Effect of 360His mutation in apolipoprotein A-IV on plasma HDL-cholesterol response to dietary fat.

In order to determine whether genetic variability of apolipoprotein (apo) A-IV is responsible for the improvement in lipid profile when dietary saturated fats are replaced by carbohydrates or monounsaturated fats, 41 healthy male subjects were studied: 33 were homozygous for the 360Gln allele and 8 were heterozygote carriers of the 360His allele. These were administered three consecutive 4-week diets. The first was a diet rich in saturated fat (SAT diet, with 38% fat, 20% saturated. This was followed by a low fat diet (NCEP-I, with < 30% fat, < 10% saturated). The final diet was rich in monounsaturated fat (MUFA diet, with 38% fat, 22% monounsaturated). There was no difference in plasma lipid and apolipoprotein levels of both groups of individuals after consuming the SAT diet. Switching from this diet to the NCEPI diet, carriers of the 360His allele presented a greater decrease in high density lipoprotein-cholesterol (HDL-C) (-10 vs. 1 mg/dL, P< 0.004) and apoA-I levels (19 vs. -8 mg/ dL, P < 0.037). Similarly, replacement of carbohydrates by monounsaturated fats produced a greater increase in HDLC (9 vs. 1 mg/dL, P < 0.003) and apoA-I levels (9 vs. 2 mg/ dL, P < 0.036) in carriers of the 360His mutation. Lecithin: cholesterol acyltransferase (LCAT) and cholesteryl ester transfer protein (CETP) activities and apoA-IV levels were also measured. However, no genotype-related differences were observed for these parameters.I Our results suggest that variability in HDL-C and apoA-I response to diet is, at least partially, determined by the 360His mutation of apoAIV.-Jansen, S., J. Lopez-Miranda, J. M. Ordovas, J, L. Zambrana, C. Marin, M. A. Ostos, P. Castro, R. McPherson, F. Lopez Segura, A. Blanco, J. A. Jimenez Pereperez, and F. Perezjimenez. Effect of 360His mutation in apolipoprotein A-IV on plasma HDL-cholesterol response to dietary fat. J. Lifiid Res. 1997. 3 8 1995-2002. Supplementary key words acids lipid response to dietary fat apoA-IV polymorphism dietary fatty and regulate activity of cholesteryl ester transfer protein (CETP) (6) and lipoprotein lipase (LPL) (7). In humans, isoelectric focusing and immunoblotting have identified up to eight different isoforms of this apolipoprotein (apoA-IV-0 to A-IV-7) (8-10). The most prevalent is apoA-N-1, with a frequency of 0.885-0.986 (1 1, 12). Another prevalent isoform is apoA-IV-2, due to a G to T substitution in the gene that causes the appearance of histidine (CAT) instead of glutamine (GAG) in amino acid 360 of the protein (1 3). Its frequency in the different studies varies from 0.05 to 0.117 (8, 11). The 360His allele is present mainly in Caucasian populations, and it is significantly less frequent or undetectable in other populations (8). There is also a rare variant in apoA-IV-2 caused by a deletion of 12 base pairs that results in the loss of amino acids 362-365 (one glutamic acid and three glutamines) from the mature protein (14). Several population studies have examined the association of apoA-IV (Gln/His) variant at codon 360 with plasma lipid levels. The conclusions of these studies are highly variable. Whereas some reported no significant differences between genotypes (10, 15-21), others observed elevated HDL-C (22,23) or apoA-I levels (24) in subjects carrying the His allele. These differences could possibly be due to interactions between this isoform and dietary factors within each of the population studied. As apoA-IV is primarily found in HDL (25, 261, the main objective of this study was to determine to what extent Apolipoprotein (apo) A-IV is synthesized in the intestine (1) and has been associated with fat absorption (14) Moreover, it has been shown to activate the enzyme lecithin: cholesterol acyltransferase (LCAT) in vitro (5) Abbreviations: apo, apolipoprotein; LCAT, lecithin :cholesterol acyltransferase; CETP, cholesteryl ester transfer protein; LPL, lipoprotein lipase; HDL-C, high density lipoprotein cholesterol; BMI, body mass index; SFA, saturated fat; MUFA, monounsaturated fatty acids; PUFA, polyunsaturated fatty acids; NCEP, National Cholesterol Education Program; LDL-C, low density lipoprotein cholesterol. ‘To whom correspondence should be addressed. Journal of Lipid Research Volume 38, 1997 1995 the apoA-IV 360His variant is associated with different HDL-C responses to changes in dietary fat. and all subjects consumed a MUFA-rich diel (MUFA diet) with 15% of energy as protein, 47% as cat-boh),drate, and 38% as fat (10% SFA, 22% MUFA, and 6?4 PUFA). Dietary cholesterol was maintained constant and the mean intake was 115 mg/1000 kcal over tlic SUBJECTS AND METHODS