Effect of apolipoprotein A-IV genotype and dietary fat on cholesterol absorption in humans

We investigated the effect of the A-IV-2 allele, which encodes a Q360H substitution in apolipoprotein (apo) A-IV, and dietary fat on cholesterol absorption in humans. In three separate studies we compared fractional intestinal cholesterol absorption between groups of subjects heterozygous for the A-IV-2 allele (1/2) and homozygous for the common allele (1/1) receiving high cholesterol (∼800 mg/day) diets with different fatty acid compositions. All subjects had the apoE 3/3 genotype. There was no difference in cholesterol absorption between the two genotype groups receiving a high saturated fat diet (33% of total energy as fat; 18% saturated, 3% polyunsaturated, 12% monounsaturated) or a low fat diet (22% of total energy as fat; 7% saturated, 7% polyunsaturated, 8% monounsaturated) diet. However, on a high polyunsaturated fat diet (32% of total energy as fat; 7% saturated, 13% polyunsaturated, 12% monounsaturated) mean fractional cholesterol absorption was 56.7% ± 1.9 in 1/1 subjects versus 47.5% ± 2.1 in 1/2 subjects (P = 0.004). A post hoc analysis of the effect of the apoA-IV T347S polymorphism across all diets revealed a Q360H × T347S interaction on cholesterol absorption, and suggested that the A-IV-2 allele lowers cholesterol only in subjects with the 347 T/T genotype. We conclude that a complex interaction between apoA-IV genotype and dietary fatty acid composition modulates fractional intestinal cholesterol absorption in humans.—Weinberg, R. B., B. W. Geissinger, K. Kasala, K. J. Hockey, J. G. Terry, L. Easter, and J. R. Crouse. Effect of apolipoprotein A-IV genotype and dietary fat on cholesterol absorption in humans. J. Lipid Res. 2000. 41: 2035–2041. We investigated the effect of the A-IV-2 allele, which encodes a Q360H substitution in apolipoprotein (apo) A-IV, and dietary fat on cholesterol absorption in humans. In three separate studies we compared fractional intestinal cholesterol absorption between groups of subjects heterozygous for the A-IV-2 allele (1/2) and homozygous for the common allele (1/1) receiving high cholesterol (∼800 mg/day) diets with different fatty acid compositions. All subjects had the apoE 3/3 genotype. There was no difference in cholesterol absorption between the two genotype groups receiving a high saturated fat diet (33% of total energy as fat; 18% saturated, 3% polyunsaturated, 12% monounsaturated) or a low fat diet (22% of total energy as fat; 7% saturated, 7% polyunsaturated, 8% monounsaturated) diet. However, on a high polyunsaturated fat diet (32% of total energy as fat; 7% saturated, 13% polyunsaturated, 12% monounsaturated) mean fractional cholesterol absorption was 56.7% ± 1.9 in 1/1 subjects versus 47.5% ± 2.1 in 1/2 subjects (P = 0.004). A post hoc analysis of the effect of the apoA-IV T347S polymorphism across all diets revealed a Q360H × T347S interaction on cholesterol absorption, and suggested that the A-IV-2 allele lowers cholesterol only in subjects with the 347 T/T genotype. We conclude that a complex interaction between apoA-IV genotype and dietary fatty acid composition modulates fractional intestinal cholesterol absorption in humans.—Weinberg, R. B., B. W. Geissinger, K. Kasala, K. J. Hockey, J. G. Terry, L. Easter, and J. R. Crouse. Effect of apolipoprotein A-IV genotype and dietary fat on cholesterol absorption in humans. J. Lipid Res. 2000. 41: 2035–2041. Plasma low density lipoprotein (LDL) cholesterol is a strong risk factor for atherosclerotic cardiovascular disease (1Basha B.J. Sowers J.R. Atherosclerosis: an update.Am. Heart J. 1996; 131: 1192-1202Google Scholar), and interventions that lower LDL levels can reduce the risk for these lethal disorders (2Gould A.L. Rossouw J.E. Santanello N.C. Heyse J.F. Furberg C.D. Cholesterol reduction yields clinical benefit. Impact of statin trials.Circulation. 1998; 97: 946-952Google Scholar). Because dietary saturated fats and cholesterol raise LDL cholesterol in most people (3Schaefer E.J. Brousseau M.E. Diet, lipoproteins, and coronary heart disease.Endocrinol. Metab. Clin. N. Am. 1998; 27: 711-732Google Scholar), current Dietary Guidelines recommend a reduction in the consumption of foods containing these lipids, such as eggs, certain meats, and dairy products (4Krauss R.M. Deckelbaum R.J. Ernst N. Fisher E. Howard B.V. Knopp R.H. Kotchen T. Lichtenstein A.H. McGill H.C. Pearson T.A. 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Lipid Res. 1983; 24: 52-59Google Scholar) that is synthesized by the intestinal enterocytes of mammalian species (11Weisgraber K.H. Bersot T.P. Mahley R.W. Isolation and characterization of an apoprotein from the d<1. 006 lipoproteins of human and canine lymph homologous with the rat A-IV apoprotein.Biochem. Biophys. Res. Commun. 1978; 85: 287-292Google Scholar) during lipid absorption (12Hayashi H. Nutting D.F. Fujimoto K. Cardelli J.A. Black D. Tso P. Transport of lipid and apolipoproteins apo A-I and apoA-IV in intestinal lymph of the rat.J. Lipid Res. 1990; 31: 1613-1625Google Scholar). ApoA-IV enters the circulation on the surface of nascent chylomicrons (13Green P.H. Glickman R.M. Saudek C.D. Blum C.B. Tall A.R. Human intestinal lipoproteins: studies in chyluric subjects.J. Clin. Invest. 1979; 64: 233-242Google Scholar, 14Green P.H. Glickman R.M. Riley J.W. Quinet E. Human apolipoprotein A-IV: intestinal origin and distribution in plasma.J. Clin. Invest. 1980; 65: 911-919Google Scholar), and thereafter dissociates from the chylomicron surface (14Green P.H. Glickman R.M. Riley J.W. Quinet E. Human apolipoprotein A-IV: intestinal origin and distribution in plasma.J. Clin. Invest. 1980; 65: 911-919Google Scholar) and circulates primarily as a lipid-free protein (15Bisgaier C.L. Sachdev O.P. Megna L. Glickman R.M. Distribution of apolipoprotein A-IV in human plasma.J. Lipid Res. 1985; 26: 11-25Google Scholar). Although a broad spectrum of physiologic functions has been proposed for apoA-IV, a preponderance of evidence suggests that its primary biological role is in intestinal lipid absorption (16Kalogeris T.J. Rodriquez M.D. Tso P. Control of synthesis and secretion of intestinal apolipoprotein A-IV by lipid.J. Nutr. 1997; 127: 537S-543SGoogle Scholar). Approximately 15% of the U.S. population carry a common variant allele, A-IV-2, which encodes a Q360H substitution near the C terminus of apoA-IV (17Lohse P. Kindt M.R. Rader D.J. Brewer H.B. Genetic polymorphism of human plasma apolipoprotein A-IV is due to nucleotide substitutions in the apolipoprotein A-IV gene.J. Biol. Chem. 1990; 265: 10061-10064Google Scholar) and significantly alters its biophysical properties (18Weinberg R.B. Jordan M. Steinmetz A. Distinctive structure and function of human apolipoprotein variant, apoA-IV-2.J. Biol. Chem. 1990; 265: 18372-18378Google Scholar). Two studies have observed that the A-IV-2 allele attenuates the LDL response to a high dietary cholesterol intake (19McCombs R.J. Marcadis D.E. Ellis J. Weinberg R.B. Attenuated hypercholesterolemic response to a high cholesterol diet in subjects heterozygous for the apolipoprotein A-IV-2 allele.N. Engl. J. Med. 1994; 331: 706-710Google Scholar, 20Mata P. Ordovas J.M. Lopez-Miranda J. Lichtenstein A.H. Clevidence B. Judd J.T. Schaefer E.J. Apo A-IV phenotype affects diet-induced plasma LDL cholesterol lowering.Arterioscler. Thromb. 1994; 14: 884-891Google Scholar). Given the role of intestinal cholesterol absorption in regulating plasma LDL levels (21Kesaniemi Y.A. Miettinen T.A. Intestinal cholesterol absorption efficiency regulates plasma cholesterol in the Finnish population.Eur. J. Clin. Invest. 1987; 17: 391-395Google Scholar, 22Miettinen T.A. Gylling H. Vanhanen H. Ollus A. Cholesterol absorption, elimination, and synthesis related to LDL kinetics during varying fat intake in men with different apoprotein E phenotypes.Arterioscler. Thromb. 1992; 12: 1044-1052Google Scholar), and the involvement of apoA-IV in intestinal lipid absorption, we hypothesized that the A-IV-2 allele might affect the efficiency of intestinal cholesterol absorption. We therefore compared fractional intestinal cholesterol absorption between subjects heterozygous for the A-IV-2 allele and homozygous for the common allele, A-IV-1. Because genetic polymorphisms of apoE have been found in some studies to affect cholesterol absorption (23Kesaniemi Y.A. Ehnholm C. Miettinen T.A. Intestinal cholesterol absorption efficiency in man is related to apoprotein E phenotype.J. Clin. Invest. 1987; 80: 578-581Google Scholar, 24Gylling H. Miettinen T.A. Cholesterol absorption and synthesis related to low density lipoprotein metabolism during varying cholesterol intake in men with different apoprotein E phenotypes.J. Lipid Res. 1992; 33: 1361-1371Google Scholar), we studied only subjects with the apoE 3/3 genotype. Moreover, because dietary total fat and fatty acid content may also exert a strong effect on cholesterol absorption (22Miettinen T.A. Gylling H. Vanhanen H. Ollus A. Cholesterol absorption, elimination, and synthesis related to LDL kinetics during varying fat intake in men with different apoprotein E phenotypes.Arterioscler. Thromb. 1992; 12: 1044-1052Google Scholar, 24Gylling H. Miettinen T.A. Cholesterol absorption and synthesis related to low density lipoprotein metabolism during varying cholesterol intake in men with different apoprotein E phenotypes.J. Lipid Res. 1992; 33: 1361-1371Google Scholar), we measured cholesterol absorption on high cholesterol diets with three different fatty acid compositions: high saturated fat, high polyunsaturated fat, and low total fat. Subjects heterozygous for the A-IV-2 allele (1/2) and homozygous for the common allele, A-IV-1 (1/1), were recruited from a cohort of subjects whose apoA-IV and apoE phenotypes were determined by isoelectrofocusing-immunoblot analysis (25Weinberg R.B. Hopkins R.A. Jones J.B. Purification, isoform characterization, and quantitation of human apolipoprotein A-IV.Methods Enzymol. 1996; 263: 282-296Google Scholar, 26Terry J.G. Howard G. Mercuri M. Bond M.G. Crouse J.R. Apolipoprotein E polymorphism is associated with 1996; 27: Scholar). The Q360H genotype was by polymorphism analysis of A. H. M. M. H. G. in the apolipoprotein (apo) A-IV gene associated with changes in the of apo and apo lipoproteins in a J. 1992; from subjects with apoA-IV and was with analysis for quality All subjects had the apoE 3/3 genotype. were as or or total cholesterol or or of for and of that affect lipoprotein with the of and of All subjects a of by the of Cholesterol absorption studies were in the of Subjects were studied on three different a high high saturated fat diet a high high polyunsaturated fat diet and a high low fat diet diet. individual cholesterol absorption dietary intake was determined with a of the and a G. A. C. M. J. L. A to diet and J. Scholar). the subjects only by the intestinal cholesterol absorption was measured during The for have been to the three diets in to a cohort of or to all three diets to in a However, the of and groups of subjects with was these studies were in three between and and some subjects in diet subjects in all three diet subjects in the and subjects in the and and in the and In a total of subjects in these were were was and were A was with low fat and eggs, and to of total as protein and of cholesterol the and or were to a of at for the diet no fat was the studies the subjects only the by the and no or from the diet were reported to the was and the total content of individual diets was to ± subjects from The diet cholesterol absorption studies were between and The diet of total energy as as and as fat of total energy as saturated fat, 3% of total energy as polyunsaturated fat, and 12% of total energy as The diet cholesterol absorption studies were between and The diet of total energy as as and as fat of total energy as saturated fat, 13% of total energy as polyunsaturated fat, and 12% of total energy as The diet cholesterol absorption studies were between and The diet of total energy as as and as fat of total energy as saturated fat, 7% of total energy as polyunsaturated fat, and 8% of total energy as In for plasma lipid and lipoprotein were on two at the of and at the of was a acid Plasma was and for total LDL and high density lipoprotein cholesterol in the for Lipid of the of J.G. Howard G. Mercuri M. Bond M.G. Crouse J.R. Apolipoprotein E polymorphism is associated with 1996; 27: Scholar). The lipid and lipoprotein for were to individual and intestinal cholesterol absorption was measured by a J.R. of a for of cholesterol absorption in Lipid Res. 1978; Scholar), with a to genotype. and were from was by on subjects of and of with for were for the of A from was with in and with were to to and the were in a that and and J.G. McGill Crouse J.R. of the of as a for cholesterol Lipid Res. Scholar). and were by were in for the of and the for were cholesterol absorption was as the in the by the in the diet. The mean of for the was = as ± the of the three diets were as three The of differences in fractional cholesterol absorption, and change in dietary intake between the 1/1 and 1/2 genotype groups on diet was determined by The of changes in plasma lipoprotein levels between to genotype groups on diet was determined by The interaction between and the apoA-IV Q360H and T347S polymorphisms on cholesterol absorption across all three studies was determined by analysis of by post hoc The between intestinal cholesterol absorption and changes in lipoprotein levels was by Pearson In of the three separate diet were no differences between the 1/1 and 1/2 groups in mean or plasma lipids at In of the three diet were no differences between the 1/1 and 1/2 groups in intake of or in the of total from total fat, or saturated, polyunsaturated, or fatty on an diet. in of the three diet studies was no difference between the 1/1 and 1/2 groups in the diet change in the intake of dietary ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± and lipoprotein ± diet were no differences in mean between genotype of of and total plasma plasma plasma low density lipoprotein plasma high density lipoprotein in a Lipid and lipoprotein ± diet were no differences in mean between genotype of of and total plasma plasma plasma low density lipoprotein plasma high density lipoprotein apoA-IV genotype and dietary fat composition fractional intestinal cholesterol absorption In the subjects the mean cholesterol absorption was ± for the 1/1 versus ± 2.1 for the 1/2 (P = In the subjects the mean cholesterol absorption was ± 1.9 for the 1/1 versus ± 2.1 for the 1/2 (P = 0.004). In the subjects the mean cholesterol absorption was ± for the 1/1 versus ± for the 1/2 (P = Although the of was such that most subjects were studied on only a of subjects were studied on the and diets to a of the diet response the 1/1 subjects were studied on the and diets = mean cholesterol absorption was ± on the diet versus ± on the diet. In the 1/2 subjects were studied on the and diets = mean cholesterol absorption was ± on the diet versus ± on the diet. The difference in cholesterol absorption between the 1/1 and 1/2 ± versus ± was significantly different at = by analysis of across all apoA-IV genotype had an effect on cholesterol absorption, ± for 1/1 subjects versus ± for 1/2 subjects (P = However, across diet had an effect on cholesterol absorption in the 1/1 subjects (P = in the 1/2 subjects (P = of from all three studies found no or × allele on cholesterol absorption. There was no in genotype between fractional cholesterol absorption and the or diet changes in plasma lipids and we were these Lopez-Miranda J. J. Ordovas J.M. P. C. J.A. A. Effect of the in apoprotein A-IV on plasma LDL cholesterol response to dietary Thromb. Biol. 1997; 17: Scholar) reported that common apoA-IV the plasma LDL response to a high cholesterol that might affect fractional cholesterol absorption. We therefore T347S on from the in these from of the subjects was for of from all three diet studies revealed a Q360H × T347S polymorphism interaction on cholesterol absorption In subjects with the cholesterol absorption was significantly lower in subjects the A-IV-2 allele was no difference in cholesterol absorption between the and 1/2 groups in subjects with the 347 or analysis of all cholesterol absorption for subjects for apoA-IV Q360H and T347S in a Although these studies were to the effect of genotype on the lipid response to dietary we measured plasma lipids and lipoproteins at the and of dietary the total and and significantly in genotype the only significantly in and on the were no changes in lipid in was no difference between in the diet change in LDL or on the three diets and change in plasma cholesterol in subjects with the and between and on different high cholesterol high saturated fat; high polyunsaturated fat; low total fat. There were no differences in the mean changes in between the and groups on Although is a of in a effect of genotype on the efficiency of intestinal cholesterol absorption J.A. and to dietary fat and cholesterol for level and Lipid Res. Scholar, Genetic in cholesterol absorption efficiency of Nutr. 1997; 127: Scholar, C.D. J.M. Genetic differences in cholesterol absorption in and effect on cholesterol J. Scholar), to only a studies have the impact of genetic polymorphisms on cholesterol absorption in humans. In two studies in which the subjects fractional cholesterol absorption was found to be in subjects an allele, in and in subjects with or phenotypes (22Miettinen T.A. Gylling H. Vanhanen H. Ollus A. Cholesterol absorption, elimination, and synthesis related to LDL kinetics during varying fat intake in men with different apoprotein E phenotypes.Arterioscler. Thromb. 1992; 12: 1044-1052Google Scholar, Y.A. Ehnholm C. Miettinen T.A. Intestinal cholesterol absorption efficiency in man is related to apoprotein E phenotype.J. Clin. Invest. 1987; 80: 578-581Google Scholar). However, on low or high cholesterol the differences in absorption apoE genotype groups were H. Miettinen T.A. Cholesterol absorption and synthesis related to low density lipoprotein metabolism during varying cholesterol intake in men with different apoprotein E phenotypes.J. Lipid Res. 1992; 33: 1361-1371Google Scholar). to of apoE polymorphisms on cholesterol absorption, in we studied only subjects with the genotype. that subjects heterozygous for the A-IV-2 allele have lower fractional cholesterol absorption homozygous subjects on a high high polyunsaturated fat diet. Moreover, we also observed that cholesterol absorption in the subjects on a as in studies Fisher H. Effect of and dietary protein on cholesterol absorption and in the Nutr. Scholar, N. Effect of of dietary fat and cholesterol on cholesterol absorption in Nutr. Scholar, R. J. T. Dietary saturated fatty acid content affects lymph lipoproteins: studies in the rat.J. Lipid Res. 1983; 24: Scholar, Lewis McGill H.C. The role of cholesterol absorption and cholesterol content in high and low to dietary cholesterol and fat in 1993; Scholar), in the subjects dietary fatty acid content had little impact on cholesterol absorption. we observed that apoA-IV may the impact of the A-IV-2 allele on cholesterol absorption. these that a complex apoA-IV fatty acid interaction may modulate the efficiency of cholesterol absorption in humans. In on by which apoA-IV polymorphisms modulate cholesterol absorption, is that of chylomicron cholesterol absorption R.E. B.J. A. L. A genetic for chylomicron apo in the in the Clin. Invest. Scholar). In the of chylomicron is by protein to J. of apolipoprotein Biol. Chem. 1996; Scholar). which have apoA-IV on surface isolation and J. 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J.B. of intestinal lipid by in the J. Scholar). suggests that apoA-IV a role in the of chylomicron Moreover, human apoA-IV and at R.B. J. properties of apolipoproteins A-IV and at the and Lipid Res. 41: Scholar), properties that in by and Scholar). by at the chylomicron surface during apoA-IV modulate the of cholesterol to the regulating cholesterol the efficiency of cholesterol absorption. a the A-IV-2 allele had an impact on cholesterol absorption only on the diet. have an and a lower density of cholesterol in human low density Scholar, J.A. of lipid composition and on the of apolipoprotein A-I to lipid 27: Scholar), properties that the of cholesterol of cholesterol in human low density Scholar, of and on the of cholesterol 27: Scholar). of cholesterol to polyunsaturated chylomicrons may have cholesterol absorption in the 1/1 subjects on the diet. However, the has surface (18Weinberg R.B. Jordan M. Steinmetz A. Distinctive structure and function of human apolipoprotein variant, apoA-IV-2.J. Biol. Chem. 1990; 265: 18372-18378Google Scholar), of to chylomicrons may have cholesterol of apolipoproteins on the kinetics of cholesterol Scholar), cholesterol absorption in the 1/2 Although its biophysical properties have been studied to that the be found to have lower lipid The of an effect of apoA-IV genotype on the LDL response to the an in cholesterol In a cholesterol intake was with no change in fat intake of total the A-IV-2 allele an in LDL cholesterol (19McCombs R.J. Marcadis D.E. Ellis J. Weinberg R.B. Attenuated hypercholesterolemic response to a high cholesterol diet in subjects heterozygous for the apolipoprotein A-IV-2 allele.N. Engl. J. Med. 1994; 331: 706-710Google Scholar). cholesterol intake was with a reduction in total fat subjects the A-IV-2 allele had a in LDL P. Ordovas J.M. Lopez-Miranda J. Lichtenstein A.H. Clevidence B. Judd J.T. Schaefer E.J. Apo A-IV phenotype affects diet-induced plasma LDL cholesterol lowering.Arterioscler. Thromb. 1994; 14: 884-891Google Scholar). However, in in which cholesterol intake was and saturated and fat intake was no impact of the A-IV-2 allele on LDL levels was observed Lopez-Miranda J. Ordovas J.M. C. P. R. A. J.A. Effect of the in apolipoprotein apoA-IV on plasma response to dietary Lipid Res. 1997; Scholar), subjects the A-IV-2 allele had changes in in studies in which saturated fat and cholesterol were no effect on LDL was E.J. Ordovas J.M. Clevidence Judd J.T. M. Lichtenstein A.H. in lipoprotein cholesterol response to Cholesterol J. Clin. Nutr. 1997; 65: Scholar, R. J.F. J.T. Ordovas J.M. R. Genetic at the apoA-IV gene and response to diet in Thromb. Biol. 1998; Scholar). that dietary fatty can the impact of the A-IV-2 allele on the LDL response to changes in cholesterol intake because fatty a factor in regulating LDL dietary cholesterol (5McNamara D.J. Kolb R. Parker T.S. Batwin H. Samuel P. Brown C.D. Ahrens E.H. Heterogeneity of cholesterol homeostasis in man. Response to changes in dietary fat quality and cholesterol quantity.J. Clin. Invest. 1987; 79: 1729-1739Google Scholar, J.M. Dietary fatty and the of plasma low density lipoprotein cholesterol Nutr. 1998; Scholar). also we found no between fractional cholesterol absorption and the changes in plasma In we observed that the A-IV-2 allele cholesterol absorption in the of a high polyunsaturated fat diet. the of an apolipoprotein fatty acid interaction human intestinal cholesterol absorption. the A-IV-2 allele had no effect on the lipoprotein response to high cholesterol the impact of apoA-IV genotype on the lipoprotein response to diet may be determined by a complex interaction between a genotype effect on cholesterol absorption and a effect of dietary fatty on cholesterol was by a from the American by from the American Heart and from the and and by the of of analysis of apolipoprotein high density lipoprotein high high polyunsaturated fat high high saturated fat low density lipoprotein high low fat.

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