln and nine carriers of the A-IV-360His allele, homozygous for the apo E3 allele, were subjected to a vitamin A-fat load test consisting of 1 g of fatkg body weight and 60 000 IU of vitamin A. Blood was drawn at time 0 and every hour for 11 h. Plasma cholesterol C, triacylglycerol TG, and C, TG, apo B-100, apo B-48, apo A-IV and retinyl palmitate RP were determined in lipoprotein fractions. Data of postprandial lipemia revealed that subjects with the apo A-IV 360His allele had significantly greater postprandial levels in small triacylglycerol rich lipoproteins TRL-C P B 0.02, small TRL-TG P B 0.01 and large TRL-TG P B 0.05 than apo A-IV 360GlnGln subjects. In conclusion, the modifications observed in postprandial lipoprotein metabolism in subjects with the A-IV 360His allele could be involved in the different low density lipoprotein LDL-C responses observed in these subjects following a diet rich in cholesterol and saturated fats. © 2000 Elsevier Science Ireland Ltd. All rights reserved. Keywords : Postprandial lipemia; Apolipoprotein A-IV; Apo IV-360His polymorphism; Triacylglycerol; Retinyl palmitate; Cholesterol www.elsevier.comlocateatherosclerosis

1. Introduction

Apolipoprotein apo A-IV is a plasma glycoprotein with a molecular mass of 46 000 Da consisting of 376 amino acid residues. It is synthesized primarily in the enterocytes of the small intestine during fat absorption. Several roles have been assigned to this apolipoprotein. It has been shown to participate in the absorption of dietary fat [1,2], in triacylglycerol transport [3] and in reverse cholesterol transport [4]. Moreover, apo A-IV seems to modulate the activity of lecithin cholesterol acyl transferase LCAT [5] and of cholesteryl ester transfer protein CETP [6]. Apo A-IV is secreted into mesenteric lymph in the chylomicrons [7,8], where it is exchanged for the apo C-II from high density lipo- protein HDL [9]. Apo C-II is a cofactor required for lipoprotein lipase LPL activity [10,11], which is neces- sary for the hydrolysis of triacylglycerol contained in chylomicrons. Thus, apo A-IV may regulate the clear- ance of triacylglycerol-rich lipoproteins of intestinal origin. The gene coding for apo A-IV is located in the long arm of chromosome 11 [12,13]. Several polymorphisms at this gene locus have been described and different associations with plasma lipid levels have been re- ported. One of the most frequent mutations is a G to T Corresponding author. Tel.: + 34-57-217239; fax: + 34-57- 218229. E-mail address : mdipejifcod.servicom.es F. Perez-Jimenez. 0021-915000 - see front matter © 2000 Elsevier Science Ireland Ltd. All rights reserved. PII: S 0 0 2 1 - 9 1 5 0 0 0 0 0 4 0 0 - 7 substitution that changes the glutamine CAG residue at position 360 of the mature apo A-IV to histidine CAT. The frequency of this allele has been studied in several populations and it ranges from 0.05 to 0.117 [14,15]. Several authors have reported an association between this mutation and changes in fast- ing plasma lipid levels, but these results are controver- sial. These variations are dependent on the sex [16], insulin levels and degree of obesity of the subjects [17]. Individuals with the apo A-IV 360His mutation have also been shown to present a different response in dietary intervention studies with a de- creased response of low density lipoprotein LDL-C to cholesterol-enriched diets [18] and to diets with a high fat and cholesterol content [19]. Moreover, in a recent study it was demonstrated how the re- placement of saturated fats by carbohydrates in the diet produced a greater decrease in HDL-C and apo A-I plasma levels in carriers of the apo A-IV 360His muta- tion [20]. In addition, it has been shown that this polymorphism interacts with body mass index BMI to determine the postprandial lipemia in the EARS study [21]. Since apo A-IV can modulate LPL and postprandial lipid metabolism, it was studied whether the apo A-IV 360His mutation could bring about changes in the postprandial metabolism and if these changes could explain the different lipid responses to dietary fat and cholesterol reported in the cited studies.

2. Materials and methods