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Plasma lipid response to dietary fat and cholesterol is, in part, genetically controlled. The apolipoprotein A-IV (apoA-IV protein; APOA4, gene) has been shown to influence the response to dietary changes in normolipidemic individuals. The response to diet in subjects with familial hypercholesterolemia (FH) is also variable, and no studies are available on the influence of APOA4 mutations on dietary response in these subjects. We studied the effect of 2 common apoA-IV genetic variants (Gln360-->His and Thr347-->Ser) on the lipid response to the National Cholesterol Education Program type I (NCEP-I) diet in 67 FH heterozygotes (43 women and 24 men). Subjects were studied at baseline (after consuming for 1 month a diet with 35% fat [10% saturated] and 300 mg/d cholesterol) and after 3 months of consuming a low-fat diet. No sex-related differences were found, and results were combined for men and women. The APOA4-360 mutation was assessed in 67 subjects, 51 with genotype 1/1 and 16 with genotype 1/2. The APOA4-2 allele was associated with marginally significantly lower (P=0.049) low density lipoprotein (LDL) cholesterol levels and significantly lower (P=0.027) apoB levels independent of diet effects. After consuming an NCEP-I diet, carriers of the APOA4-2 allele showed a significantly lower reduction in apoB concentration (6.2%) than 1/1 subjects (14.1%; P=0.036); however, no significant differences in response were noted for LDL cholesterol. The APOA4-347 mutation was assessed in 63 individuals, 44 with the A/A allele and 19 with the A/T and T/T alleles. No significant differences were observed in baseline or post-NCEP-I diet values for these 2 groups in total, LDL, and high density lipoprotein cholesterol and plasma apoB levels. After dietary intervention, A/A individuals showed significant reductions in plasma triglyceride and very low density lipoprotein cholesterol levels; no changes were found in carriers of the T allele. Haplotype analysis suggested that in these FH subjects, the APOA4-360-2 allele was associated with lower plasma lipid levels during the NCEP-I diet period, whereas no significant effects were observed for the APOA4-347-T allele. Show less

Apolipoprotein A-IV (apoA-IV) is a glycoprotein constituent of triglyceride-rich and high-density lipoproteins (HDL) and may thus play an important role in lipid metabolism. In Finland two common isoforms (A-IV-1 and A-IV-2) of apoA-IV have been found. The isoforms are the result of the G to T substitution in the third base of the codon 360 in the apoA-IV-2 allele of the apoA-IV gene. The purpose of the study was to determine the apoA-IV allele frequencies in the Saami and the Finns, and to relate the apoA-IV phenotypes to serum lipids. The sample was drawn in connection with a Reindeer Herders' Health Survey performed in northern Finland in 1989. The study group included 248 men with known ethnic origin, Saami and Finns, who lived in the area of the nine northernmost municipalities of Finland. ApoA-IV phenotypes from 71 Saami (both parents Saami) and 177 Finns (both parents Finns) were determined by isoelectric focusing and Western blotting. Serum lipids were determined enzymatically. ApoA-IV allele frequencies in the Saami and the Finns were for A-IV-1 0.894 vs 0.944 and for A-IV-2 0.106 vs 0.056, respectively (chi2-test, P < 0.05). The effect of the apoA-IV phenotype on serum HDL-cholesterol levels differed significantly between the Saami and the Finns (two-way ANCOVA, interaction between ethnicity and apoA-IV phenotype, P < 0.02). In the Saami, HDL-cholesterol levels were significantly higher in the apoA-IV-2/1 than in the apoA-IV-1/1 phenotypes (ANCOVA, P < 0.05). Mean total cholesterol, low-density lipoprotein (LDL)-cholesterol, apolipoprotein B, HDL-cholesterol and triglyceride levels did not differ statistically significantly between the Saami and the Finns. Yet, there was a trend in the Saami of having higher mean total cholesterol, LDL-cholesterol and apolipoprotein B levels than the Finns among the apoA-IV-2/1 phenotypes, while there was only a small difference in these parameters between the Saami and the Finns among the apoA-IV-1/1 phenotypes. In conclusion, the Saami have a higher frequency of the apoA-IV-2 allele than the Finns and most of the other studied populations. Show less

Apolipoprotein (apo) A-IV is a protein synthesized, in humans, only by the small intestine. It has a molecular weight of 46 000 Da. This paper summarizes the evidence supporting its role as a satiety factor following the ingestion of fat. This function of apo A-IV is unique and not shared by other apolipoproteins, including apo A-I. The satiety effect of apo A-IV is centrally mediated. The mechanism of how apo A-IV inhibits food intake is not clear but it probably acts by inhibiting both gastric acid secretion as well as gastric motility. Lipid absorption stimulates apo A-IV synthesis and secretion by the jejunum. In addition to lipid feeding, there is evidence that a factor which is released as a result of lipid absorption in the distal small intestine also stimulates the synthesis and release of apo A-IV by the jejunum. This factor is probably PYY. Show less

Small, dense LDL particles consistently have been associated with hypertriglyceridemia, premature coronary artery disease (CAD), and familial combined hyperlipidemia (FCH). Previously, we have observed linkage of LDL particle size with four separate candidate-gene loci in a study of families enriched for CAD. These loci contain the genes for manganese superoxide dismutase (MnSOD), on chromosome 6q; for apolipoprotein AI-CIII-AIV, on chromosome 11q; for cholesteryl ester transfer protein (CETP) and lecithin:cholesterol acyltransferase (LCAT), on chromosome 16q; and for the LDL receptor (LDLR), on chromosome 19p. We have now tested whether these loci also contribute to LDL particle size in families ascertained for FCH. The members of 18 families (481 individuals) were typed for genetic markers at the four loci, and linkage to LDL particle size was assessed by nonparametric sib-pair linkage analysis. The presence of small, dense LDL (pattern B) was much more frequent in the FCH probands (39%) than in the spouse controls (4%). Evidence for linkage was observed at the MnSOD (P=.02), CETP/LCAT (P=.03), and apolipoprotein AI-CIII-AIV loci (P=.005) but not at the LDLR locus. We conclude that there is a genetically based association between FCH and small, dense LDL and that the genetic determinants for LDL particle size are shared, at least in part, among FCH families and the more general population at risk for CAD. Show less

We tested whether exogenous peptide YY (PYY) can stimulate synthesis and lymphatic secretion of intestinal apolipoprotein AIV (apo AIV). Rats with mesenteric lymph fistulas and right atrial cannulas were given continuous intravenous infusions of control vehicle or PYY at 25, 50, 75, 100, or 200 pmol . kg-1 . h-1. PYY (75-200 pmol . kg-1 . h-1) stimulated lymphatic apo AIV output from 1.5- to 3.5-fold higher than basal output. In separate experiments, PYY (100 pmol . kg-1 . h-1) produced a 60% increase in jejunal mucosal apo AIV synthesis but had no effect on mucosal apo AIV mRNA levels at doses up to 200 pmol . kg-1 . h-1. Finally, exogenous PYY infusion (100 pmol . kg-1 . h-1) produced a plasma PYY increment of 30 pM compared with an increment of 18.7 pM in response to ileal infusion of lipid. These results support the hypothesis that PYY may be an endocrine mediator of the effects of distal gut lipid on production and release of intestinal apo AIV, likely via a posttranscriptional mechanism of action. Show less

We postulated that dose-responsive satiety after oil premeals varies with the number of gut sensors stimulated by lipolytic products along intestine. These experiments in fasted rats on satiety after oil premeals were performed to 1) determine whether satiety was induced by lipolytic products but not triglycerides; 2) confirm that oil empties from the stomach at rates that vary with oil loads; 3) ascertain that increasing rates of oil entry into duodenum extend the length of gut contacted by lipolytic products; and 4) judge whether length of gut contacted correlated with dose-responsive satieties to dietary oils. 5) Using specific antagonists, we attempted to define how satiety was signalled by gut sensors. Timing and degrees of satiety did not correlate with timing and extent of gastric distensions but, rather, with the timing and extent of spread of lipolytic products along small bowel. Satiety after the highest premeal load of oil was blocked by Pluronic L-81, an inhibitor of intestinal secretion of apolipoprotein A-IV, but was unaffected by MK-329 (a specific antagonist of cholecystokinin) or by capsaicin blockade of chemosensory nerves. Show less