High-fat meal effect on LDL, HDL, and VLDL particle size and number in the Genetics of Lipid-Lowering drugs and diet network (GOLDN): an interventional study

Postprandial lipemia (PPL) is an important risk factor for cardiovascular disease. Inter-individual variation in the dietary response to a meal is known to be influenced by genetic factors, yet genes that dictate variation in postprandial lipids are not completely characterized. Genetic studies of the plasma lipidome can help to better understand postprandial metabolism by isolating lipid molecular species which are more closely related to the genome. We measured the plasma lipidome at fasting and 6 h after a standardized high-fat meal in 668 participants from the Genetics of Lipid-Lowering Drugs and Diet Network study (GOLDN) using ultra-performance liquid chromatography coupled to (quadrupole) time-of-flight mass spectrometry. A total of 413 unique lipids were identified. Heritable and responsive lipid species were examined for association with single-nucleotide polymorphisms (SNPs) genotyped on the Affymetrix 6.0 array. The most statistically significant SNP findings were replicated in the Amish Heredity and Phenotype Intervention (HAPI) Heart Study. We further followed up findings from GOLDN with a regional analysis of cytosine-phosphate-guanine (CpGs) sites measured on the Illumina HumanMethylation450 array. A total of 132 lipids were both responsive to the meal challenge and heritable in the GOLDN study. After correction for multiple testing of 132 lipids (α = 5 × 10−8/132 = 4 × 10−10), no SNP was statistically significantly associated with any lipid response. Four SNPs in the region of a known lipid locus (fatty acid desaturase 1 and 2/FADS1 and FADS2) on chromosome 11 had p < 8.0 × 10−7 for arachidonic acid FA(20:4). Those SNPs replicated in HAPI Heart with p < 3.3 × 10−3. CpGs around the FADS1/2 region were associated with arachidonic acid and the relationship of one SNP was partially mediated by a CpG (p = 0.005). Both SNPs and CpGs from the fatty acid desaturase region on chromosome 11 contribute jointly and independently to the diet response to a high-fat meal.

Download Full-text

An exome-wide sequencing study of lipid response to high-fat meal and fenofibrate in Caucasians from the GOLDN cohort

The Journal of Lipid Research ◽

10.1194/jlr.p080333 ◽

2018 ◽

Vol 59 (4) ◽

pp. 722-729 ◽

Cited By ~ 5

Author(s):

Xin Geng ◽

Marguerite R. Irvin ◽

Bertha Hidalgo ◽

Stella Aslibekyan ◽

Vinodh Srinivasasainagendra ◽

...

Keyword(s):

Rare Variants ◽

Transcript Level ◽

Lipid Lowering ◽

Gene Transcript ◽

High Fat ◽

Heart Study ◽

Lipid Response ◽

Coding Variants ◽

Fat Meal ◽

Meal Challenge

Our understanding of genetic influences on the response of lipids to specific interventions is limited. In this study, we sought to elucidate effects of rare genetic variants on lipid response to a high-fat meal challenge and fenofibrate (FFB) therapy in the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN) cohort using an exome-wide sequencing-based association study. Our results showed that the rare coding variants in ITGA7, SIPA1L2, and CEP72 are significantly associated with fasting LDL cholesterol response to FFB (P = 1.24E-07), triglyceride postprandial area under the increase (AUI) (P = 2.31E-06), and triglyceride postprandial AUI response to FFB (P = 1.88E-06), respectively. We sought to replicate the association for SIPA1L2 in the Heredity and Phenotype Intervention (HAPI) Heart Study, which included a high-fat meal challenge but not FFB treatment. The associated rare variants in GOLDN were not observed in the HAPI Heart study, and thus the gene-based result was not replicated. For functional validation, we found that gene transcript level of SIPA1L2 is associated with triglyceride postprandial AUI (P < 0.05) in GOLDN. Our study suggests unique genetic mechanisms contributing to the lipid response to the high-fat meal challenge and FFB therapy.

Download Full-text

Older adults have an altered chylomicron response to a high-fat meal

British Journal Of Nutrition ◽

10.1017/s000711451500505x ◽

2016 ◽

Vol 115 (5) ◽

pp. 791-799 ◽

Cited By ~ 7

Author(s):

Amber M. Milan ◽

Anu Nuora ◽

Shikha Pundir ◽

Chantal A. Pileggi ◽

James F. Markworth ◽

...

Keyword(s):

Particle Size ◽

Fatty Acid Composition ◽

Fatty Acid ◽

Acid Composition ◽

Older Individuals ◽

High Fat ◽

Postprandial Lipaemia ◽

Chylomicron Particle ◽

Older Subjects ◽

Fat Meal

AbstractAgeing is associated with a prolonged and exaggerated postprandial lipaemia. This study aimed to examine the contribution of alterations in chylomicron synthesis, size and lipid composition to increased lipaemia. Healthy older (60–75 years; n 15) and younger (20–25 years; n 15) subjects consumed a high-fat breakfast. Chylomicron dynamics and fatty acid composition were analysed for 5 h in the postprandial state. Plasma TAG levels were elevated following the meal in the older subjects, relative to younger subjects (P<0·01). For older subjects compared with younger subjects, circulating chylomicron particle size was smaller (P<0·05), with greater apoB content (P<0·05) at all postprandial time points. However, total chylomicron TAG concentration between the groups was unaltered post-meal. Compared with younger subjects, the older subjects exhibited a greater proportion of oleic acid in the TAG and phospholipid (PL) fraction (P<0·05), plus lower proportions of linoleic acid in the TAG fraction of the chylomicrons (P<0·01). Thus, following the ingestion of a high-fat meal, older individuals demonstrate both smaller, more numerous chylomicrons, with a greater total MUFA and lower PUFA contents. These data suggest that the increased postprandial lipaemia of ageing cannot be attributed to increased chylomicron TAG. Rather, ageing is associated with changes in chylomicron particle size, apoB content and fatty acid composition of the chylomicron TAG and PL fractions.

Download Full-text

Second meal effect: modified sham feeding does not provoke the release of stored triacylglycerol from a previous high-fat meal

British Journal Of Nutrition ◽

10.1079/bjn2000226 ◽

2001 ◽

Vol 85 (2) ◽

pp. 149-156 ◽

Cited By ~ 19

Author(s):

Kim G. Jackson ◽

M. Denise Robertson ◽

Barbara A. Fielding ◽

Keith N. Frayn ◽

Christine M. Williams

Keyword(s):

Sensory Stimulation ◽

High Fat ◽

Water Control ◽

Low Fat ◽

Sham Feeding ◽

Blood Samples ◽

Early Entry ◽

Cephalic Phase ◽

Meal Effect ◽

Fat Meal

The present study was carried out to determine whether cephalic stimulation, associated with eating a meal, was sufficient stimulus to provoke the release of stored triacylglycerol (TAG) from a previous high-fat meal. Ten subjects were studied on three separate occasions. Following a 12 h overnight fast, subjects were given a standard mixed test meal which contained 56 g fat. Blood samples were taken before the meal and for 5 h after the meal when the subjects were randomly allocated to receive either water (control) or were modified sham fed a low-fat (6 g fat) or moderate-fat (38 g fat) meal. Blood samples were collected for a further 3 h. Compared with the control, modified sham feeding a low- or moderate-fat meal did not provoke an early entry of TAG, analysed in either plasma or TAG-rich lipoprotein (TRL) fraction (density <1.006 kg/l). The TRL-retinyl ester data showed similar findings. A cephalic phase secretion of pancreatic polypeptide, without a significant increase in cholecystokinin levels, was observed on modified sham feeding. Although these data indicate that modified sham feeding was carried out successfully, analysis of the fat content of the expectorant showed that our subjects may have accidentally ingested a small amount of fat (0.7 g for the low-fat meal and 2.4 g for the moderate-fat meal). Nevertheless, an early TAG peak following modified sham feeding was not demonstrated in the present study, suggesting that significant ingestion of food, and not just oro-sensory stimulation, is necessary to provoke the release of any TAG stored from a previous meal.

Download Full-text

Atherogenic changes in postprandial lipoprotein subclass particle size and concentration after a restricted carbohydrate, high fat meal vs a high carbohydrate, low fat meal

The FASEB Journal ◽

10.1096/fasebj.20.5.lb102-c ◽

2006 ◽

Vol 20 (5) ◽

Author(s):

Diane Stadler ◽

Glenn Gerhard ◽

Bart Duell ◽

Njeri Karanja

Keyword(s):

Particle Size ◽

High Fat ◽

Lipoprotein Subclass ◽

Low Fat ◽

High Carbohydrate ◽

Postprandial Lipoprotein ◽

Fat Meal

Download Full-text

Abstract P328: Genetic Variants Involved in Postprandial Triglyceride Metabolism are Modified by Fenofibrate Treatment in the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN) Study

Circulation ◽

10.1161/circ.125.suppl_10.ap328 ◽

2012 ◽

Vol 125 (suppl_10) ◽

Author(s):

Mary K Wojczynski ◽

Laurence D Parnell ◽

M R Irvin ◽

Robert J Straka ◽

Jose M Ordovas ◽

...

Keyword(s):

Genetic Variants ◽

Repeated Measures ◽

Linkage Disequilibrium Block ◽

Dietary Factors ◽

Lipid Lowering ◽

High Fat ◽

Gene Effects ◽

Postprandial Triglyceride ◽

Before And After ◽

Fat Meal

Genetic variants associated with fasting plasma triglycerides (TG) have been reported in the literature. Less is known about genetic variants influencing TG response to dietary factors, specifically a fat challenge (postprandial lipemia, PPL). Additionally, little is known about genetic variants associated with response to pharmacologic agents, such as fenofibrate (FFB), which are used to reduce plasma levels of TG. Preliminary genome-wide association (GWA) analyses on three interventions: 1) FFB; 2) PPL before FFB; and 3) PPL after FFB, implicated different genetic variants associated with the TG response. Therefore, we hypothesized that FFB treatment modifies gene effects on TG response to a dietary postprandial fat challenge. We analyzed participants (N=693) from the GOLDN study who ingested a standardized high-fat meal containing 83% fat and 700 calories/m2 both before and after 3 weeks of daily FFB treatment, thereby having two postprandial plasma TG assessments. Plasma TG was measured at baseline, 3.5 hrs, and 6 hrs after each high-fat meal. The area under the curve (AUC) describing the change in plasma TG concentration over the PPL period was calculated using the trapezoid method. Standardized TG AUC residuals were obtained by using a growth curve method and a stepwise regression approach, retaining covariate terms (age, age2, age3, sex, field center, baseline TG, and principle components (EIGENSTRAT)) that were significant at 5% level. A GWA scan of ∼2.5 million typed or imputed single nucleotide polymorphisms (SNPs) was undertaken to identify gene by FFB treatment interaction effects on the TG AUC PPL response using a repeated measures mixed model with a random effect to adjust for family relatedness. The GWA model included a SNP effect, FFB effect (before or after treatment), and an interaction term (SNP*FFB). For TG AUC residuals, we found GWA significant associations with 8 variants in LDLRAD3 (11p13) for the SNP*FFB term (p<5E-08), and the accompanying main effect terms had suggestive (p<1E-05) associations. These 8 variants are in one linkage disequilibrium block, and indicate that FFB interacts with these variants to decrease their independent effects on TG AUC. In analyses using only the SNP, these 8 variants had p-values <0.005 for TG response to PPL both before and after FFB. SNPs in this group associate with expression of CD44, a molecule which binds osteopontin which is an activator of human adipose tissue macrophages and adipocyte function. This analysis highlights a new gene implicated in TG metabolism whose effect on dietary TG responses to fat ingestion is modified by FFB, possibly by acting through CD44. Further investigation into this gene region is needed in order to enhance our understanding of the underlying mechanistic processes involved in TG metabolism during the postprandial state and the effect of FFB treatment.

Download Full-text