Fatty Acid Binding Protein 2
FABP2 Ala54Thr G>A
In the meta-analysis from Qiu et al.(2014), Thr54-allele frequencies fluctuated from 28-34%. Liu et al. (2015) reports the frequency at around 30% in most populations whilst the CARDIA study reported the variant allele (A or Thr54) present in 43% of the study population.
FABP2 Gene Detail
The fatty acid-binding protein 2 (FABP2) is considered essential for the absorption, intracellular metabolism and/or transport of dietary long chain fatty acids.
It has been demonstrated that a deletion of the FABP2 gene in mice resulted in weight gain and higher circulating triglyceride concentrations than wild type mice. The Ala54Thr polymorphism has been associated with dyslipidemia, insulin resistance and obesity in human populations.
FABP2 Ala54Thr G>A
The FABP2 gene, which codes for intestinal fatty acid-binding protein (I-FABP or FABP2), is located on the long arm of chromosome 4 (4q28-4q31). FABP2 is a member of the FABPs superfamily responsible for making at least nine different intracellular proteins in mammals, which reversibly bind to hydrophobic ligands. FABP2 seems to primarily express in the intestinal epithelial cells where it acts as a cytosolic intracellular lipid-binding protein and is reported to have a high affinity-binding site for both saturated and unsaturated long chain fatty acids. It is said to actively partake in dietary lipid metabolism.
The roles of FABP2 have been described as trans-cytoplasmic and trans-mitochondrial fatty acid carrier, while it is also thought to relieve intracellular enzymes’ hypofunction caused by long chain fatty acids. It has been stated that, in addition to its role in fat metabolism, FABP2 may serve as a free radical scavenger and remove peroxidised acids from cells.
The G-to-A polymorphism located in exon 2 results in a missense mutation at codon 54 where amino acid threonine is substituted for alanine (Ala54Thr). The amino acid substitution affects the primary structure of the protein, causing changes in its fatty acid-binding ability. The Thr-containing protein is said to possess a two-fold higher affinity for long chain fatty acids than the Ala-containing protein.
Several studies have implicated the FABP2 gene as a potential genetic contributor of obesity, dyslipidemia, T2DM and insulin resistance risk because its protein product is involved in fatty acid absorption and metabolism. Previous studies have demonstrated that the FABP2 variant was associated with an increased flux of dietary fatty acids into circulation, an increased fasting insulin concentration, fasting fatty acid oxidation and reduced glucose uptake as well as fasting hypertriglyceridemia. The Thr54 carriers are reported to have lower glucose tolerance and lower insulin action than Ala54-homozygotes, whilst dyslipidemia and insulin resistance was observed after a high-fat meal in sedentary non-diabetic men and women.
Many studies conducted in various populations to determine the association particularly between the Ala54Thr SNP and T2DM risk, delivered inconsistent results. A HuGE review and meta-analysis performed by Qiu et al., which involved 13 studies, comprising of 2020 T2DM cases and 2910 controls, suggested that the Thr54 variant is associated with increased susceptibility to T2DM risk among Asians but not Caucasians.. Liu et al. performed both a population-based case-control study in a Chinese cohort and a systematic meta-analysis to determine the association between the Ala54Thr SNP and obesity, T2DM and metabolic syndrome (MetS). The meta-analysis showed significant associations for T2DM and MetS but not for obesity, whilst the case-control study demonstrated significant association for obesity and MetS by logistic regression with adjustment for covariates but no association for T2DM.
A meta-analysis of autosomal genome-wide association (GWA) scans of 35 T2DM, 36 obesity (or body mass index-defined obesity) and 22 coronary artery disease (CAD) studies using the genome search meta-analysis (GSMA) method, found that FABP2 may be a candidate gene for T2DM and obesity, but not for CAD. The FABP2 gene is found in a chromosomal region which achieved genome wide significance evidence for T2DM and obesity.
The presence of the Thr54 allele has also been significantly associated with fat intolerance (postprandial hypertriglyceridemia) in 158 apparently healthy, normolipidemic subjects with a normal body mass index and without diabetes. A simplified oral fat tolerance test (OFTT) was performed where 26.3g of fat was ingested; blood samples were taken at 0, 2 and 4-hour intervals to determine postprandial triglyceride concentrations. The levels of plasma triglycerides at 4 h after the test meal were higher in Thr54 carriers – these carriers were up to six times more prevalent in the fat-intolerant group than the non-carriers (Ala54 homozygous persons). Although the authors note that the small sample size may be considered a potential shortfall, Auinger et al. also discussed how the Thr54 variant may lead to increased serum free fatty acids, resultant elevated triglyceride and low-density lipoprotein (LDL) levels with lower high-density lipoprotein (HDL) concentrations.
Although there are several studies that show no significant association between the Ala54Thr variant and obesity or other metabolic abnormalities, there might be an influence of the FABP2 gene on metabolic rate which could indirectly impact obesity risk. Gene-environmental interactions must also be considered when establishing an association.
Research suggests that it may be beneficial for A-allele carriers (Thr54) to follow a low-fat diet, and to limit dietary saturated fat intake to less than 7% of total calories as recommended by the American Heart Association.
An intervention study from Martinez-Lopez et al. (2013) concluded that Thr54 carriers responded better to a moderate fat diet (30% fat with < 7% of total calories saturated fat; 15% protein; 55% carbohydrates) with significant decreases in parameters such as BMI, waist circumference, waist-to-hip ratio and C-reactive protein (CRP). The authors suggested that “the dietary restriction and composition (moderate-fat diet, <7% saturated fat) gradually had influenced weight loss and adipose tissue, which can favour the decrease of oxidative stress and inflammation”. It was also found by De Luis et al. (2011) that obese Thr54 carriers, in comparison to obese Ala54 homozygotes, showed significantly greater reductions in BMI, body weight, fat mass and waist circumference in response to a high-polyunsaturated fat diet.
The Coronary Artery Risk Development in Young Adults (CARDIA) study is a prospective study that stretched over 20 years. In the cross-sectional analysis at year 20, involving 2148 participants, researchers found that in the presence of a high saturated fat diet (≥ 53.2 grams per day) the Thr54 carriers (AA/AG genotypes) evidently showed a borderline association with adverse lipids and increased insulin resistance as compared to the GG genotype. This is reportedly consistent with other studies which examined the effect of the Thr54 variant and dietary fat intake on plasma lipid levels and insulin resistance. Research reported that following a high-fat meal, post-prandial lipid oxidation rates were higher in Thr54 carriers as compared to the Ala54 homozygotes, suggesting amplified lipid absorption in AA/AG genotypes. This promotes the principle of a low to moderate fat diet.
Also, in a study comparing three different diets (high saturated fat diet, Mediterranean diet high in monounsaturated fat and low-fat and high-carbohydrate diet), Thr54 carriers had elevated free fatty acid concentrations and less insulin sensitivity only after consuming the high saturated fat diet.
Focusing predominantly on monounsaturated fat seems beneficial, as supported by a cross-sectional study from Morcillo et al. (2007), where the interaction between the type of cooking oil used (olive oil versus sunflower oil and an olive oil / sunflower oil mixture) and the outcome of insulin resistance was investigated. It was found that Thr54 carriers showed higher insulin resistance only when they consumed sunflower or the sunflower oil mixture rather than olive oil. Researchers suggested that olive oil ameliorated the genetic risk for insulin resistance in Thr54 carriers as insulin resistance did not differ by genotype amongst participants only consuming olive oil.
Data on the impact of fat intake on FABP2 expression in animal studies do however present some inconsistencies. In contrast to the abovementioned findings, another study reported that Thr54 carriers presented with increased chylomicron cholesterol after ingesting olive oil only, and not after the consumption of safflower oil or butter when compared to Ala54 homozygotes.
Physical activity amongst middle-aged Korean women with abdominal obesity, specifically referring to a 12-week aerobic exercise plan, has been found to improve obesity indices, cardiorespiratory fitness, blood lipids, and blood glucose and insulin resistance index regardless of the FABP2 gene mutation.
Postprandial Hypertriglyceridemia Is Associated with the Variant 54 Threonine FABP2 Gene
Da Silva et al, 2018.